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DTT 2024; 3(1): 62-73

Published online March 31, 2024 https://doi.org/10.58502/DTT.23.0027

Copyright © The Pharmaceutical Society of Korea.

Polyelectrolyte Complex for Drug Delivery

Chaemin Lim1, Yuseon Shin2, Kyung Taek Oh2,3

1College of Pharmacy, CHA University, Seongnam, Korea
2Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Seoul, Korea
3College of Pharmacy, Chung-Ang University, Seoul, Korea

Correspondence to:Kyung Taek Oh, kyungoh@cau.ac.kr

Received: October 4, 2023; Revised: November 22, 2023; Accepted: January 25, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Polyelectrolyte complexes (PICs) have emerged as promising candidates in the field of drug delivery. This manuscript presents a comprehensive investigation organized into four main sections to elucidate the potential of PICs for drug delivery applications. The first section provides a foundational understanding of polyelectrolytes, highlighting their unique properties and characteristics. Subsequently, we delve into an examination of the physicochemical properties of polyelectrolytes, shedding light on the mechanisms governing the formation of PICs and the critical parameters involved in preparing polyelectrolyte nanoparticles. In the third section, we explore the formation of polyelectrolyte-based nanoparticles, encompassing hydrophilic polyelectrolytes, hydrophobically modified polyelectrolytes, and PICs formed with oppositely charged polymers. This section offers insights into the versatile applications of PICs in drug delivery systems. The final section delves into the biological functions of polyelectrolytes, revealing their role in enhancing cellular uptake, facilitating endosomal escape, acting as immune stimulators, and exhibiting antitumor activity. These insights emphasize the potential of PICs to overcome barriers in drug delivery and enhance therapeutic outcomes. In summary, this manuscript serves as a comprehensive resource for researchers and practitioners in the field, offering a holistic understanding of the multifaceted applications of PICs in drug delivery.

Keywordscationic polymer, drug delivery, gene delivery, polyelectrolyte

Polyelectrolytes are an intriguing group of macromolecules that contain repeating units with either positive or negative charges. They possess unique theoretical and practical properties that distinguish them from uncharged polymers (Förster and Schmidt 1995; Dobrynin and Rubinstein 2005; Barrat and Joanny 2007). Even the dissociation of a small fraction of ionic units can significantly alter their properties, such as chain conformation, viscosity, diffusion coefficients, polarizability, and counter ion condensation. Polyelectrolytes have found various applications in different industries, including water treatment, cosmetics, pharmaceuticals, mineral separation, paper coating, and paints (Sato et al. 1979; Ito et al. 1986; Senuma et al. 1986; Vergaro et al. 2011; De Geest et al. 2012). Depending on their origin and charge type, polyelectrolytes can be classified as natural, modified natural, synthetic, cationic, anionic, or polyampholyte. Their potential applications are diverse and depend on factors such as charge density, dissociation constant of ionic groups, and type of charge. Polyelectrolytes have recently garnered attention in drug delivery applications. Their charged repeating segments make them soluble in aqueous conditions, which allows for complex formation with oppositely charged drugs or polymers via electrostatic interaction, resulting in the formation of nanoparticles with core and shell structures, also known as PICs. These nano vehicles can enhance drug bioavailability by increasing cellular uptake via endocytosis pathways and protecting the complexed drug from enzymatic degradation in vivo conditions (Shu and Zhu 2000; Kim et al. 2008b; Liu et al. 2008; Hamman 2010). Additionally, hydrophobically modified polyelectrolytes can self-assemble to form nanoparticles with a surface charge that can encapsulate hydrophobic drugs in the core (Shuai et al. 2003; Lim et al. 2016). Some polyelectrolytes also exhibit various biological functions, such as endosome disruption, antimicrobial activity, and immune system activation (Cakmak et al. 2004; Dyakonova et al. 2004; Müller et al. 2011). Thus, the pharmaceutical industry has shown great interest in studying different types of polyelectrolytes for drug delivery applications. In this review, we focus on the use of polyelectrolytes as bioavailability enhancers for anticancer treatment.

Mechanism for the formation of PIC

The formation of PICs occurs when oppositely charged polyelectrolytes come into contact with each other (Fig. 1). The interaction between the polyelectrolytes is driven by electrostatic forces, which cause the charged segments of the polyelectrolytes to attract each other. The interaction can lead to the formation of a nanoparticle with a core-shell structure, in which one polyelectrolyte forms the core and the other forms the shell. The formation of PICs is influenced by several factors, including the charge density, chain length, and degree of ionization of the polyelectrolytes, as well as the ionic strength and pH of the solution. In general, higher charge densities and longer chains lead to stronger interactions between the polyelectrolytes and the formation of more stable nanoparticles. The degree of ionization of the polyelectrolytes also affects the formation of PICs, as the dissociation of the charged segments can affect the electrostatic interaction between the polyelectrolytes. As shown in Fig. 1, the mechanism of PIC formation can be further divided into three stages: (1) initial contact between the polyelectrolytes, forming the primary complex, (2) formation of a diffuse polyelectrolyte cloud around the oppositely charged polyelectrolyte, and (3) coacervation, in which the polyelectrolyte chains come into close proximity and form a stable nanoparticle, resulting in the secondary complex. The secondary aggregates are composed of about 100 primary complex particles, and the inter-complex aggregation process is mainly progressed by hydrophobic interactions (Chornet and Dumitriu 1998; Starchenko et al. 2008; Müller et al. 2011).

Figure 1.Mechanism for formation of polyelectrolyte complexes (PICs).

Parameters in preparation of polyelectrolyte nanoparticles

Polyelectrolyte nanoparticles are formed by the interaction of oppositely charged polyelectrolytes, and several parameters can be controlled during their preparation to optimize their physical properties and drug delivery efficiency. These parameters include the true charge and charge density of the polyelectrolytes, the mixing ratio of the polyelectrolytes, the order of addition of the polyelectrolytes, and the effect of salt concentration in the solution.

True charge

The true charge of polyelectrolytes refers to the actual charge of the repeating units. When preparing oppositely charged polyelectrolytes in stoichiometric ratios to form PIC nanoparticles, the determination of true charge and charge density is very important. As mentioned above, the driving force for PIC formation is the electrostatic interaction between oppositely charged macromolecules. However, the true charge or charge density of polyelectrolytes could be affected by the colloidal pH, and the aggregation formation may not be identical to the experimental design. Wang et al. (2006) reported the effect of pH on linear poly (ethyleneimine) (PEI) affinity for complex formation. Under acidic conditions, the PEI is a strong cationic polymer, and the binding affinity with anionic surfactants is very high. However, at pH 7, the electrostatic attraction becomes weaker, and at pH 10, PEI is essentially nonionic, and there is no electrostatic attraction anymore (Wang et al. 2006). In our previous study, we also reported the pH-sensitive PEI/PASP complex system for anticancer drug delivery. At pH 7.4, the PEI/PASP complex system formed a compacted nanoparticle with a narrow size distribution. However, under acidic conditions, the true charge of PASP decreased, and the PASP dissociated from the PEI-based platform, resulting in accelerated drug release (Lim et al. 2016).

Charge density

The charge density of polyelectrolytes is also related to the formation of PICs. When preparing complex nanoparticles, core compacted structures can be obtained with similar charge densities of the polyelectrolytes. Conversely, loose and unstable structures become prevalent in systems with strongly deviating charge densities of the polyelectrolytes (Dautzenberg and Jaeger 2002; Mende et al. 2002). Mende et al. (2002) investigated the role of charge density in the formation of PICs. Among various charge densities of polymers, the most stable and smallest complex systems were obtained from oppositely charged polyelectrolytes with similar charge densities (Mende et al. 2002).

Mixing ratio

The mixing ratio of charges between polyelectrolytes and oppositely charged macromolecules is a crucial parameter that should be considered to create small-sized nanoparticles with good stability. Depending on the cationic/anionic charge ratio (C/A ratio), the particle size and surface charge can be dramatically changed. Zelphati et al. (1998) investigated the change in size and zeta charge of liposome-gene complexes depending on the mixing ratio. At a charge ratio near 1, the surface charge of the PIC became about zero and exhibited a significantly increased particle size with poor physical stability due to increased hydrophobicity (Zelphati et al. 1998). Kabanov and Zezin (1984) also reported the change in size and aggregation number of PDMAEMA/phosphate polymers at different C/A ratios. The size of the PIC dropped from 49 nm at a C/A value of 0.067 down to about 30 nm at C/A = 0.5, and the aggregation number of the polymer increased due to the change in structures (Kabanov and Zezin 1984).

Order of addition

The order of polymer addition for PIC formation can affect the particle size and stability. In principle, the smallest particle size of PIC can be achieved by adding the minority component into the majority component. Zelphati et al. (1998) studied the particle size of PIC with different orders of addition. To prepare the cationic lipid/DNA complex (C/A ratio > 1), DNA was added to excess lipid materials, and a stable and small-sized nanoparticle was formed. However, large aggregates were produced when lipid materials were added to DNA (Zelphati et al. 1998). In the former case, the 1:1 stoichiometry between lipid and DNA cannot be achieved, and they form homogeneously complexed PIC nanoparticles. However, in the latter case, the binding of DNA to cationic lipid is not homogeneous because the 1:1 complex ratio must be exceeded, resulting in the formation of aggregates. Similar studies were also reported by Müller et al. (2011) and Sæther et al. (2008). All the studies reveal that adding the minor component to the major solution can produce more equilibrated and compacted PIC nanoparticles.

The structure of polyelectrolytes has been tailor-made to correspond with the physico-chemical properties required for the target drug and disease environment conditions. In this chapter, we will provide an overview of these polyelectrolyte types for various drug formulations (Fig. 2) and summarize the PICs in Table 1.

Figure 2.Various type of drug delivery platform using polyelectrolytes. (a) Polymer-drug complex via electrostatic interaction. (b) Polymer-drug complex via electrostatic and hydrophobic interactions. (c) Polymer-polymer-drug complex via electrostatic and hydrophobic interactions. (d) Layer-by-layer formation of a polymer-polymer-drug complex via electrostatic and hydrophobic interactions.

Table 1 Application of PICs as a drug delivery system

PolyelecrolytePropertyTypes of interactions between polymers and drugsReferences
Poly (ethyleneimine) (PEI)Hydrophilic cationicElectrostatic interactionFischer et al. (1999), Kunath et al. (2003), Lungwitz et al. (2005), Ogris et al. (1999)
Polyamidoamine (PAMAM)Hydrophilic cationicElectrostatic interactionHaensler and Szoka (1993)
Poly-β-Aminoesters (PBAE)Hydrophilic cationicElectrostatic interactionRui et al. (2019)
Poly-L-Lysine (PLL)Hydrophilic cationicElectrostatic interactionZhang et al. (2010)
ChitosanHydrophilic cationicElectrostatic interactionLoo et al. (2022), Bowman and Leong (2006), Riezk et al. (2020)
Glycol chitosan modified with 5B cholanic acidAmphiphilic cationicElectrostatic and hydrophobic interactionsPark et al. (2004)
Poly (lactic acid)–poly (ethylene glycol)–poly (histidine) (PLA-b-PEG-b-P (His))Amphiphilic pH-responsiveHydrophobic interactionLee et al. (2007)
Poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate) (PEG-PVBP)Amphiphilic anionicHydrophobic interactionKamimura et al. (2012)
Poly (ethylene glycol)–poly (lactic acid)–poly (ethyleneimine) (PEG-PLA-PEI)Amphiphilic cationicElectrostatic and hydrophobic interactionsLim et al. (2016)
Poly (aspartic acid) (P (Asp))Hydrophilic anionic
Poly-alkyl amine derivativeAmphiphilic cationicElectrostatic and hydrophobic interactionsFatima et al. (2016)
P (Asp)Hydrophilic anionic
Carboxymethyl celluloseHydrophilic anionicElectrostatic and hydrophobic interactionsZhao et al. (2007)
ChitosanHydrophilic cationicElectrostatic and hydrophobic interactionsChen et al. (2009)
AlginateHydrophilic anionic

Hydrophilic polyelectrolyte

Polymer-drug complex via electrostatic interaction

A wide range of polyelectrolytes have been synthesized and used as materials for drug delivery systems. Among them, copolymers containing cationic groups have been extensively investigated (Kabanov et al. 1996; Kataoka et al. 1996; Kabanov et al. 2004). As shown in fig. 2a, the cationic segments can bind to oppositely charged drugs by electrostatic interaction, and they can spontaneously form nanosized PICs.

1) Poly (ethyleneimine)

The representative cationic polyelectrolyte for PIC is PEI, which has been known as the most effective non-viral vector due to its condensation and enhanced transfection ability for complexed genetic materials (Fischer et al. 1999; Kunath et al. 2003; Lungwitz et al. 2005). Ogris et al. (1999) investigated the in vitro and in vivo properties of pegylated gene/PEI complexes. Pegylated PEI condenses the DNA into nanosized particles by forming complexes and protects it from enzymatic degradation. They demonstrated that the pegylated gene/PEI complex system could reduce the plasma protein binding into the nanoparticle and prolong blood circulation time with enhanced gene expression levels at the tumor site (Ogris et al. 1999).

2) Polyamidoamine

Polyamidoamine (PAMAM) dendrimers, which contain a large number of secondary and tertiary amines, have also been widely used for gene or cytokine delivery. Haensler et al. originally reported the use of PAMAM dendrimers as gene delivery agents. They demonstrated that the sixth generation PAMAM dendrimer exhibits improved gene delivery efficacy with good biocompatibility. These synthetic non-viral vectors using PIC systems provide opportunities for simple preparation, improved safety, and greater flexibility in the gene therapeutic area (Haensler and Szoka 1993).

3) Poly-β-Aminoesters

Poly-β-Aminoesters (PBAEs) are versatile polymers composed of repeating units with varying charge states. Their flexibility in design during synthesis is a key attribute. PBAEs are primarily used to interact with anionic drugs. These can include small-molecule drugs, nucleic acids (such as siRNA or DNA), and proteins (such as antibodies or enzymes). The electrostatic interaction between PBAEs and these drug molecules allows for the formation of nanoparticles or the encapsulation of drugs. PBAE-based drug delivery systems find applications in cancer therapy, gene therapy, and vaccination. Rui et al. (2019) reported PBAE-based protein delivery system for efficient cellular uptake of protein therapeutics. The delivery system enabled rapid cellular uptake, efficient endosomal escape, and nanoparticles loading CRISPR-Cas9 ribonucleoproteins induced strong gene editing (Rui et al. 2019).

4) Poly-L-Lysine

Poly-L-Lysine (PLL) is a cationic polypeptide polymer made up of repeating units of L-lysine. It possesses high biocompatibility, biodegradability, and antimicrobial properties. PLL is frequently used to interact with anionic drugs such as nucleic acids (DNA or RNA), peptides, and proteins. The electrostatic interactions between PLL and these drug molecules enable the formation of nanoparticles or the surface binding of drugs. PLL-based drug delivery systems are applied in gene therapy, protein delivery, and vaccine development. Zhang et al. (2010) designed PLL-based nanoparticle co-loading a plasmid DNA and a peptide hormone. Zhang’s data showed that melanin secretion was induced by efficient gene transfer and hormone stimulation (Zhang et al. 2010).

5) Chitosan

Chitosan is a natural polymer derived from chitin, found in crustacean shells. Its amino groups confer a cationic nature. Chitosan interacts strongly with anionic drugs, which can include small molecules, peptides, proteins, and even nucleic acids. This electrostatic interaction is leveraged for encapsulating drugs within its matrix or forming drug-loaded nanoparticles. Chitosan-based drug delivery systems are utilized in various applications, such as wound healing (Loo et al. 2022), oral drug delivery (Bowman and Leong 2006), and dermal drug delivery (Riezk et al. 2020). In particular, its versatility extends even further as it can be extensively modified for a wide range of applications. Modified Chitosan derivatives, such as carboxymethyl chitosan, thiolated chitosan, or pegylated chitosan, offer enhanced properties and functionalities. These modifications allow Chitosan to be tailored for specific drug delivery applications, such as targeted drug delivery, sustained release, and improved stability.

Hydrophobically modified polyelectrolytes

As mentioned earlier, the formation of PICs involves not only electrostatic interactions but also hydrophobic interactions. It has been reported that the presence of a hydrophobic moiety in the polyelectrolyte can enhance the colloidal stability of particles and increase tissue permeability (Shuai et al. 2003; Kamimura et al. 2012; Xun et al. 2013). Additionally, it is known to assist in the encapsulation of hydrophobic drugs (Yun et al. 2012; Hoang et al. 2016). In this chapter, we introduce polyelectrolytes that incorporate hydrophobic interactions for drug formulation.

Polymer-drug complex via hydrophobic and electrostatic interaction

Using the mechanism shown in Fig. 2b, Park et al. (2004) developed self-assembled nanoparticles based on glycol chitosan bearing a hydrophobic moiety. The glycol chitosan was hydrophobically modified with 5B cholanic acid (HGC) to have self-assembling properties, and RGD peptides labeled with fluorescein isothiocyanate (FITC) were loaded into the nano-sized HGC. FITC-labeled peptides have several potential interactions with other molecules, including hydrophobic, hydrogen bonding, and electrostatic interactions. These interactions allow the self-assembled HGC to form a compact particle with a small size. The FITC-RGD peptides were successfully loaded into HGC with high loading efficiency and exhibited enhanced biological activity in vivo conditions (Park et al. 2004).

Polymer-drug complex via hydrophobic interaction

Polymer-drug complexes via hydrophobic interaction can be used as smart drug delivery systems for insoluble drug formulations. Lee et al. (2007) reported enhanced antitumor activity with pH-responsive polyelectrolytes. They prepared self-assembled PLA-b-PEG-b-P (His) triblock copolymers, optimized Dox formulation, and reported its pH-dependent physical changes and cell cytotoxicity. The protonation of the imidazole ring in P (His) can be changed in acidic conditions, showing pH-induced micelle interior structural changes from shrinking to swelling. This provides a mechanism for accelerated drug release and enhanced cytotoxicity in acidic pH conditions. The hydrophobic moiety in polyelectrolytes can increase colloidal stability and enhance tissue permeability due to hydrophobic interactions. Kamimura et al. (2012) reported a highly stable and pH-responsive PIC system formed by poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate) (PEG-b-PVBP) and cationic surfactants. The polyanionic segment in PEG-b-PVBP contained a hydrophobic styrene moiety in the repeating unit, which could strongly affect the colloidal stability of the PIC system against changes in ionic strength and dilution. They revealed that additional hydrophobic interactions of benzyl groups in PEG-b-PVBP contribute to the highest stability of PEG-b-PVBP/surfactants among PIC systems in vivo conditions. Accelerated drug release from PEG-b-PVBP/surfactants systems was also observed at acidic pH conditions due to the protonation of phosphate groups in PVBP chains (Fig. 3).

Figure 3.Illustration of self-assembly of the block ionomer complexes. Reused from Kamimura et al. (2012), with permission from Elsevier (license number: 5633941492156). PEG-b-PVBP, poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate); DTAB, dodecyltrimethylammonium bromide; C12Py, Dodecylpyridinium chloride; HTAB, hexadecyltrimethylammonium bromide; C16Py, cetylpyridinium chloride; DOX, Doxorubicin hydrochloride.

PICs with oppositely charged polymer

Nanoparticles formed by complexation of amphiphilic polyelectrolyte and oppositely charged surfactant or polymers can be used as a strategy to control the drug release profile and toxicity (Fig. 2c). In a previous study, we developed a polyelectrolyte ionomer complex composed of positively charged poly (ethylene glycol)–poly (lactic acid)–poly (ethyleneimine) (PEG-PLA-PEI) triblock copolymer and a negatively charged poly (aspartic acid) (P (Asp)) polymer. These polyelectrolytes formed stable aggregates via electrostatic interaction between PEI and PASP blocks and showed pH sensitivity by protonation and deprotonation of the carboxyl groups in P (Asp) for targeting the extracellular pH of cancers. At acidic conditions, the release of Dox loaded in the platforms was accelerated, improving the antitumor activity (Lim et al. 2016). The surfactant complex with polyelectrolyte can also be used to reduce the toxicity of charged platforms themselves. Fatima et al. (2016) developed a PIC system with amphiphilic poly-alkyl amine derivatives and poly-aspartic acid for anticancer drug delivery. Due to its unique cell permeating property, the poly-alkyl amine derivatives have been widely explored as drug delivery platforms. However, the amphiphilic polyelectrolyte has membrane-disrupting activity, which can induce hemolysis in blood circulation. They demonstrated that the inherent cytotoxicity of the polymer can be overcome by complexing polyelectrolytes with anionic-charged P (Asp) to form a PIC system. The cytotoxicity of poly-alkyl amine derivative was significantly decreased, and the aqueous stability of curcumin, a model hydrophobic drug, was significantly improved with enhanced antitumor activity (Fatima et al. 2016).

Layer by layer polyelectrolyte

Layer-by-layer (LbL) polyelectrolyte assembly is also widely used in the drug delivery area. As shown in Fig. 2d, a LbL nanoparticle is a thin-film consecutive absorption technique using positively and negatively charged polymers on the surface. This multi-layered nanoparticle can be used to control the release profile, increase the stability, and improve the solubility of various drugs (Johnston et al. 2006; Kim et al. 2008a; Ariga et al. 2011). Zhao et al. (2007) investigated the encapsulation of the anticancer drug Dox in LbL nanoparticles and validated their therapeutic efficacy under in vitro conditions (Fig. 4). The positively charged Dox was successfully accumulated in negatively charged carboxymethyl cellulose-based LbL nanoparticles, and the drug-loaded LbL nanoparticle exhibited enhanced antitumor activity (Zhao et al. 2007). Chen et al. (2009) also studied anticancer drug-loaded LbL nanoparticles with chitosan, gelatin, and alginate. They demonstrated the feasibility of controlling the drug release profile by changing several parameters, such as polyelectrolyte type, concentration of polymer, and number of coating layers (Chen et al. 2009).

Figure 4.Illustration of LBL nanoparticle formation and in vivo antitumor activity. Reused from Zhao et al. (2007), with permission from Elsevier (license number: 5633951000634).

Polyelectrolytes possess a variety of preferential biological properties as well as physicochemical characteristics for nanoparticle formation, making them useful for drug delivery purposes. In this chapter, we will provide a representative overview of the biological properties of polyelectrolytes that can maximize the therapeutic efficacy of drugs in anticancer treatment (Table 2).

Table 2 Polyelectrolytes according to biological function

PolyelecrolytesBiological functionPropertyReferences
ChitosanEnhanced cellular uptakeElectrostatic interaction between positively charged polymer and negatively charged cell membraneYue et al. (2011)
Poly (l-lysine)-poly (l-leucine)-based block copolymerHan et al. (2015)
PEIEndosomal escapeProton-sponge effectHan et al. (2012)
pH-sensitive methacrylic acid copolymersDestabilization of membrane bilayersYessine et al. (2003)
OligoarginineLeakiness and rupture of membrane bilayersHitz et al. (2006)
PolyoxidoniumImmune stimulatorAntigen-conjugated polyoxidoniumDyakonova et al. (2004)
Pyran (divinyl ether-maleic anhydride) copolymerImmunoactive propertiesMohr et al. (1975)
Chondroitin sulfateStrong immune response activatorChaurasia et al. (2015)
Cationic polyelectrolytesAntitumor activityStimulating secretion of several antitumor cytokines and promoting Th1 and NK cell infiltrationChen et al. (2010)
Chitosan derivativesHydrophobic and electrostatic interaction between the chitosan derivatives and the tumor cell surfaceLee et al. (2002)
PEICell membrane damage due to its high charge densityYim et al. (2014)

Enhanced cellular uptake

Cellular uptake of nanoparticles is influenced by several factors, including size, shape, surface charge, and hydrophobicity (González et al. 1996; Win and Feng 2005; Chithrani et al. 2006). Surface charge plays an especially important role in the cellular uptake of nanoparticles. Thus, polyelectrolyte-based nanoplatforms with a positive charge exhibit a stronger affinity to the negatively charged cell membrane by electrostatic interaction and are generally better taken up than negatively charged particles. Yue et al. (2011) demonstrated the effect of nanoparticle surface charge on cellular uptake with chitosan-based polyelectrolytes. They prepared three kinds of chitosan-based polyelectrolytes with different surface charges and evaluated the effect of surface charge on cellular uptake profiles. The results showed that a positive charge promotes the internalization rate and increases the internalization amount of nanoparticles in different eight cell lines (Yue et al. 2011). Han et al. (2015) reported charge-reversal micelles with Poly (l-lysine)-poly (l-leucine)-based block copolymer for tumor targeting. PLLeu-PLYS (DMA)-Tat (SA) has β-carboxylic amide, which allows the polypeptides to self-assemble into negatively charged micelles. At acidic conditions, the amide can be cleaved, and the micelles switch to a positively charged state, significantly enhancing their cellular uptake (Han et al. 2015).

Endosomal escape

The endocytic pathway is the major uptake mechanism of cells. Particles or drugs entering the cells via the endocytic pathway become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving effective therapy is to facilitate endosomal escape and ensure cytosolic delivery of the therapeutics (Panyam et al. 2002; Nel et al. 2009; Dominska and Dykxhoorn 2010). There are several ways to use polyelectrolytes to destabilize the lipid membrane, releasing the endocytosed active compounds into the cytoplasm. The most extensively studied way for endosomal escape is using a “proton-sponge effect” (Yezhelyev et al. 2008; Chou et al. 2011). The proton-sponge effect has been observed in several cationic polymers containing protonable residues with pKa close to endosomal/lysosomal pH. When polymers with the proton-sponge effect are taken up into the acidic environment of endosomes, the polymer residue becomes protonable and resists the acidification of endosomes. As a result, more protons are continuously pumped into endosomes, promoting endosome osmotic swelling, rupture of endosomes, and intracellular release of their contents to the cytosol. Polyethyleneimine (PEI) is one of the most widely used polyelectrolytes for endosomal escape. Due to the amine residue in PEI, it exhibits considerable buffering capacity and subsequently leads to endosome disruption. Han et al. reported on PEI endosomal escape with PEI and PAH-Cit polymer (Han et al. 2012). They demonstrated enhanced gene expression efficiency with polyelectrolyte-coated gold nanoparticles through layer-by-layer techniques. PEI and charge reversion polymer are protonated in acidic conditions, facilitating the escape of the platform from the endosome/lysosome and releasing siRNA into the cytoplasm. Since endosomes have an acidic environment, anionic carboxylated polymers with pH-sensitive properties could also be used as a membrane-disrupting agent. The anionic polymer can destabilize membrane bilayers by pH-triggered conformational change. Yessine et al. (2003) reported intracellular delivery of biomacromolecules from endosomes into the cytoplasm with pH-sensitive methacrylic acid copolymers. They demonstrated that negatively charged polymers with a sharp phase transition property have high hemolytic activity and can efficiently destabilize membrane bilayers (Yessine et al. 2003). Hitz et al. (2006) studied the interaction of oligoarginine with anionic lipid vesicles. They demonstrated that firstly, the positively charged guanidine group in oligoarginine binds to the lipid membrane via electrostatic interaction and forms a nonpolar ion pair with negatively charged components of cell membranes. Secondly, the oligoarginine attaches to the lipid membrane more strongly through non-electrostatic interaction, and the bilayer becomes rigidified, resulting in leakiness and rupture of the lipid membrane (Hitz et al. 2006).

Immune stimulator

Individual bacterial or viral antigens, which may not be sufficiently active alone, can induce a specific strong immune response when chemically conjugated to specific polyelectrolytes (Kabanov et al. 2005; Kabanov 2006). Therefore, synthetic polyelectrolytes combined with specific antigens can enhance the immune response and be successfully used to develop a synthetic vaccine. Synthetic polyelectrolytes, such as polyacrylic acid, dextran sulfate, polyvinylpyridine, and polyvinylimidazole, have no structural similarity with antigens but when complexed with specific antigens, they enhance the immune response and increase antibody production several times over. A representative polyelectrolyte as an immune stimulator is polyoxidonium. Polyoxidonium is an N-oxidized polyethylene-piperazine derivative, a water-soluble high-molecular synthetic immune modulator. Antigen-conjugated polyoxidonium can enhance the specific immune response by orders of magnitude, and many studies have reported its efficacy in the immunotherapy area (Dyakonova et al. 2004). Mohr et al. (1975) reported significantly increased antitumor activity with polyanion as an effective adjuvant to chemotherapy. The pyran (divinyl ether-maleic anhydride) copolymer has highly immunoactive properties, and when it is co-treated with chemotherapeutic drugs, it exhibits significantly enhanced antiproliferative activity against cancer cells via immune activation (Mohr et al. 1975). Chaurasia et al. (2015) also reported the function of polyelectrolyte as a strong immune response activator. Chondroitin sulfate-based nanocapsules exhibit enhanced Dox-mediated apoptosis via Th1 immune response as a selective immune stimulator, resulting in improved chemotherapeutic efficacy (Chaurasia et al. 2015).

Antitumor activity

Positively charged polyelectrolytes are promising candidates as antimicrobial agents. The cationic polyelectrolytes interact with the phospholipid component of the cell membrane, penetrate into the cell wall, and cause cytoplasmic membrane disorganization and wall lysis due to autolytic enzymes (Zhang et al. 2001; Bechinger and Lohner 2006). Cationic antimicrobial polypeptides can also be used as novel cytotoxic agents for cancer treatment. The antitumor effect of antimicrobial cationic peptides occurs through a cell membrane lytic effect and apoptosis via mitochondrial membrane disruption. This happens via electrostatic interaction due to the more negatively charged tumor cell membrane than neutrally charged healthy cell membranes, which results from the greater expression of anionic molecules such as heparin sulfate, phosphatidylserine, or sialic acid-rich glycoproteins in tumor cells. In addition, the activation of toll-like receptors is known as a potential strategy for immuno-cancer therapy, and cationic polyelectrolytes were reported to have immunological activity mediated by toll-like receptors (TLRs) (Chen et al. 2010). Thus, cationic polyelectrolytes could stimulate the secretion of several antitumor cytokines, including IL2 and LPS, and could also promote Th1 and NK cell infiltration and suppression of tumor angiogenesis, which are directly related to antitumor activity (Huang et al. 2013). Lee et al. (2002) reported the cytotoxic activity of cationic chitosan derivatives against various cancer cell lines. They demonstrated the role of charge density and hydrophobicity against cancer cell viability with different types of chitosan derivatives. The antiproliferative activity was enhanced with increasing charge density and hydrophobicity of chitosan derivatives, indicating the hydrophobic interaction as well as electrostatic interaction between the chitosan derivatives and the tumor cell surface are closely related to cancer cell-killing activity. Yim et al. (2014) also revealed the antitumor activity with the all-trans-retinoic acid-g-polyethyleneimine/hyaluronic acid complex system (ATRA-PEI/HA) against various cancer cells. The PEI could result in cell membrane damage due to its high charge density. The toxicity of PEI could be controlled by hyaluronic acid complex via electrostatic interaction, and it minimizes systemic toxicity after IV administration. At the tumor site, the HA/ATRA-PEI is unshielded by hyaluronidase, and PEI could induce specific cell death. It also exhibited synergistic effects with ATRA-induced immune response to kill the cancer cells.

This review paper provides a brief overview of the use of polyelectrolytes in anticancer therapy. Polyelectrolytes are widely used in drug delivery as they can form nanoplatforms through self-assembly or by mixing with oppositely charged polymers. The physical properties of these nanoplatforms can be optimized by controlling various parameters during preparation, including particle size, surface charge, and platform stability. Additionally, polyelectrolytes have demonstrated promising biological functions, making them ideal therapeutic carriers for a variety of drugs.

Furthermore, PIC is used not only for therapeutic carriers but also for the development of biosensors, vaccines, and dialysis membranes. There is also a trend toward the application of polyelectrolytes in the field of tissue engineering materials, where complex constructs made of charged biocompatible polymers can be used to create scaffolds similar to biological matrices. In the future, PIC will have multiple applications in various fields. In conclusion, the use of polyelectrolytes with advantageous properties has the potential to significantly improve drug delivery systems, and comprehensive and systematic characterization should be performed to maximize their efficacy.

This work was supported by the National Research Foundation of Korea (NRF), which is funded by the Korean government (MSIT) (grant nos. 2021R1A2C2008519, 2022R1C1C2002949, and 2022R1A5A600076012).

  1. Ariga K, Lvov YM, Kawakami K, Ji Q, Hill JP (2011) Layer-by-layer self-assembled shells for drug delivery. Adv Drug Deliv Rev 63:762-771. doi: 10.1016/j.addr.2011.03.016
    Pubmed CrossRef
  2. Barrat JL, Joanny F (2007) Theory of polyelectrolyte solutions. In: Rice SA (ed) Advances in chemical physics, John Wiley & Sons, Hoboken, pp 1-66.
  3. Bechinger B, Lohner K (2006) Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim Biophys Acta 1758:1529-1539. doi: 10.1016/j.bbamem.2006.07.001
    Pubmed CrossRef
  4. Bowman K, Leong KW (2006) Chitosan nanoparticles for oral drug and gene delivery. Int J Nanomedicine 1:117-128. doi: 10.2147/nano.2006.1.2.117
    Pubmed KoreaMed CrossRef
  5. Cakmak I, Ulukanli Z, Tuzcu M, Karabuga S, Genctav K (2004) Synthesis and characterization of novel antimicrobial cationic polyelectrolytes. Eur Polym J 40:2373-2379. doi: 10.1016/j.eurpolymj.2004.06.004
    CrossRef
  6. Chaurasia M, Pawar VK, Jaiswal AK, Dube A, Paliwal SK, Chourasia MK (2015) Chondroitin nanocapsules enhanced doxorubicin induced apoptosis against leishmaniasis via Th1 immune response. Int J Biol Macromol 79:27-36. doi: 10.1016/j.ijbiomac.2015.04.043
    Pubmed CrossRef
  7. Chen H, Li P, Yin Y, Cai X, Huang Z, Chen J, Dong L, Zhang J (2010) The promotion of type 1 T helper cell responses to cationic polymers in vivo via toll-like receptor-4 mediated IL-12 secretion. Biomaterials 31:8172-8180. doi: 10.1016/j.biomaterials.2010.07.056
    Pubmed CrossRef
  8. Chen Y, Lin X, Park H, Greever R (2009) Study of artemisinin nanocapsules as anticancer drug delivery systems. Nanomedicine 5:316-322. doi: 10.1016/j.nano.2008.12.005
    Pubmed CrossRef
  9. Chithrani BD, Ghazani AA, Chan WC (2006) Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett 6:662-668. doi: 10.1021/nl052396o
    Pubmed CrossRef
  10. Chornet E, Dumitriu S (1998) Inclusion and release of proteins from polysaccharide-based polyion complexes. Adv Drug Deliv Rev 31:223-246. doi: 10.1016/s0169-409x(97)00120-8
    Pubmed CrossRef
  11. Chou LY, Ming K, Chan WC (2011) Strategies for the intracellular delivery of nanoparticles. Chem Soc Rev 40:233-245. doi: 10.1039/c0cs00003e
    Pubmed CrossRef
  12. Dautzenberg H, Jaeger W (2002) Effect of charge density on the formation and salt stability of polyelectrolyte complexes. Macromol Chem Phys 203:2095-2102. doi: 10.1002/1521-3935(200210) 203:14<2095::AID-MACP2095>3.0.CO;2-9
    CrossRef
  13. De Geest BG, Willart MA, Lambrecht BN, Pollard C, Vervaet C, Remon JP, Grooten J, De Koker S (2012) Surface-engineered polyelectrolyte multilayer capsules: synthetic vaccines mimicking microbial structure and function. Angew Chem Int Ed Engl 51:3862-3866. doi: 10.1002/anie.201200048
    Pubmed CrossRef
  14. Dobrynin AV, Rubinstein M (2005) Theory of polyelectrolytes in solutions and at surfaces. Prog Polym Sci 30:1049-1118. doi: 10.1016/j.progpolymsci.2005.07.006
    CrossRef
  15. Dominska M, Dykxhoorn DM (2010) Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci 123(Pt 8):1183-1189. doi: 10.1242/jcs.066399
    Pubmed CrossRef
  16. Dyakonova VA, Dambaeva SV, Pinegin BV, Khaitov RM (2004) Study of interaction between the polyoxidonium immunomodulator and the human immune system cells. Int Immunopharmacol 4:1615-1623. doi: 10.1016/j.intimp.2004.07.015
    Pubmed CrossRef
  17. Fatima MT, Chanchal A, Yavvari PS, Bhagat SD, Gujrati M, Mishra RK, ivastava A Sr (2016) Cell permeating nano-complexes of amphiphilic polyelectrolytes enhance solubility, stability, and anti-cancer efficacy of curcumin. Biomacromolecules 17:2375-2383. doi: 10.1021/acs.biomac.6b00417
    Pubmed CrossRef
  18. Fischer D, Bieber T, Li Y, Elsässer HP, Kissel T (1999) A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity. Pharm Res 16:1273-1279. doi: 10.1023/a:1014861900478
    Pubmed CrossRef
  19. Förster S, Schmidt M (1995) Polyelectrolytes in solution. Physical properties of polymers, Springer, Berlin, Heidelberg, pp 51-133.
    CrossRef
  20. González O, Smith RL, Goodman SB (1996) Effect of size, concentration, surface area, and volume of polymethylmethacrylate particles on human macrophages in vitro. J Biomed Mater Res 30:463-473. doi: 10.1002/(SICI)1097-4636(199604)30:4<463::AID-JBM4>3.0.CO;2-N
    CrossRef
  21. Haensler J, Szoka FC Jr (1993) Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem 4:372-379. doi: 10.1021/bc00023a012
    Pubmed CrossRef
  22. Hamman JH (2010) Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Mar Drugs 8:1305-1322. doi: 10.3390/md8041305
    Pubmed KoreaMed CrossRef
  23. Han L, Zhao J, Zhang X, Cao W, Hu X, Zou G, Duan X, Liang XJ (2012) Enhanced siRNA delivery and silencing gold-chitosan nanosystem with surface charge-reversal polymer assembly and good biocompatibility. ACS Nano 6:7340-7351. doi: 10.1021/nn3024688
    Pubmed CrossRef
  24. Han SS, Li ZY, Zhu JY, Han K, Zeng ZY, Hong W, Li WX, Jia HZ, Liu Y, Zhuo RX, Zhang XZ (2015) Dual-pH sensitive charge-reversal polypeptide micelles for tumor-triggered targeting uptake and nuclear drug delivery. Small 11:2543-2554. doi: 10.1002/smll.201402865
    Pubmed CrossRef
  25. Hitz T, Iten R, Gardiner J, Namoto K, Walde P, Seebach D (2006) Interaction of alpha-and beta-oligoarginine-acids and amides with anionic lipid vesicles: a mechanistic and thermodynamic study. Biochemistry 45:5817-5829. doi: 10.1021/bi060285d
    Pubmed CrossRef
  26. Hoang NH, Lim C, Sim T, Lee ES, Youn YS, Kim D, Oh KT (2016) Characterization of a triblock copolymer, poly(ethylene glycol)-polylactide-poly(ethylene glycol), with different structures for anticancer drug delivery applications. Polym Bull 74:1595-1609. doi: 10.1007/s00289-016-1791-3
    CrossRef
  27. Huang Z, Yang Y, Jiang Y, Shao J, Sun X, Chen J, Dong L, Zhang J (2013) Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers. Biomaterials 34:746-755. doi: 10.1016/j.biomaterials.2012.09.062
    Pubmed CrossRef
  28. Ito H, Shibata T, Miyamoto T, Noishiki Y, Inagaki H (1986) Formation of polyelectrolyte complexes between cellulose derivatives and their blood compatibility. J Appl Polym Sci 31:2491-2500. doi: 10.1002/app.1986.070310810
    CrossRef
  29. Johnston APR, Cortez C, Angelatos AS, Caruso F (2006) Layer-by-layer engineered capsules and their applications. Curr Opin Colloid Interface Sci 11:203-209. doi: 10.1016/j.cocis.2006.05.001
    CrossRef
  30. Kabanov AV (2006) Polymer genomics: an insight into pharmacology and toxicology of nanomedicines. Adv Drug Deliv Rev 58:1597-1621. doi: 10.1016/j.addr.2006.09.019
    Pubmed KoreaMed CrossRef
  31. Kabanov AV, Batrakova EV, iadibhatla S Sr, Yang Z, Kelly DL, Alakov VY (2005) Polymer genomics: shifting the gene and drug delivery paradigms. J Control Release 101:259-271. doi: 10.1016/j.jconrel.2004.07.009
    Pubmed CrossRef
  32. Kabanov AV, Bronich TK, Kabanov VA, Yu K, Eisenberg A (1996) Soluble stoichiometric complexes from poly(N-ethyl-4-vinylpyridinium) cations and poly(ethylene oxide)-block-polymethacrylate anions. Macromolecules 29:6797-6802. doi: 10.1021/ma960120k
    CrossRef
  33. Kabanov VA, Skobeleva VB, Rogacheva VB, Zezin AB (2004) Sorption of proteins by slightly cross-linked polyelectrolyte hydrogels: kinetics and mechanism. J Phys Chem B 108:1485-1490. doi: 10.1021/jp035821f
    CrossRef
  34. Kabanov VA, Zezin AB (1984) Soluble interpolymeric complexes as a new class of synthetic polyelectrolytes. Pure Appl Chem 56:343-354. doi: 10.1351/pac198456030343
    CrossRef
  35. Kamimura M, Kim JO, Kabanov AV, Bronich TK, Nagasaki Y (2012) Block ionomer complexes of PEG-block-poly(4-vinylbenzylphosphonate) and cationic surfactants as highly stable, pH responsive drug delivery system. J Control Release 160:486-494. doi: 10.1016/j.jconrel.2012.04.027
    Pubmed CrossRef
  36. Kataoka K, Togawa H, Harada A, Yasugi K, Matsumoto T, Katayose S (1996) Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29:8556-8557. doi: 10.1021/ma961217+
    CrossRef
  37. Kim BS, Park SW, Hammond PT (2008a) Hydrogen-bonding layer-by-layer-assembled biodegradable polymeric micelles as drug delivery vehicles from surfaces. ACS Nano 2:386-392. doi: 10.1021/nn700408z
    Pubmed CrossRef
  38. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG (2008b) Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. J Control Release 129:107-116. doi: 10.1016/j.jconrel.2008.03.008
    Pubmed CrossRef
  39. Kunath K, von Harpe A, Fischer D, Petersen H, Bickel U, Voigt K, Kissel T (2003) Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J Control Release 89:113-125. doi: 10.1016/s0168-3659(03)00076-2
    Pubmed CrossRef
  40. Lee ES, Oh KT, Kim D, Youn YS, Bae YH (2007) Tumor pH-responsive flower-like micelles of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine). J Control Release 123:19-26. doi: 10.1016/j.jconrel.2007.08.006
    Pubmed KoreaMed CrossRef
  41. Lee JK, Lim HS, Kim JH (2002) Cytotoxic activity of aminoderivatized cationic chitosan derivatives. Bioorg Med Chem Lett 12:2949-2951. doi: 10.1016/s0960-894x(02)00530-9
    Pubmed CrossRef
  42. Lim C, Youn YS, Lee KS, Hoang NH, Sim T, Lee ES, Oh KT (2016) Development of a robust pH-sensitive polyelectrolyte ionomer complex for anticancer nanocarriers. Int J Nanomedicine 11:703-713. doi: 10.2147/IJN.S99271
    Pubmed KoreaMed CrossRef
  43. Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z (2008) Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev 60:1650-1662. doi: 10.1016/j.addr.2008.09.001
    Pubmed CrossRef
  44. Loo HL, Goh BH, Lee LH, Chuah LH (2022) Application of chitosan-based nanoparticles in skin wound healing. Asian J Pharm Sci 17:299-332. doi: 10.1016/j.ajps.2022.04.001
    Pubmed KoreaMed CrossRef
  45. Lungwitz U, Breunig M, Blunk T, Göpferich A (2005) Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 60:247-266. doi: 10.1016/j.ejpb.2004.11.011
    Pubmed CrossRef
  46. Mende M, Petzold G, Buchhammer HM (2002) Polyelectrolyte complex formation between poly(diallyldimethyl-ammonium chloride) and copolymers of acrylamide and sodium-acrylate. Colloid Polym Sci 280:342-351. doi: 10.1007/s00396-001-0614-7
    CrossRef
  47. Mohr SJ, Chirigos MA, Fuhrman FS, Pryor JW (1975) Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor. Cancer Res 35:3750-3754.
  48. Müller M, Keßler B, Fröhlich J, Poeschla S, Torger B (2011) Polyelectrolyte complex nanoparticles of poly(ethyleneimine) and poly(acrylic acid): preparation and applications. Polymers 3:762-778. doi: 10.3390/polym3020762
    CrossRef
  49. Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M (2009) Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8:543-557. doi: 10.1038/nmat2442
    Pubmed CrossRef
  50. Ogris M, Brunner S, Schüller S, Kircheis R, Wagner E (1999) PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther 6:595-605. doi: 10.1038/sj.gt.3300900
    Pubmed CrossRef
  51. Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V (2002) Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J 16:1217-1226. doi: 10.1096/fj.02-0088com
    Pubmed CrossRef
  52. Park JH, Kwon S, Nam JO, Park RW, Chung H, Seo SB, Kim IS, Kwon IC, Jeong SY (2004) Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery. J Control Release 95:579-588. doi: 10.1016/j.jconrel.2003.12.020
    Pubmed CrossRef
  53. Riezk A, Van Bocxlaer K, Yardley V, Murdan S, Croft SL (2020) Activity of Amphotericin B-loaded chitosan nanoparticles against experimental cutaneous leishmaniasis. Molecules 25:4002. doi: 10.3390/molecules25174002
    Pubmed KoreaMed CrossRef
  54. Rui Y, Wilson DR, Choi J, Varanasi M, Sanders K, Karlsson J, Lim M, Green JJ (2019) Carboxylated branched poly(β-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing. Sci Adv 5:eaay3255. doi: 10.1126/sciadv.aay3255
    Pubmed KoreaMed CrossRef
  55. Sato H, Maeda M, Nakajima A (1979) Mechanochemistry and permeability of polyelectrolyte complex membranes composed of poly(vinyl alcohol) derivatives. J Appl Polym Sci 23:1759-1767. doi: 10.1002/app.1979.070230616
    CrossRef
  56. Senuma M, Kuwabara S, Kaeriyama K, Hase F, Shimura Y (1986) Polymer complex from copolymers of acrylonitrile and ionic vinyl benzyl compounds. J Appl Polym Sci 31:1687-1697. doi: 10.1002/app.1986.070310615
    CrossRef
  57. Sæther HV, Holme HK, Maurstad G, Smidsrød O, Stokke BT (2008) Polyelectrolyte complex formation using alginate and chitosan. Carbohydr Polym 74:813-821. doi: 10.1016/j.carbpol.2008.04.048
    CrossRef
  58. Shu XZ, Zhu KJ (2000) A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery. Int J Pharm 201:51-58. doi: 10.1016/s0378-5173(00)00403-8
    Pubmed CrossRef
  59. Shuai X, Merdan T, Unger F, Wittmar M, Kissel T (2003) Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG: synthesis, characterization, and potential as efficient nonviral gene delivery vectors. Macromolecules 36:5751-5759. doi: 10.1021/ma034390w
    CrossRef
  60. Starchenko V, Müller M, Lebovka N (2008) Growth of polyelectrolyte complex nanoparticles: computer simulations and experiments. J Phys Chem C 112:8863-8869. doi: 10.1021/jp800581y
    CrossRef
  61. Vergaro V, Scarlino F, Bellomo C, Rinaldi R, Vergara D, Maffia M, Baldassarre F, Giannelli G, Zhang X, Lvov YM, Leporatti S (2011) Drug-loaded polyelectrolyte microcapsules for sustained targeting of cancer cells. Adv Drug Deliv Rev 63:847-864. doi: 10.1016/j.addr.2011.05.007
    Pubmed CrossRef
  62. Wang H, Wang Y, Yan H, Zhang J, Thomas RK (2006) Binding of sodium dodecyl sulfate with linear and branched polyethyleneimines in aqueous solution at different pH values. Langmuir 22:1526-1533. doi: 10.1021/la051988j
    Pubmed CrossRef
  63. Win KY, Feng SS (2005) Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 26:2713-2722. doi: 10.1016/j.biomaterials.2004.07.050
    Pubmed CrossRef
  64. Xun MM, Zhang XC, Zhang J, Jiang QQ, Yi WJ, Zhu W, Yu XQ (2013) Low molecular weight PEI-based biodegradable lipopolymers as gene delivery vectors. Org Biomol Chem 11:1242-1250. doi: 10.1039/c2ob27211c
    Pubmed CrossRef
  65. Yessine MA, Lafleur M, Meier C, Petereit HU, Leroux JC (2003) Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers. Biochim Biophys Acta 1613:28-38. doi: 10.1016/s0005-2736(03)00137-8
    CrossRef
  66. Yezhelyev MV, Qi L, O'Regan RM, Nie S, Gao X (2008) Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging. J Am Chem Soc 130:9006-9012. doi: 10.1021/ja800086u
    Pubmed KoreaMed CrossRef
  67. Yim H, Park W, Kim D, Fahmy TM, Na K (2014) A self-assembled polymeric micellar immunomodulator for cancer treatment based on cationic amphiphilic polymers. Biomaterials 35:9912-9919. doi: 10.1016/j.biomaterials.2014.08.029
    Pubmed CrossRef
  68. Yue ZG, Wei W, Lv PP, Yue H, Wang LY, Su ZG, Ma GH (2011) Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles. Biomacromolecules 12:2440-2446. doi: 10.1021/bm101482r
    Pubmed CrossRef
  69. Yun JM, Park SY, Lee ES, Youn YS, Park GY, Lim C, Lee BJ, Song HT, Oh YT, Oh KT (2012) Physicochemical characterizations of amphiphilic block copolymers with different MWs and micelles for development of anticancer drug nanocarriers. Macromol Res 20:944-953. doi: 10.1007/s13233-012-0133-z
    CrossRef
  70. Zelphati O, Nguyen C, Ferrari M, Felgner J, Tsai Y, Felgner PL (1998) Stable and monodisperse lipoplex formulations for gene delivery. Gene Ther 5:1272-1282. doi: 10.1038/sj.gt.3300707
    Pubmed CrossRef
  71. Zhang L, Rozek A, Hancock RE (2001) Interaction of cationic antimicrobial peptides with model membranes. J Biol Chem 276:35714-35722. doi: 10.1074/jbc.M104925200
    Pubmed CrossRef
  72. Zhang X, Oulad-Abdelghani M, Zelkin AN, Wang Y, Haîkel Y, Mainard D, Voegel JC, Caruso F, Benkirane-Jessel N (2010) Poly(L-lysine) nanostructured particles for gene delivery and hormone stimulation. Biomaterials 31:1699-1706. doi: 10.1016/j.biomaterials.2009.11.032
    Pubmed CrossRef
  73. Zhao Q, Han B, Wang Z, Gao C, Peng C, Shen J (2007) Hollow chitosan-alginate multilayer microcapsules as drug delivery vehicle: doxorubicin loading and in vitro and in vivo studies. Nanomedicine 3:63-74. doi: 10.1016/j.nano.2006.11.007
    Pubmed CrossRef

Article

Review

DTT 2024; 3(1): 62-73

Published online March 31, 2024 https://doi.org/10.58502/DTT.23.0027

Copyright © The Pharmaceutical Society of Korea.

Polyelectrolyte Complex for Drug Delivery

Chaemin Lim1, Yuseon Shin2, Kyung Taek Oh2,3

1College of Pharmacy, CHA University, Seongnam, Korea
2Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Seoul, Korea
3College of Pharmacy, Chung-Ang University, Seoul, Korea

Correspondence to:Kyung Taek Oh, kyungoh@cau.ac.kr

Received: October 4, 2023; Revised: November 22, 2023; Accepted: January 25, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Polyelectrolyte complexes (PICs) have emerged as promising candidates in the field of drug delivery. This manuscript presents a comprehensive investigation organized into four main sections to elucidate the potential of PICs for drug delivery applications. The first section provides a foundational understanding of polyelectrolytes, highlighting their unique properties and characteristics. Subsequently, we delve into an examination of the physicochemical properties of polyelectrolytes, shedding light on the mechanisms governing the formation of PICs and the critical parameters involved in preparing polyelectrolyte nanoparticles. In the third section, we explore the formation of polyelectrolyte-based nanoparticles, encompassing hydrophilic polyelectrolytes, hydrophobically modified polyelectrolytes, and PICs formed with oppositely charged polymers. This section offers insights into the versatile applications of PICs in drug delivery systems. The final section delves into the biological functions of polyelectrolytes, revealing their role in enhancing cellular uptake, facilitating endosomal escape, acting as immune stimulators, and exhibiting antitumor activity. These insights emphasize the potential of PICs to overcome barriers in drug delivery and enhance therapeutic outcomes. In summary, this manuscript serves as a comprehensive resource for researchers and practitioners in the field, offering a holistic understanding of the multifaceted applications of PICs in drug delivery.

Keywords: cationic polymer, drug delivery, gene delivery, polyelectrolyte

Polyelectrolytes

Polyelectrolytes are an intriguing group of macromolecules that contain repeating units with either positive or negative charges. They possess unique theoretical and practical properties that distinguish them from uncharged polymers (Förster and Schmidt 1995; Dobrynin and Rubinstein 2005; Barrat and Joanny 2007). Even the dissociation of a small fraction of ionic units can significantly alter their properties, such as chain conformation, viscosity, diffusion coefficients, polarizability, and counter ion condensation. Polyelectrolytes have found various applications in different industries, including water treatment, cosmetics, pharmaceuticals, mineral separation, paper coating, and paints (Sato et al. 1979; Ito et al. 1986; Senuma et al. 1986; Vergaro et al. 2011; De Geest et al. 2012). Depending on their origin and charge type, polyelectrolytes can be classified as natural, modified natural, synthetic, cationic, anionic, or polyampholyte. Their potential applications are diverse and depend on factors such as charge density, dissociation constant of ionic groups, and type of charge. Polyelectrolytes have recently garnered attention in drug delivery applications. Their charged repeating segments make them soluble in aqueous conditions, which allows for complex formation with oppositely charged drugs or polymers via electrostatic interaction, resulting in the formation of nanoparticles with core and shell structures, also known as PICs. These nano vehicles can enhance drug bioavailability by increasing cellular uptake via endocytosis pathways and protecting the complexed drug from enzymatic degradation in vivo conditions (Shu and Zhu 2000; Kim et al. 2008b; Liu et al. 2008; Hamman 2010). Additionally, hydrophobically modified polyelectrolytes can self-assemble to form nanoparticles with a surface charge that can encapsulate hydrophobic drugs in the core (Shuai et al. 2003; Lim et al. 2016). Some polyelectrolytes also exhibit various biological functions, such as endosome disruption, antimicrobial activity, and immune system activation (Cakmak et al. 2004; Dyakonova et al. 2004; Müller et al. 2011). Thus, the pharmaceutical industry has shown great interest in studying different types of polyelectrolytes for drug delivery applications. In this review, we focus on the use of polyelectrolytes as bioavailability enhancers for anticancer treatment.

Physicochemical Properties of Polyelectrolyte

Mechanism for the formation of PIC

The formation of PICs occurs when oppositely charged polyelectrolytes come into contact with each other (Fig. 1). The interaction between the polyelectrolytes is driven by electrostatic forces, which cause the charged segments of the polyelectrolytes to attract each other. The interaction can lead to the formation of a nanoparticle with a core-shell structure, in which one polyelectrolyte forms the core and the other forms the shell. The formation of PICs is influenced by several factors, including the charge density, chain length, and degree of ionization of the polyelectrolytes, as well as the ionic strength and pH of the solution. In general, higher charge densities and longer chains lead to stronger interactions between the polyelectrolytes and the formation of more stable nanoparticles. The degree of ionization of the polyelectrolytes also affects the formation of PICs, as the dissociation of the charged segments can affect the electrostatic interaction between the polyelectrolytes. As shown in Fig. 1, the mechanism of PIC formation can be further divided into three stages: (1) initial contact between the polyelectrolytes, forming the primary complex, (2) formation of a diffuse polyelectrolyte cloud around the oppositely charged polyelectrolyte, and (3) coacervation, in which the polyelectrolyte chains come into close proximity and form a stable nanoparticle, resulting in the secondary complex. The secondary aggregates are composed of about 100 primary complex particles, and the inter-complex aggregation process is mainly progressed by hydrophobic interactions (Chornet and Dumitriu 1998; Starchenko et al. 2008; Müller et al. 2011).

Figure 1. Mechanism for formation of polyelectrolyte complexes (PICs).

Parameters in preparation of polyelectrolyte nanoparticles

Polyelectrolyte nanoparticles are formed by the interaction of oppositely charged polyelectrolytes, and several parameters can be controlled during their preparation to optimize their physical properties and drug delivery efficiency. These parameters include the true charge and charge density of the polyelectrolytes, the mixing ratio of the polyelectrolytes, the order of addition of the polyelectrolytes, and the effect of salt concentration in the solution.

True charge

The true charge of polyelectrolytes refers to the actual charge of the repeating units. When preparing oppositely charged polyelectrolytes in stoichiometric ratios to form PIC nanoparticles, the determination of true charge and charge density is very important. As mentioned above, the driving force for PIC formation is the electrostatic interaction between oppositely charged macromolecules. However, the true charge or charge density of polyelectrolytes could be affected by the colloidal pH, and the aggregation formation may not be identical to the experimental design. Wang et al. (2006) reported the effect of pH on linear poly (ethyleneimine) (PEI) affinity for complex formation. Under acidic conditions, the PEI is a strong cationic polymer, and the binding affinity with anionic surfactants is very high. However, at pH 7, the electrostatic attraction becomes weaker, and at pH 10, PEI is essentially nonionic, and there is no electrostatic attraction anymore (Wang et al. 2006). In our previous study, we also reported the pH-sensitive PEI/PASP complex system for anticancer drug delivery. At pH 7.4, the PEI/PASP complex system formed a compacted nanoparticle with a narrow size distribution. However, under acidic conditions, the true charge of PASP decreased, and the PASP dissociated from the PEI-based platform, resulting in accelerated drug release (Lim et al. 2016).

Charge density

The charge density of polyelectrolytes is also related to the formation of PICs. When preparing complex nanoparticles, core compacted structures can be obtained with similar charge densities of the polyelectrolytes. Conversely, loose and unstable structures become prevalent in systems with strongly deviating charge densities of the polyelectrolytes (Dautzenberg and Jaeger 2002; Mende et al. 2002). Mende et al. (2002) investigated the role of charge density in the formation of PICs. Among various charge densities of polymers, the most stable and smallest complex systems were obtained from oppositely charged polyelectrolytes with similar charge densities (Mende et al. 2002).

Mixing ratio

The mixing ratio of charges between polyelectrolytes and oppositely charged macromolecules is a crucial parameter that should be considered to create small-sized nanoparticles with good stability. Depending on the cationic/anionic charge ratio (C/A ratio), the particle size and surface charge can be dramatically changed. Zelphati et al. (1998) investigated the change in size and zeta charge of liposome-gene complexes depending on the mixing ratio. At a charge ratio near 1, the surface charge of the PIC became about zero and exhibited a significantly increased particle size with poor physical stability due to increased hydrophobicity (Zelphati et al. 1998). Kabanov and Zezin (1984) also reported the change in size and aggregation number of PDMAEMA/phosphate polymers at different C/A ratios. The size of the PIC dropped from 49 nm at a C/A value of 0.067 down to about 30 nm at C/A = 0.5, and the aggregation number of the polymer increased due to the change in structures (Kabanov and Zezin 1984).

Order of addition

The order of polymer addition for PIC formation can affect the particle size and stability. In principle, the smallest particle size of PIC can be achieved by adding the minority component into the majority component. Zelphati et al. (1998) studied the particle size of PIC with different orders of addition. To prepare the cationic lipid/DNA complex (C/A ratio > 1), DNA was added to excess lipid materials, and a stable and small-sized nanoparticle was formed. However, large aggregates were produced when lipid materials were added to DNA (Zelphati et al. 1998). In the former case, the 1:1 stoichiometry between lipid and DNA cannot be achieved, and they form homogeneously complexed PIC nanoparticles. However, in the latter case, the binding of DNA to cationic lipid is not homogeneous because the 1:1 complex ratio must be exceeded, resulting in the formation of aggregates. Similar studies were also reported by Müller et al. (2011) and Sæther et al. (2008). All the studies reveal that adding the minor component to the major solution can produce more equilibrated and compacted PIC nanoparticles.

Formation of Polyelectrolyte-Based Nanoparticles

The structure of polyelectrolytes has been tailor-made to correspond with the physico-chemical properties required for the target drug and disease environment conditions. In this chapter, we will provide an overview of these polyelectrolyte types for various drug formulations (Fig. 2) and summarize the PICs in Table 1.

Figure 2. Various type of drug delivery platform using polyelectrolytes. (a) Polymer-drug complex via electrostatic interaction. (b) Polymer-drug complex via electrostatic and hydrophobic interactions. (c) Polymer-polymer-drug complex via electrostatic and hydrophobic interactions. (d) Layer-by-layer formation of a polymer-polymer-drug complex via electrostatic and hydrophobic interactions.

Table 1 . Application of PICs as a drug delivery system.

PolyelecrolytePropertyTypes of interactions between polymers and drugsReferences
Poly (ethyleneimine) (PEI)Hydrophilic cationicElectrostatic interactionFischer et al. (1999), Kunath et al. (2003), Lungwitz et al. (2005), Ogris et al. (1999)
Polyamidoamine (PAMAM)Hydrophilic cationicElectrostatic interactionHaensler and Szoka (1993)
Poly-β-Aminoesters (PBAE)Hydrophilic cationicElectrostatic interactionRui et al. (2019)
Poly-L-Lysine (PLL)Hydrophilic cationicElectrostatic interactionZhang et al. (2010)
ChitosanHydrophilic cationicElectrostatic interactionLoo et al. (2022), Bowman and Leong (2006), Riezk et al. (2020)
Glycol chitosan modified with 5B cholanic acidAmphiphilic cationicElectrostatic and hydrophobic interactionsPark et al. (2004)
Poly (lactic acid)–poly (ethylene glycol)–poly (histidine) (PLA-b-PEG-b-P (His))Amphiphilic pH-responsiveHydrophobic interactionLee et al. (2007)
Poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate) (PEG-PVBP)Amphiphilic anionicHydrophobic interactionKamimura et al. (2012)
Poly (ethylene glycol)–poly (lactic acid)–poly (ethyleneimine) (PEG-PLA-PEI)Amphiphilic cationicElectrostatic and hydrophobic interactionsLim et al. (2016)
Poly (aspartic acid) (P (Asp))Hydrophilic anionic
Poly-alkyl amine derivativeAmphiphilic cationicElectrostatic and hydrophobic interactionsFatima et al. (2016)
P (Asp)Hydrophilic anionic
Carboxymethyl celluloseHydrophilic anionicElectrostatic and hydrophobic interactionsZhao et al. (2007)
ChitosanHydrophilic cationicElectrostatic and hydrophobic interactionsChen et al. (2009)
AlginateHydrophilic anionic


Hydrophilic polyelectrolyte

Polymer-drug complex via electrostatic interaction

A wide range of polyelectrolytes have been synthesized and used as materials for drug delivery systems. Among them, copolymers containing cationic groups have been extensively investigated (Kabanov et al. 1996; Kataoka et al. 1996; Kabanov et al. 2004). As shown in fig. 2a, the cationic segments can bind to oppositely charged drugs by electrostatic interaction, and they can spontaneously form nanosized PICs.

1) Poly (ethyleneimine)

The representative cationic polyelectrolyte for PIC is PEI, which has been known as the most effective non-viral vector due to its condensation and enhanced transfection ability for complexed genetic materials (Fischer et al. 1999; Kunath et al. 2003; Lungwitz et al. 2005). Ogris et al. (1999) investigated the in vitro and in vivo properties of pegylated gene/PEI complexes. Pegylated PEI condenses the DNA into nanosized particles by forming complexes and protects it from enzymatic degradation. They demonstrated that the pegylated gene/PEI complex system could reduce the plasma protein binding into the nanoparticle and prolong blood circulation time with enhanced gene expression levels at the tumor site (Ogris et al. 1999).

2) Polyamidoamine

Polyamidoamine (PAMAM) dendrimers, which contain a large number of secondary and tertiary amines, have also been widely used for gene or cytokine delivery. Haensler et al. originally reported the use of PAMAM dendrimers as gene delivery agents. They demonstrated that the sixth generation PAMAM dendrimer exhibits improved gene delivery efficacy with good biocompatibility. These synthetic non-viral vectors using PIC systems provide opportunities for simple preparation, improved safety, and greater flexibility in the gene therapeutic area (Haensler and Szoka 1993).

3) Poly-β-Aminoesters

Poly-β-Aminoesters (PBAEs) are versatile polymers composed of repeating units with varying charge states. Their flexibility in design during synthesis is a key attribute. PBAEs are primarily used to interact with anionic drugs. These can include small-molecule drugs, nucleic acids (such as siRNA or DNA), and proteins (such as antibodies or enzymes). The electrostatic interaction between PBAEs and these drug molecules allows for the formation of nanoparticles or the encapsulation of drugs. PBAE-based drug delivery systems find applications in cancer therapy, gene therapy, and vaccination. Rui et al. (2019) reported PBAE-based protein delivery system for efficient cellular uptake of protein therapeutics. The delivery system enabled rapid cellular uptake, efficient endosomal escape, and nanoparticles loading CRISPR-Cas9 ribonucleoproteins induced strong gene editing (Rui et al. 2019).

4) Poly-L-Lysine

Poly-L-Lysine (PLL) is a cationic polypeptide polymer made up of repeating units of L-lysine. It possesses high biocompatibility, biodegradability, and antimicrobial properties. PLL is frequently used to interact with anionic drugs such as nucleic acids (DNA or RNA), peptides, and proteins. The electrostatic interactions between PLL and these drug molecules enable the formation of nanoparticles or the surface binding of drugs. PLL-based drug delivery systems are applied in gene therapy, protein delivery, and vaccine development. Zhang et al. (2010) designed PLL-based nanoparticle co-loading a plasmid DNA and a peptide hormone. Zhang’s data showed that melanin secretion was induced by efficient gene transfer and hormone stimulation (Zhang et al. 2010).

5) Chitosan

Chitosan is a natural polymer derived from chitin, found in crustacean shells. Its amino groups confer a cationic nature. Chitosan interacts strongly with anionic drugs, which can include small molecules, peptides, proteins, and even nucleic acids. This electrostatic interaction is leveraged for encapsulating drugs within its matrix or forming drug-loaded nanoparticles. Chitosan-based drug delivery systems are utilized in various applications, such as wound healing (Loo et al. 2022), oral drug delivery (Bowman and Leong 2006), and dermal drug delivery (Riezk et al. 2020). In particular, its versatility extends even further as it can be extensively modified for a wide range of applications. Modified Chitosan derivatives, such as carboxymethyl chitosan, thiolated chitosan, or pegylated chitosan, offer enhanced properties and functionalities. These modifications allow Chitosan to be tailored for specific drug delivery applications, such as targeted drug delivery, sustained release, and improved stability.

Hydrophobically modified polyelectrolytes

As mentioned earlier, the formation of PICs involves not only electrostatic interactions but also hydrophobic interactions. It has been reported that the presence of a hydrophobic moiety in the polyelectrolyte can enhance the colloidal stability of particles and increase tissue permeability (Shuai et al. 2003; Kamimura et al. 2012; Xun et al. 2013). Additionally, it is known to assist in the encapsulation of hydrophobic drugs (Yun et al. 2012; Hoang et al. 2016). In this chapter, we introduce polyelectrolytes that incorporate hydrophobic interactions for drug formulation.

Polymer-drug complex via hydrophobic and electrostatic interaction

Using the mechanism shown in Fig. 2b, Park et al. (2004) developed self-assembled nanoparticles based on glycol chitosan bearing a hydrophobic moiety. The glycol chitosan was hydrophobically modified with 5B cholanic acid (HGC) to have self-assembling properties, and RGD peptides labeled with fluorescein isothiocyanate (FITC) were loaded into the nano-sized HGC. FITC-labeled peptides have several potential interactions with other molecules, including hydrophobic, hydrogen bonding, and electrostatic interactions. These interactions allow the self-assembled HGC to form a compact particle with a small size. The FITC-RGD peptides were successfully loaded into HGC with high loading efficiency and exhibited enhanced biological activity in vivo conditions (Park et al. 2004).

Polymer-drug complex via hydrophobic interaction

Polymer-drug complexes via hydrophobic interaction can be used as smart drug delivery systems for insoluble drug formulations. Lee et al. (2007) reported enhanced antitumor activity with pH-responsive polyelectrolytes. They prepared self-assembled PLA-b-PEG-b-P (His) triblock copolymers, optimized Dox formulation, and reported its pH-dependent physical changes and cell cytotoxicity. The protonation of the imidazole ring in P (His) can be changed in acidic conditions, showing pH-induced micelle interior structural changes from shrinking to swelling. This provides a mechanism for accelerated drug release and enhanced cytotoxicity in acidic pH conditions. The hydrophobic moiety in polyelectrolytes can increase colloidal stability and enhance tissue permeability due to hydrophobic interactions. Kamimura et al. (2012) reported a highly stable and pH-responsive PIC system formed by poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate) (PEG-b-PVBP) and cationic surfactants. The polyanionic segment in PEG-b-PVBP contained a hydrophobic styrene moiety in the repeating unit, which could strongly affect the colloidal stability of the PIC system against changes in ionic strength and dilution. They revealed that additional hydrophobic interactions of benzyl groups in PEG-b-PVBP contribute to the highest stability of PEG-b-PVBP/surfactants among PIC systems in vivo conditions. Accelerated drug release from PEG-b-PVBP/surfactants systems was also observed at acidic pH conditions due to the protonation of phosphate groups in PVBP chains (Fig. 3).

Figure 3. Illustration of self-assembly of the block ionomer complexes. Reused from Kamimura et al. (2012), with permission from Elsevier (license number: 5633941492156). PEG-b-PVBP, poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate); DTAB, dodecyltrimethylammonium bromide; C12Py, Dodecylpyridinium chloride; HTAB, hexadecyltrimethylammonium bromide; C16Py, cetylpyridinium chloride; DOX, Doxorubicin hydrochloride.

PICs with oppositely charged polymer

Nanoparticles formed by complexation of amphiphilic polyelectrolyte and oppositely charged surfactant or polymers can be used as a strategy to control the drug release profile and toxicity (Fig. 2c). In a previous study, we developed a polyelectrolyte ionomer complex composed of positively charged poly (ethylene glycol)–poly (lactic acid)–poly (ethyleneimine) (PEG-PLA-PEI) triblock copolymer and a negatively charged poly (aspartic acid) (P (Asp)) polymer. These polyelectrolytes formed stable aggregates via electrostatic interaction between PEI and PASP blocks and showed pH sensitivity by protonation and deprotonation of the carboxyl groups in P (Asp) for targeting the extracellular pH of cancers. At acidic conditions, the release of Dox loaded in the platforms was accelerated, improving the antitumor activity (Lim et al. 2016). The surfactant complex with polyelectrolyte can also be used to reduce the toxicity of charged platforms themselves. Fatima et al. (2016) developed a PIC system with amphiphilic poly-alkyl amine derivatives and poly-aspartic acid for anticancer drug delivery. Due to its unique cell permeating property, the poly-alkyl amine derivatives have been widely explored as drug delivery platforms. However, the amphiphilic polyelectrolyte has membrane-disrupting activity, which can induce hemolysis in blood circulation. They demonstrated that the inherent cytotoxicity of the polymer can be overcome by complexing polyelectrolytes with anionic-charged P (Asp) to form a PIC system. The cytotoxicity of poly-alkyl amine derivative was significantly decreased, and the aqueous stability of curcumin, a model hydrophobic drug, was significantly improved with enhanced antitumor activity (Fatima et al. 2016).

Layer by layer polyelectrolyte

Layer-by-layer (LbL) polyelectrolyte assembly is also widely used in the drug delivery area. As shown in Fig. 2d, a LbL nanoparticle is a thin-film consecutive absorption technique using positively and negatively charged polymers on the surface. This multi-layered nanoparticle can be used to control the release profile, increase the stability, and improve the solubility of various drugs (Johnston et al. 2006; Kim et al. 2008a; Ariga et al. 2011). Zhao et al. (2007) investigated the encapsulation of the anticancer drug Dox in LbL nanoparticles and validated their therapeutic efficacy under in vitro conditions (Fig. 4). The positively charged Dox was successfully accumulated in negatively charged carboxymethyl cellulose-based LbL nanoparticles, and the drug-loaded LbL nanoparticle exhibited enhanced antitumor activity (Zhao et al. 2007). Chen et al. (2009) also studied anticancer drug-loaded LbL nanoparticles with chitosan, gelatin, and alginate. They demonstrated the feasibility of controlling the drug release profile by changing several parameters, such as polyelectrolyte type, concentration of polymer, and number of coating layers (Chen et al. 2009).

Figure 4. Illustration of LBL nanoparticle formation and in vivo antitumor activity. Reused from Zhao et al. (2007), with permission from Elsevier (license number: 5633951000634).

Biological Function of Polyelectrolyte

Polyelectrolytes possess a variety of preferential biological properties as well as physicochemical characteristics for nanoparticle formation, making them useful for drug delivery purposes. In this chapter, we will provide a representative overview of the biological properties of polyelectrolytes that can maximize the therapeutic efficacy of drugs in anticancer treatment (Table 2).

Table 2 . Polyelectrolytes according to biological function.

PolyelecrolytesBiological functionPropertyReferences
ChitosanEnhanced cellular uptakeElectrostatic interaction between positively charged polymer and negatively charged cell membraneYue et al. (2011)
Poly (l-lysine)-poly (l-leucine)-based block copolymerHan et al. (2015)
PEIEndosomal escapeProton-sponge effectHan et al. (2012)
pH-sensitive methacrylic acid copolymersDestabilization of membrane bilayersYessine et al. (2003)
OligoarginineLeakiness and rupture of membrane bilayersHitz et al. (2006)
PolyoxidoniumImmune stimulatorAntigen-conjugated polyoxidoniumDyakonova et al. (2004)
Pyran (divinyl ether-maleic anhydride) copolymerImmunoactive propertiesMohr et al. (1975)
Chondroitin sulfateStrong immune response activatorChaurasia et al. (2015)
Cationic polyelectrolytesAntitumor activityStimulating secretion of several antitumor cytokines and promoting Th1 and NK cell infiltrationChen et al. (2010)
Chitosan derivativesHydrophobic and electrostatic interaction between the chitosan derivatives and the tumor cell surfaceLee et al. (2002)
PEICell membrane damage due to its high charge densityYim et al. (2014)


Enhanced cellular uptake

Cellular uptake of nanoparticles is influenced by several factors, including size, shape, surface charge, and hydrophobicity (González et al. 1996; Win and Feng 2005; Chithrani et al. 2006). Surface charge plays an especially important role in the cellular uptake of nanoparticles. Thus, polyelectrolyte-based nanoplatforms with a positive charge exhibit a stronger affinity to the negatively charged cell membrane by electrostatic interaction and are generally better taken up than negatively charged particles. Yue et al. (2011) demonstrated the effect of nanoparticle surface charge on cellular uptake with chitosan-based polyelectrolytes. They prepared three kinds of chitosan-based polyelectrolytes with different surface charges and evaluated the effect of surface charge on cellular uptake profiles. The results showed that a positive charge promotes the internalization rate and increases the internalization amount of nanoparticles in different eight cell lines (Yue et al. 2011). Han et al. (2015) reported charge-reversal micelles with Poly (l-lysine)-poly (l-leucine)-based block copolymer for tumor targeting. PLLeu-PLYS (DMA)-Tat (SA) has β-carboxylic amide, which allows the polypeptides to self-assemble into negatively charged micelles. At acidic conditions, the amide can be cleaved, and the micelles switch to a positively charged state, significantly enhancing their cellular uptake (Han et al. 2015).

Endosomal escape

The endocytic pathway is the major uptake mechanism of cells. Particles or drugs entering the cells via the endocytic pathway become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving effective therapy is to facilitate endosomal escape and ensure cytosolic delivery of the therapeutics (Panyam et al. 2002; Nel et al. 2009; Dominska and Dykxhoorn 2010). There are several ways to use polyelectrolytes to destabilize the lipid membrane, releasing the endocytosed active compounds into the cytoplasm. The most extensively studied way for endosomal escape is using a “proton-sponge effect” (Yezhelyev et al. 2008; Chou et al. 2011). The proton-sponge effect has been observed in several cationic polymers containing protonable residues with pKa close to endosomal/lysosomal pH. When polymers with the proton-sponge effect are taken up into the acidic environment of endosomes, the polymer residue becomes protonable and resists the acidification of endosomes. As a result, more protons are continuously pumped into endosomes, promoting endosome osmotic swelling, rupture of endosomes, and intracellular release of their contents to the cytosol. Polyethyleneimine (PEI) is one of the most widely used polyelectrolytes for endosomal escape. Due to the amine residue in PEI, it exhibits considerable buffering capacity and subsequently leads to endosome disruption. Han et al. reported on PEI endosomal escape with PEI and PAH-Cit polymer (Han et al. 2012). They demonstrated enhanced gene expression efficiency with polyelectrolyte-coated gold nanoparticles through layer-by-layer techniques. PEI and charge reversion polymer are protonated in acidic conditions, facilitating the escape of the platform from the endosome/lysosome and releasing siRNA into the cytoplasm. Since endosomes have an acidic environment, anionic carboxylated polymers with pH-sensitive properties could also be used as a membrane-disrupting agent. The anionic polymer can destabilize membrane bilayers by pH-triggered conformational change. Yessine et al. (2003) reported intracellular delivery of biomacromolecules from endosomes into the cytoplasm with pH-sensitive methacrylic acid copolymers. They demonstrated that negatively charged polymers with a sharp phase transition property have high hemolytic activity and can efficiently destabilize membrane bilayers (Yessine et al. 2003). Hitz et al. (2006) studied the interaction of oligoarginine with anionic lipid vesicles. They demonstrated that firstly, the positively charged guanidine group in oligoarginine binds to the lipid membrane via electrostatic interaction and forms a nonpolar ion pair with negatively charged components of cell membranes. Secondly, the oligoarginine attaches to the lipid membrane more strongly through non-electrostatic interaction, and the bilayer becomes rigidified, resulting in leakiness and rupture of the lipid membrane (Hitz et al. 2006).

Immune stimulator

Individual bacterial or viral antigens, which may not be sufficiently active alone, can induce a specific strong immune response when chemically conjugated to specific polyelectrolytes (Kabanov et al. 2005; Kabanov 2006). Therefore, synthetic polyelectrolytes combined with specific antigens can enhance the immune response and be successfully used to develop a synthetic vaccine. Synthetic polyelectrolytes, such as polyacrylic acid, dextran sulfate, polyvinylpyridine, and polyvinylimidazole, have no structural similarity with antigens but when complexed with specific antigens, they enhance the immune response and increase antibody production several times over. A representative polyelectrolyte as an immune stimulator is polyoxidonium. Polyoxidonium is an N-oxidized polyethylene-piperazine derivative, a water-soluble high-molecular synthetic immune modulator. Antigen-conjugated polyoxidonium can enhance the specific immune response by orders of magnitude, and many studies have reported its efficacy in the immunotherapy area (Dyakonova et al. 2004). Mohr et al. (1975) reported significantly increased antitumor activity with polyanion as an effective adjuvant to chemotherapy. The pyran (divinyl ether-maleic anhydride) copolymer has highly immunoactive properties, and when it is co-treated with chemotherapeutic drugs, it exhibits significantly enhanced antiproliferative activity against cancer cells via immune activation (Mohr et al. 1975). Chaurasia et al. (2015) also reported the function of polyelectrolyte as a strong immune response activator. Chondroitin sulfate-based nanocapsules exhibit enhanced Dox-mediated apoptosis via Th1 immune response as a selective immune stimulator, resulting in improved chemotherapeutic efficacy (Chaurasia et al. 2015).

Antitumor activity

Positively charged polyelectrolytes are promising candidates as antimicrobial agents. The cationic polyelectrolytes interact with the phospholipid component of the cell membrane, penetrate into the cell wall, and cause cytoplasmic membrane disorganization and wall lysis due to autolytic enzymes (Zhang et al. 2001; Bechinger and Lohner 2006). Cationic antimicrobial polypeptides can also be used as novel cytotoxic agents for cancer treatment. The antitumor effect of antimicrobial cationic peptides occurs through a cell membrane lytic effect and apoptosis via mitochondrial membrane disruption. This happens via electrostatic interaction due to the more negatively charged tumor cell membrane than neutrally charged healthy cell membranes, which results from the greater expression of anionic molecules such as heparin sulfate, phosphatidylserine, or sialic acid-rich glycoproteins in tumor cells. In addition, the activation of toll-like receptors is known as a potential strategy for immuno-cancer therapy, and cationic polyelectrolytes were reported to have immunological activity mediated by toll-like receptors (TLRs) (Chen et al. 2010). Thus, cationic polyelectrolytes could stimulate the secretion of several antitumor cytokines, including IL2 and LPS, and could also promote Th1 and NK cell infiltration and suppression of tumor angiogenesis, which are directly related to antitumor activity (Huang et al. 2013). Lee et al. (2002) reported the cytotoxic activity of cationic chitosan derivatives against various cancer cell lines. They demonstrated the role of charge density and hydrophobicity against cancer cell viability with different types of chitosan derivatives. The antiproliferative activity was enhanced with increasing charge density and hydrophobicity of chitosan derivatives, indicating the hydrophobic interaction as well as electrostatic interaction between the chitosan derivatives and the tumor cell surface are closely related to cancer cell-killing activity. Yim et al. (2014) also revealed the antitumor activity with the all-trans-retinoic acid-g-polyethyleneimine/hyaluronic acid complex system (ATRA-PEI/HA) against various cancer cells. The PEI could result in cell membrane damage due to its high charge density. The toxicity of PEI could be controlled by hyaluronic acid complex via electrostatic interaction, and it minimizes systemic toxicity after IV administration. At the tumor site, the HA/ATRA-PEI is unshielded by hyaluronidase, and PEI could induce specific cell death. It also exhibited synergistic effects with ATRA-induced immune response to kill the cancer cells.

Conclusion and Future Perspectives

This review paper provides a brief overview of the use of polyelectrolytes in anticancer therapy. Polyelectrolytes are widely used in drug delivery as they can form nanoplatforms through self-assembly or by mixing with oppositely charged polymers. The physical properties of these nanoplatforms can be optimized by controlling various parameters during preparation, including particle size, surface charge, and platform stability. Additionally, polyelectrolytes have demonstrated promising biological functions, making them ideal therapeutic carriers for a variety of drugs.

Furthermore, PIC is used not only for therapeutic carriers but also for the development of biosensors, vaccines, and dialysis membranes. There is also a trend toward the application of polyelectrolytes in the field of tissue engineering materials, where complex constructs made of charged biocompatible polymers can be used to create scaffolds similar to biological matrices. In the future, PIC will have multiple applications in various fields. In conclusion, the use of polyelectrolytes with advantageous properties has the potential to significantly improve drug delivery systems, and comprehensive and systematic characterization should be performed to maximize their efficacy.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF), which is funded by the Korean government (MSIT) (grant nos. 2021R1A2C2008519, 2022R1C1C2002949, and 2022R1A5A600076012).

Fig 1.

Figure 1.Mechanism for formation of polyelectrolyte complexes (PICs).
Drug Targets and Therapeutics 2024; 3: 62-73https://doi.org/10.58502/DTT.23.0027

Fig 2.

Figure 2.Various type of drug delivery platform using polyelectrolytes. (a) Polymer-drug complex via electrostatic interaction. (b) Polymer-drug complex via electrostatic and hydrophobic interactions. (c) Polymer-polymer-drug complex via electrostatic and hydrophobic interactions. (d) Layer-by-layer formation of a polymer-polymer-drug complex via electrostatic and hydrophobic interactions.
Drug Targets and Therapeutics 2024; 3: 62-73https://doi.org/10.58502/DTT.23.0027

Fig 3.

Figure 3.Illustration of self-assembly of the block ionomer complexes. Reused from Kamimura et al. (2012), with permission from Elsevier (license number: 5633941492156). PEG-b-PVBP, poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate); DTAB, dodecyltrimethylammonium bromide; C12Py, Dodecylpyridinium chloride; HTAB, hexadecyltrimethylammonium bromide; C16Py, cetylpyridinium chloride; DOX, Doxorubicin hydrochloride.
Drug Targets and Therapeutics 2024; 3: 62-73https://doi.org/10.58502/DTT.23.0027

Fig 4.

Figure 4.Illustration of LBL nanoparticle formation and in vivo antitumor activity. Reused from Zhao et al. (2007), with permission from Elsevier (license number: 5633951000634).
Drug Targets and Therapeutics 2024; 3: 62-73https://doi.org/10.58502/DTT.23.0027

Table 1 Application of PICs as a drug delivery system

PolyelecrolytePropertyTypes of interactions between polymers and drugsReferences
Poly (ethyleneimine) (PEI)Hydrophilic cationicElectrostatic interactionFischer et al. (1999), Kunath et al. (2003), Lungwitz et al. (2005), Ogris et al. (1999)
Polyamidoamine (PAMAM)Hydrophilic cationicElectrostatic interactionHaensler and Szoka (1993)
Poly-β-Aminoesters (PBAE)Hydrophilic cationicElectrostatic interactionRui et al. (2019)
Poly-L-Lysine (PLL)Hydrophilic cationicElectrostatic interactionZhang et al. (2010)
ChitosanHydrophilic cationicElectrostatic interactionLoo et al. (2022), Bowman and Leong (2006), Riezk et al. (2020)
Glycol chitosan modified with 5B cholanic acidAmphiphilic cationicElectrostatic and hydrophobic interactionsPark et al. (2004)
Poly (lactic acid)–poly (ethylene glycol)–poly (histidine) (PLA-b-PEG-b-P (His))Amphiphilic pH-responsiveHydrophobic interactionLee et al. (2007)
Poly (ethylene glycol)-block-poly (4-vinylbenzylphosphonate) (PEG-PVBP)Amphiphilic anionicHydrophobic interactionKamimura et al. (2012)
Poly (ethylene glycol)–poly (lactic acid)–poly (ethyleneimine) (PEG-PLA-PEI)Amphiphilic cationicElectrostatic and hydrophobic interactionsLim et al. (2016)
Poly (aspartic acid) (P (Asp))Hydrophilic anionic
Poly-alkyl amine derivativeAmphiphilic cationicElectrostatic and hydrophobic interactionsFatima et al. (2016)
P (Asp)Hydrophilic anionic
Carboxymethyl celluloseHydrophilic anionicElectrostatic and hydrophobic interactionsZhao et al. (2007)
ChitosanHydrophilic cationicElectrostatic and hydrophobic interactionsChen et al. (2009)
AlginateHydrophilic anionic

Table 2 Polyelectrolytes according to biological function

PolyelecrolytesBiological functionPropertyReferences
ChitosanEnhanced cellular uptakeElectrostatic interaction between positively charged polymer and negatively charged cell membraneYue et al. (2011)
Poly (l-lysine)-poly (l-leucine)-based block copolymerHan et al. (2015)
PEIEndosomal escapeProton-sponge effectHan et al. (2012)
pH-sensitive methacrylic acid copolymersDestabilization of membrane bilayersYessine et al. (2003)
OligoarginineLeakiness and rupture of membrane bilayersHitz et al. (2006)
PolyoxidoniumImmune stimulatorAntigen-conjugated polyoxidoniumDyakonova et al. (2004)
Pyran (divinyl ether-maleic anhydride) copolymerImmunoactive propertiesMohr et al. (1975)
Chondroitin sulfateStrong immune response activatorChaurasia et al. (2015)
Cationic polyelectrolytesAntitumor activityStimulating secretion of several antitumor cytokines and promoting Th1 and NK cell infiltrationChen et al. (2010)
Chitosan derivativesHydrophobic and electrostatic interaction between the chitosan derivatives and the tumor cell surfaceLee et al. (2002)
PEICell membrane damage due to its high charge densityYim et al. (2014)

References

  1. Ariga K, Lvov YM, Kawakami K, Ji Q, Hill JP (2011) Layer-by-layer self-assembled shells for drug delivery. Adv Drug Deliv Rev 63:762-771. doi: 10.1016/j.addr.2011.03.016
    Pubmed CrossRef
  2. Barrat JL, Joanny F (2007) Theory of polyelectrolyte solutions. In: Rice SA (ed) Advances in chemical physics, John Wiley & Sons, Hoboken, pp 1-66.
  3. Bechinger B, Lohner K (2006) Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim Biophys Acta 1758:1529-1539. doi: 10.1016/j.bbamem.2006.07.001
    Pubmed CrossRef
  4. Bowman K, Leong KW (2006) Chitosan nanoparticles for oral drug and gene delivery. Int J Nanomedicine 1:117-128. doi: 10.2147/nano.2006.1.2.117
    Pubmed KoreaMed CrossRef
  5. Cakmak I, Ulukanli Z, Tuzcu M, Karabuga S, Genctav K (2004) Synthesis and characterization of novel antimicrobial cationic polyelectrolytes. Eur Polym J 40:2373-2379. doi: 10.1016/j.eurpolymj.2004.06.004
    CrossRef
  6. Chaurasia M, Pawar VK, Jaiswal AK, Dube A, Paliwal SK, Chourasia MK (2015) Chondroitin nanocapsules enhanced doxorubicin induced apoptosis against leishmaniasis via Th1 immune response. Int J Biol Macromol 79:27-36. doi: 10.1016/j.ijbiomac.2015.04.043
    Pubmed CrossRef
  7. Chen H, Li P, Yin Y, Cai X, Huang Z, Chen J, Dong L, Zhang J (2010) The promotion of type 1 T helper cell responses to cationic polymers in vivo via toll-like receptor-4 mediated IL-12 secretion. Biomaterials 31:8172-8180. doi: 10.1016/j.biomaterials.2010.07.056
    Pubmed CrossRef
  8. Chen Y, Lin X, Park H, Greever R (2009) Study of artemisinin nanocapsules as anticancer drug delivery systems. Nanomedicine 5:316-322. doi: 10.1016/j.nano.2008.12.005
    Pubmed CrossRef
  9. Chithrani BD, Ghazani AA, Chan WC (2006) Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett 6:662-668. doi: 10.1021/nl052396o
    Pubmed CrossRef
  10. Chornet E, Dumitriu S (1998) Inclusion and release of proteins from polysaccharide-based polyion complexes. Adv Drug Deliv Rev 31:223-246. doi: 10.1016/s0169-409x(97)00120-8
    Pubmed CrossRef
  11. Chou LY, Ming K, Chan WC (2011) Strategies for the intracellular delivery of nanoparticles. Chem Soc Rev 40:233-245. doi: 10.1039/c0cs00003e
    Pubmed CrossRef
  12. Dautzenberg H, Jaeger W (2002) Effect of charge density on the formation and salt stability of polyelectrolyte complexes. Macromol Chem Phys 203:2095-2102. doi: 10.1002/1521-3935(200210) 203:14<2095::AID-MACP2095>3.0.CO;2-9
    CrossRef
  13. De Geest BG, Willart MA, Lambrecht BN, Pollard C, Vervaet C, Remon JP, Grooten J, De Koker S (2012) Surface-engineered polyelectrolyte multilayer capsules: synthetic vaccines mimicking microbial structure and function. Angew Chem Int Ed Engl 51:3862-3866. doi: 10.1002/anie.201200048
    Pubmed CrossRef
  14. Dobrynin AV, Rubinstein M (2005) Theory of polyelectrolytes in solutions and at surfaces. Prog Polym Sci 30:1049-1118. doi: 10.1016/j.progpolymsci.2005.07.006
    CrossRef
  15. Dominska M, Dykxhoorn DM (2010) Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci 123(Pt 8):1183-1189. doi: 10.1242/jcs.066399
    Pubmed CrossRef
  16. Dyakonova VA, Dambaeva SV, Pinegin BV, Khaitov RM (2004) Study of interaction between the polyoxidonium immunomodulator and the human immune system cells. Int Immunopharmacol 4:1615-1623. doi: 10.1016/j.intimp.2004.07.015
    Pubmed CrossRef
  17. Fatima MT, Chanchal A, Yavvari PS, Bhagat SD, Gujrati M, Mishra RK, ivastava A Sr (2016) Cell permeating nano-complexes of amphiphilic polyelectrolytes enhance solubility, stability, and anti-cancer efficacy of curcumin. Biomacromolecules 17:2375-2383. doi: 10.1021/acs.biomac.6b00417
    Pubmed CrossRef
  18. Fischer D, Bieber T, Li Y, Elsässer HP, Kissel T (1999) A novel non-viral vector for DNA delivery based on low molecular weight, branched polyethylenimine: effect of molecular weight on transfection efficiency and cytotoxicity. Pharm Res 16:1273-1279. doi: 10.1023/a:1014861900478
    Pubmed CrossRef
  19. Förster S, Schmidt M (1995) Polyelectrolytes in solution. Physical properties of polymers, Springer, Berlin, Heidelberg, pp 51-133.
    CrossRef
  20. González O, Smith RL, Goodman SB (1996) Effect of size, concentration, surface area, and volume of polymethylmethacrylate particles on human macrophages in vitro. J Biomed Mater Res 30:463-473. doi: 10.1002/(SICI)1097-4636(199604)30:4<463::AID-JBM4>3.0.CO;2-N
    CrossRef
  21. Haensler J, Szoka FC Jr (1993) Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem 4:372-379. doi: 10.1021/bc00023a012
    Pubmed CrossRef
  22. Hamman JH (2010) Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Mar Drugs 8:1305-1322. doi: 10.3390/md8041305
    Pubmed KoreaMed CrossRef
  23. Han L, Zhao J, Zhang X, Cao W, Hu X, Zou G, Duan X, Liang XJ (2012) Enhanced siRNA delivery and silencing gold-chitosan nanosystem with surface charge-reversal polymer assembly and good biocompatibility. ACS Nano 6:7340-7351. doi: 10.1021/nn3024688
    Pubmed CrossRef
  24. Han SS, Li ZY, Zhu JY, Han K, Zeng ZY, Hong W, Li WX, Jia HZ, Liu Y, Zhuo RX, Zhang XZ (2015) Dual-pH sensitive charge-reversal polypeptide micelles for tumor-triggered targeting uptake and nuclear drug delivery. Small 11:2543-2554. doi: 10.1002/smll.201402865
    Pubmed CrossRef
  25. Hitz T, Iten R, Gardiner J, Namoto K, Walde P, Seebach D (2006) Interaction of alpha-and beta-oligoarginine-acids and amides with anionic lipid vesicles: a mechanistic and thermodynamic study. Biochemistry 45:5817-5829. doi: 10.1021/bi060285d
    Pubmed CrossRef
  26. Hoang NH, Lim C, Sim T, Lee ES, Youn YS, Kim D, Oh KT (2016) Characterization of a triblock copolymer, poly(ethylene glycol)-polylactide-poly(ethylene glycol), with different structures for anticancer drug delivery applications. Polym Bull 74:1595-1609. doi: 10.1007/s00289-016-1791-3
    CrossRef
  27. Huang Z, Yang Y, Jiang Y, Shao J, Sun X, Chen J, Dong L, Zhang J (2013) Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers. Biomaterials 34:746-755. doi: 10.1016/j.biomaterials.2012.09.062
    Pubmed CrossRef
  28. Ito H, Shibata T, Miyamoto T, Noishiki Y, Inagaki H (1986) Formation of polyelectrolyte complexes between cellulose derivatives and their blood compatibility. J Appl Polym Sci 31:2491-2500. doi: 10.1002/app.1986.070310810
    CrossRef
  29. Johnston APR, Cortez C, Angelatos AS, Caruso F (2006) Layer-by-layer engineered capsules and their applications. Curr Opin Colloid Interface Sci 11:203-209. doi: 10.1016/j.cocis.2006.05.001
    CrossRef
  30. Kabanov AV (2006) Polymer genomics: an insight into pharmacology and toxicology of nanomedicines. Adv Drug Deliv Rev 58:1597-1621. doi: 10.1016/j.addr.2006.09.019
    Pubmed KoreaMed CrossRef
  31. Kabanov AV, Batrakova EV, iadibhatla S Sr, Yang Z, Kelly DL, Alakov VY (2005) Polymer genomics: shifting the gene and drug delivery paradigms. J Control Release 101:259-271. doi: 10.1016/j.jconrel.2004.07.009
    Pubmed CrossRef
  32. Kabanov AV, Bronich TK, Kabanov VA, Yu K, Eisenberg A (1996) Soluble stoichiometric complexes from poly(N-ethyl-4-vinylpyridinium) cations and poly(ethylene oxide)-block-polymethacrylate anions. Macromolecules 29:6797-6802. doi: 10.1021/ma960120k
    CrossRef
  33. Kabanov VA, Skobeleva VB, Rogacheva VB, Zezin AB (2004) Sorption of proteins by slightly cross-linked polyelectrolyte hydrogels: kinetics and mechanism. J Phys Chem B 108:1485-1490. doi: 10.1021/jp035821f
    CrossRef
  34. Kabanov VA, Zezin AB (1984) Soluble interpolymeric complexes as a new class of synthetic polyelectrolytes. Pure Appl Chem 56:343-354. doi: 10.1351/pac198456030343
    CrossRef
  35. Kamimura M, Kim JO, Kabanov AV, Bronich TK, Nagasaki Y (2012) Block ionomer complexes of PEG-block-poly(4-vinylbenzylphosphonate) and cationic surfactants as highly stable, pH responsive drug delivery system. J Control Release 160:486-494. doi: 10.1016/j.jconrel.2012.04.027
    Pubmed CrossRef
  36. Kataoka K, Togawa H, Harada A, Yasugi K, Matsumoto T, Katayose S (1996) Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29:8556-8557. doi: 10.1021/ma961217+
    CrossRef
  37. Kim BS, Park SW, Hammond PT (2008a) Hydrogen-bonding layer-by-layer-assembled biodegradable polymeric micelles as drug delivery vehicles from surfaces. ACS Nano 2:386-392. doi: 10.1021/nn700408z
    Pubmed CrossRef
  38. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG (2008b) Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. J Control Release 129:107-116. doi: 10.1016/j.jconrel.2008.03.008
    Pubmed CrossRef
  39. Kunath K, von Harpe A, Fischer D, Petersen H, Bickel U, Voigt K, Kissel T (2003) Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J Control Release 89:113-125. doi: 10.1016/s0168-3659(03)00076-2
    Pubmed CrossRef
  40. Lee ES, Oh KT, Kim D, Youn YS, Bae YH (2007) Tumor pH-responsive flower-like micelles of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine). J Control Release 123:19-26. doi: 10.1016/j.jconrel.2007.08.006
    Pubmed KoreaMed CrossRef
  41. Lee JK, Lim HS, Kim JH (2002) Cytotoxic activity of aminoderivatized cationic chitosan derivatives. Bioorg Med Chem Lett 12:2949-2951. doi: 10.1016/s0960-894x(02)00530-9
    Pubmed CrossRef
  42. Lim C, Youn YS, Lee KS, Hoang NH, Sim T, Lee ES, Oh KT (2016) Development of a robust pH-sensitive polyelectrolyte ionomer complex for anticancer nanocarriers. Int J Nanomedicine 11:703-713. doi: 10.2147/IJN.S99271
    Pubmed KoreaMed CrossRef
  43. Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z (2008) Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev 60:1650-1662. doi: 10.1016/j.addr.2008.09.001
    Pubmed CrossRef
  44. Loo HL, Goh BH, Lee LH, Chuah LH (2022) Application of chitosan-based nanoparticles in skin wound healing. Asian J Pharm Sci 17:299-332. doi: 10.1016/j.ajps.2022.04.001
    Pubmed KoreaMed CrossRef
  45. Lungwitz U, Breunig M, Blunk T, Göpferich A (2005) Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 60:247-266. doi: 10.1016/j.ejpb.2004.11.011
    Pubmed CrossRef
  46. Mende M, Petzold G, Buchhammer HM (2002) Polyelectrolyte complex formation between poly(diallyldimethyl-ammonium chloride) and copolymers of acrylamide and sodium-acrylate. Colloid Polym Sci 280:342-351. doi: 10.1007/s00396-001-0614-7
    CrossRef
  47. Mohr SJ, Chirigos MA, Fuhrman FS, Pryor JW (1975) Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor. Cancer Res 35:3750-3754.
  48. Müller M, Keßler B, Fröhlich J, Poeschla S, Torger B (2011) Polyelectrolyte complex nanoparticles of poly(ethyleneimine) and poly(acrylic acid): preparation and applications. Polymers 3:762-778. doi: 10.3390/polym3020762
    CrossRef
  49. Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M (2009) Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8:543-557. doi: 10.1038/nmat2442
    Pubmed CrossRef
  50. Ogris M, Brunner S, Schüller S, Kircheis R, Wagner E (1999) PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther 6:595-605. doi: 10.1038/sj.gt.3300900
    Pubmed CrossRef
  51. Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V (2002) Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J 16:1217-1226. doi: 10.1096/fj.02-0088com
    Pubmed CrossRef
  52. Park JH, Kwon S, Nam JO, Park RW, Chung H, Seo SB, Kim IS, Kwon IC, Jeong SY (2004) Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery. J Control Release 95:579-588. doi: 10.1016/j.jconrel.2003.12.020
    Pubmed CrossRef
  53. Riezk A, Van Bocxlaer K, Yardley V, Murdan S, Croft SL (2020) Activity of Amphotericin B-loaded chitosan nanoparticles against experimental cutaneous leishmaniasis. Molecules 25:4002. doi: 10.3390/molecules25174002
    Pubmed KoreaMed CrossRef
  54. Rui Y, Wilson DR, Choi J, Varanasi M, Sanders K, Karlsson J, Lim M, Green JJ (2019) Carboxylated branched poly(β-amino ester) nanoparticles enable robust cytosolic protein delivery and CRISPR-Cas9 gene editing. Sci Adv 5:eaay3255. doi: 10.1126/sciadv.aay3255
    Pubmed KoreaMed CrossRef
  55. Sato H, Maeda M, Nakajima A (1979) Mechanochemistry and permeability of polyelectrolyte complex membranes composed of poly(vinyl alcohol) derivatives. J Appl Polym Sci 23:1759-1767. doi: 10.1002/app.1979.070230616
    CrossRef
  56. Senuma M, Kuwabara S, Kaeriyama K, Hase F, Shimura Y (1986) Polymer complex from copolymers of acrylonitrile and ionic vinyl benzyl compounds. J Appl Polym Sci 31:1687-1697. doi: 10.1002/app.1986.070310615
    CrossRef
  57. Sæther HV, Holme HK, Maurstad G, Smidsrød O, Stokke BT (2008) Polyelectrolyte complex formation using alginate and chitosan. Carbohydr Polym 74:813-821. doi: 10.1016/j.carbpol.2008.04.048
    CrossRef
  58. Shu XZ, Zhu KJ (2000) A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery. Int J Pharm 201:51-58. doi: 10.1016/s0378-5173(00)00403-8
    Pubmed CrossRef
  59. Shuai X, Merdan T, Unger F, Wittmar M, Kissel T (2003) Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG: synthesis, characterization, and potential as efficient nonviral gene delivery vectors. Macromolecules 36:5751-5759. doi: 10.1021/ma034390w
    CrossRef
  60. Starchenko V, Müller M, Lebovka N (2008) Growth of polyelectrolyte complex nanoparticles: computer simulations and experiments. J Phys Chem C 112:8863-8869. doi: 10.1021/jp800581y
    CrossRef
  61. Vergaro V, Scarlino F, Bellomo C, Rinaldi R, Vergara D, Maffia M, Baldassarre F, Giannelli G, Zhang X, Lvov YM, Leporatti S (2011) Drug-loaded polyelectrolyte microcapsules for sustained targeting of cancer cells. Adv Drug Deliv Rev 63:847-864. doi: 10.1016/j.addr.2011.05.007
    Pubmed CrossRef
  62. Wang H, Wang Y, Yan H, Zhang J, Thomas RK (2006) Binding of sodium dodecyl sulfate with linear and branched polyethyleneimines in aqueous solution at different pH values. Langmuir 22:1526-1533. doi: 10.1021/la051988j
    Pubmed CrossRef
  63. Win KY, Feng SS (2005) Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 26:2713-2722. doi: 10.1016/j.biomaterials.2004.07.050
    Pubmed CrossRef
  64. Xun MM, Zhang XC, Zhang J, Jiang QQ, Yi WJ, Zhu W, Yu XQ (2013) Low molecular weight PEI-based biodegradable lipopolymers as gene delivery vectors. Org Biomol Chem 11:1242-1250. doi: 10.1039/c2ob27211c
    Pubmed CrossRef
  65. Yessine MA, Lafleur M, Meier C, Petereit HU, Leroux JC (2003) Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers. Biochim Biophys Acta 1613:28-38. doi: 10.1016/s0005-2736(03)00137-8
    CrossRef
  66. Yezhelyev MV, Qi L, O'Regan RM, Nie S, Gao X (2008) Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging. J Am Chem Soc 130:9006-9012. doi: 10.1021/ja800086u
    Pubmed KoreaMed CrossRef
  67. Yim H, Park W, Kim D, Fahmy TM, Na K (2014) A self-assembled polymeric micellar immunomodulator for cancer treatment based on cationic amphiphilic polymers. Biomaterials 35:9912-9919. doi: 10.1016/j.biomaterials.2014.08.029
    Pubmed CrossRef
  68. Yue ZG, Wei W, Lv PP, Yue H, Wang LY, Su ZG, Ma GH (2011) Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles. Biomacromolecules 12:2440-2446. doi: 10.1021/bm101482r
    Pubmed CrossRef
  69. Yun JM, Park SY, Lee ES, Youn YS, Park GY, Lim C, Lee BJ, Song HT, Oh YT, Oh KT (2012) Physicochemical characterizations of amphiphilic block copolymers with different MWs and micelles for development of anticancer drug nanocarriers. Macromol Res 20:944-953. doi: 10.1007/s13233-012-0133-z
    CrossRef
  70. Zelphati O, Nguyen C, Ferrari M, Felgner J, Tsai Y, Felgner PL (1998) Stable and monodisperse lipoplex formulations for gene delivery. Gene Ther 5:1272-1282. doi: 10.1038/sj.gt.3300707
    Pubmed CrossRef
  71. Zhang L, Rozek A, Hancock RE (2001) Interaction of cationic antimicrobial peptides with model membranes. J Biol Chem 276:35714-35722. doi: 10.1074/jbc.M104925200
    Pubmed CrossRef
  72. Zhang X, Oulad-Abdelghani M, Zelkin AN, Wang Y, Haîkel Y, Mainard D, Voegel JC, Caruso F, Benkirane-Jessel N (2010) Poly(L-lysine) nanostructured particles for gene delivery and hormone stimulation. Biomaterials 31:1699-1706. doi: 10.1016/j.biomaterials.2009.11.032
    Pubmed CrossRef
  73. Zhao Q, Han B, Wang Z, Gao C, Peng C, Shen J (2007) Hollow chitosan-alginate multilayer microcapsules as drug delivery vehicle: doxorubicin loading and in vitro and in vivo studies. Nanomedicine 3:63-74. doi: 10.1016/j.nano.2006.11.007
    Pubmed CrossRef

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