Chemically Conjugating Polyethylenimine with Chondroitin Sulfate to Promote CD44-Mediated Endocytosis for Gene Delivery

Abstract

Polyethylenimine (PEI) is one of the most potent synthetic gene delivery vectors because of its high transfection efficiency. Although PEI has been used as a delivery vehicle for a long while, its toxicity is always an issue for clinical applications. In this study, we introduced a low molecular weight PEI of 10 kilodaltons to chondroitin sulfate (CS) via a Michael addition method. By adjusting weight ratios between cationic PEI and anionic CS, the intermolecular or intramolecular, or both, electrostatic interactions of CS-modified PEI (CP) maintained good water solubility but lost some ability to permeate cell membranes. Thus, the cytotoxicity of PEI decreased without sacrificing its gene transfection efficiency. Three CP copolymers with different PEI contents were synthesized and used to prepare polyplexes with plasmid DNA. The pDNA-formed polyplex with a low PEI content (CP(L)) was least cytotoxic and had a transfection efficiency comparable to Lipofectamine/pDNA. The good uptake of CP(L)/pDNA into U87 cells was primarily based on clatherin-dependent and CD44-mediated endocytosis.

Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

“…5B). Lo et al 47) reported that pDNA/CS-modified PEI was primarily taken up by U87 cells based on clathrinmediated endocytosis. These results suggest that CS-coated particles were predominantly taken up by clathrin-mediated endocytosis.…”

Molecular effects of chondroguard in osteoarthritis and herniated discs

“…2). Так как ХС -это моле-кулы с высокой молекулярной мас-сой (>10 кДа), они оказывают эф-фект посредством взаимодействия с белками-рецепторами CD44, TLR4 и ICAM1 [14] на поверхности хондро-цитов. Связываясь с рецептором CD44, ХС снижают транскрипцию провоспалительного сиг-нального фактора NF-кВ, блокируя провоспалительные сигнальные пути с участием белков ADAMTS, ММР, ИЛ1β и др.…”

Drug Carriers: Not an Innocent Delivery Man

“…Chondroitin sulfate has been widely used in drug delivery as a hydrophilic component of self-assembled nanocarriers (33)(34)(35)(36)(37)(38)(39). In addition, due to the anionic charge and the ability to bind to CD44, chondroitin sulfate has been used in combination with polymeric gene carriers to reduce the cationic charge (40)(41)(42)(43)(44)(45)(46) and improve the target specificity (45)(46)(47). The chondroitin sulfate associated with cationic gene carriers is also shown to modify intracellular trafficking of the gene complex (promote endosomal escape and accumulation at the nuclear periphery) in favor of gene transfection (48).…”