Delivery of antisense oligonucleotides using poly(alkylene oxide)–poly(propylacrylic acid) graft copolymers in conjunction with cationic liposomes

Abstract

The clinical application of gene silencing is hindered by poor stability and low delivery efficiency of naked oligonucleotides. Here, we present the in vitro and in vivo behavior of a rationally designed, ternary, self-assembled nanoparticle complex, consisting of an anionic copolymer, cationic DOTAP liposome, and antisense oligonucleotide (AON). The multifunctional copolymers are based on backbone poly (propylacrylic acid) (PPAA), a pH-sensitive hydrophobic polymer, with grafted poly (alkylene oxides) (PAOs) varying in extent of grafting and PAO chemistry. The nanoparticle complexes with PPAA-g-PAO copolymers enhance antisense gene silencing effects in A2780 human ovarian cancer cells. A greater amount of AON is delivered to ovarian tumor xenografts using the ternary copolymer-stabilized delivery system, compared to a binary DOTAP/AON complex, following intraperitoneal injection in mice. Further, intratumoral injection of the nanoparticle complexes containing 1 mol% grafted PAO reduced tumoral bcl-2 expression by up to 60%. The data for complexes across the set of PAO polymers support a strong role for the hydrophilic-lipophilic balance of the graft copolymer in achieving serum stability and cellular uptake. Based upon these results, we anticipate that this novel nanoparticle delivery system can be extended to the delivery of plasmid DNA, siRNA, or aptamers for preclinical and clinical development.

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery

“…In vivo studies showed that, after intraperitoneal injection in mice, a greater amount of AON is delivered to ovarian tumour xenografts using the ternary copolymer-stabilized delivery system, compared to a binary DOTAP/AON complex. These results highlight the importance of the hydrophilic-lipophilic balance of the transport system in achieving stability and cellular uptake (Peddada et al, 2014).…”

pH-Responsive Amphiphilic Carboxylate Polymers: Design and Potential for Endosomal Escape

“…Another common type of derivatives involves the incorporation of hydrophilic blocks in the copolymer, such as poly(N-(2-hydroxypropyl) methacrylamide) (HPMA), polyethylene glycol (PEG also named as PEO), or poly(oxyalkylene amine) (Jeffamine). The PEG block could Peddada et al, 2009Peddada et al, , 2014 enhance polymer solubility by forming micelles and increase the resistance to serum proteins (Peddada et al, 2014;Porfiryeva et al, 2020). However, both PEG and Jeffamine conjugated PPAA showed reduced the pH-dependent membrane-lytic activity (Peddada et al, 2009).…”

Advances in Liposomal Drug Delivery System: Fascinating Types and Potential Applications

“…Ganciclovir triphosphate gets encapsulated into DNA that is elongated and acts as a pseudo base which leads to chain termination and cell apoptosis. The advantage is that, ganciclovir terminates the dividing cells and the liposome causes the DNA insertion that stays for a short time [26].…”