Polyelectrolyte complexes: mechanisms, critical experimental aspects, and applications

Figures & data

Table 1. List of natural and synthetic polymers having PEC-forming potential.

Polymer category	Cationic	Anionic
Natural	Chitosan, poly(l-lysine), dextran, starch, cellulose	Alginate, carrageenan, carboxymethyl cellulose, gelatin, gellan gum, gum kondagogu, hyaluronic acid, pectin, xanthan gum, xyloglucan, γ-poly(glutamic acid), maleic starch, polybetaine, heparin, chodroitin sulfate, poly-(l-glutamic acid)
Synthetic	Poly(vinylbenzyl trialkyl ammonium), poly(4-vinyl-N-alkyl-pyridimiun), poly(acryloyl-oxyalkyl-trialkyl ammonium), poly(acryamidoalkyl-trialkyl ammonium), poly(diallydimethyl-ammonium), N,N,N-trimethyl chitosan	Dextran sulfate, cross-linked-poly(acrylic acid), Eudragit (poly(acrylic or methacrylic acid), polyalkylenoxide-maleic acid, poly-(l-aspartic acid), sodium cellulose sulfate, poly(styrenesulfonic acid), poly(vinylsulfonic acid), poly(itaconic acid)

Figure 1. Schematic representation of the aggregation of PECs. Figure depicts the process of PEC formation with three major steps involved, namely Primary complex formation; new bond formation process within intracomplexes; intercomplex aggregation process (modified after Tsuchida 1994).

Figure 2. Mechanism of PEC formation. On the basis of supermolecular order of polymeric chains, PECs were proposed to consist of two models, namely Ladder-like model with an ordered chain packing and Scrambled egg model with disordered packing (Modified after Purgushov et al. 2012).

Figure 3. Schematic illustration of a core-shell model for polyelectrolyte complexes of alginate (polyanion) and chitosan (polycation) at net charge ratios less than one, equal to one and larger than one (reproduced from Sæther et al. 2008, with kind permission of the copyright holder, Amsterdam).

Figure 4. Preparation methodology and structural model of PECs based on the arrangement of polymer chains involved in PEC formation, suggesting core-shell topography of the fabricated PECs (modified after Lu et al. 2012).

Figure 5. Illustrative representation of various factors affecting the formation and stability of PECs.

Table 2. Applications of PECs as drug delivery carriers.

Polycation	Polyanion	Drug	Formulation	Target disease	Reference
Chitosan	Dextran sulfate	Curcumin	PEC nanoparticles	Cancer	Anitha et al. (2011)
TMC	Alginate	Curcumin	PEC	Cancer	Martins et al. (2013)
Chitosan	Poly(l-malic acid-co-d,l-lactic acid)	Doxorubicin	PEC nanoparticles	Cancer	Wang et al. (2014)
Chitosan	Dextran sulfate	Tenofovir	PEC nanoparticles	HIV/AIDS	Polexe et al. (2013)
Chitosan	Dextran sulfate, heparin	Adenosine 5′-monophosphate  monohydrate	PEC nanoparticles	HIV/AIDS	Costalat et al. (2014)
Chitosan	Carrageenan	NS	PEC	Gastric ulcer	Volodko et al. (2013)
Chitosan	Neem gum, Hupu gum	Vancomycin	PEC nanoparticles	Staphylococci infections	Lankalapalli et al. (2014)
Eudragit RL 30D	Carboxymethyl kappa carrageenan	Miconazole	Bioadhesive matrix  tablets	Fungal infections	Lefnaoui and  Moulai-Mostefa (2014)

NS, not specified; TMC, N,N,N-trimethyl chitosan.

Table 3. Selected examples of PECs in gene delivery applications.

Polycation	Polyanion	Formulation	Therapeutic outcomes	Reference
Chitosan	pDNA	Nanocomplex	Nanocomplexes exhibited high pDNA transfection efficiencies in HEK293 cells in vitro	Cifani et al. (2015)
Chitosan	pDNA	Nanocomplexes	ELISA assay revealed an efficient expression of PDGF-BB and FGF-2 with specific antibodies in mice sera	Jean et al. (2009)
Polyethylenimine	pDNA	Nanoparticles	Nanoparticles exhibited high transfection efficiency with the gene encoding human urokinase plasminogen activator (Hu-uPA)	Zaitsev et al. (2004)
Chitosan	DNA	Chitoplexes	High binding affinity of chitosan to DNA was obtained at pH 5.4 At high charge ratio, the spherical nanocomplexes were formed, without free DNA	Liu et al. (2005)
PEI-PEG-PCP	siRNA	Polyplexes	Polyplexes exhibited high VEGF inhibition efficiency in human prostate carcinoma (PC-3) cells	Kim et al. (2009)
PEI	siRNA	Polyplexes	High uptake of siRNA by HeLa cells at higher concentration of copolymer used to modify the surface of polyplexes	Bui et al. (2012)
PEI-DA	siRNA	Polyplexes	The polyplexes showed high stability against heparin exchange reaction and improved gene silencing efficacy	Lee et al. (2012)
PFNBr	siRNA	Nanocomplexes	Nanocomplexes showed enhanced cellular uptake in PANC-1 cells	Jiang et al. (2013)

pDNA, plasmid DNA; PDGFBB, platelet-derived growth factor-bb; FGF-2, fibroblast growth factor-2; VEGF, vascular endothelial growth factor; PEI-PEG-PCP, prostate cancer-binding peptide (PCP) conjugated with polyethylenimine (PEI) via poly(ethylene glycol) (PEG) linker; PEI-DA, polyethylenimine modified by deoxycholic acid; PFNBr, brush-like conjugated polyelectrolyte nanoparticles.

Table 4. Applications of PECs in protein and peptide delivery.

Polycation	Polyanion	Therapeutic protein/peptide	Formulation	Reference
Chitosan	Dextran sulfate and alginate	Insulin	PEC nanoparticles	Sarmento et al. (2006a)
Chitosan, polyethylenimine, poly-l-lysine	Dextran sulfate	VEGF	PEC nanoparticles	Huang et al. (2007)
APEG	PMMA	BSA	PEC nanoparticles	Sajeesh and Sharma (2007)
Chitosan, polyethylenimine, poly-l-lysine	Dextran sulfate	Repifermin®	PEC nanoparticles	Huang and Berkland (2008)
Chitosan	Alginate	bFGF	Scaffolds	Ho et al. (2009)
Chitosan	Hyaluronate	Insulin or vancomycin	Nasal insert	Luppi et al. (2009)
Chitosan	Alginate	Ovalbumin	Nanocomplex	Cegnar et al. (2011)
Chitosan	Poly(γ-glutamic acid)	SDF-1	Multilayer films	Goncalves et al. (2012)
Chitosan	NaCS and PPS	Lactoferrin	PEC capsules	Wu et al. (2013)

VEGF, vascular endothelial growth factor; PMMA, poly(methacrylic acid); APEG, bis-(2-aminopropyl)poly(ethylene glycol); bFGF, basic fibroblast growth factor; SDF-1: stromal-derived factor 1; BSA, bovine serum albumin; NaCS, sodium cellulose sulfate, PPS, sodium polyphosphate.

Table 5. Patents pertinent to PECs.

Payload	Therapeutic applications	Year	Patent No.	References
Heparin	For hemophilia	1984	4471112	Johnson (1984)
Protein, nucleic acid, antigen	Nanoparticulate system for drug, protein, antigen or  nucleic acid delivery	2003	US 2003/0170313A1	Prokop (2003)
RNA, DNA, peptides, hormones, antigen	For flavor, fragrance delivery	2006	WO2006/064331	Laue and Kauper (2006)
Not specified	Coating of medical devices, kidney hemodialysis,  and dental applications	2007	WO2007/108775A1	Ying and Wan (2007)
Vitamins, enzymes, proteins peptides	As an absorption enhancer and drug carrier	2008	US2008/0254078A1	Laue and Kauper (2008)
Not specified	For dental application and kidney hemodialysis	2010	US2010/0111917A1	Ying and Wan (2010)
Protein, DNA, and peptides	For protein delivery and treatment of lysosomal disease	2012	WO2012/085888A2	Giannotti et al. (2012)
Silver, triclosan	Antimicrobial and antifungal	2012	US2012/8092854B2	Toreki and Moore (2012)
Not specified	For water disinfection and antimicrobial	2013	US2013/0273174A1	Scheuing et al. (2013)
Radio opaque contrast media	For magnetic resonance imaging	2013	US2013/0302255A1	Borbely et al. (2013)

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