Acetal Linked Oligoethylenimines for Use As pH-Sensitive Gene Carriers

Abstract

Two types of acid-degradable nonviral gene carriers, OEI-MK and OEI-BAA, were synthesized by polymerizing oligoethylenimine of 800 Da (OEI800) with the pH-sensitive acetone ketal cross-linker 2,2-bis(N-maleimidoethyloxy) propane (MK) or the 4-methoxybenzaldehyde bisacrylate acetal cross-linker 1,1-bis-(2-acryloyloxy ethoxy)-[4-methoxy-phenyl]methane) (BAA). Corresponding acid-insensitive counterparts (OEI-BM and LT-OEI-HD) were synthesized as well, representing control polymers. Kinetics of hydrolysis were measured and confirmed the pH-dependent degradation profile of the acetal functions, with short half-lives of 3 min at pH 5.0, and 5 h (OEI-MK) or 3.5 h (OEI-BAA) at physiological pH 7.4 and 37 degrees C. DNA polyplexes of a luciferase expression plasmid were tested for gene transfer efficiency and biocompatibility in two cell lines (B16F10 and Neuro2A). Polyplexes with acid-labile polymers showed an improved toxicity profile compared to those made with acid-stable polymer analogues. At low cation/plasmid (c/p) w/w ratios the transfection efficiency of pH-sensitive polymers was slightly reduced, but it became similar or superior to the efficiency of acid-stable polymers at higher c/p ratios. An improved in vivo biocompatibility of the acid-degradable polymers over the stable control polymers was confirmed by liver histology after systemic administration of polymers in Balb/c mice.

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…pH-Triggered Release: Acid-labile chemical bonds that are stable in the bloodstream (pH 7.4) but upon endocytic internalization are cleaved in the slightly acidic late endosomal (pH 5-6) and lysosomal (pH 4-5) environments, have been used to promote endolysosomal release. [30][31][32] Among the different pH sensitive linkers, which are available, such as acetal/ketal, [28][29][30][31][32][33][34][35][36][37][38][39][40][41] ortho ester, [30][31][32][42][43][44] imine, [30][31][32]36,[45][46][47][48] oxime, [28,31,36,[49][50][51] and maleic acid amide derivatives, [29,30,32,41,[52][53][54] the hydrazone linker [28][29][30][31]<...>…”

“…Endolysosomal release pH Endosomes/ lysosomes Acetal/ketal [28][29][30][31][32]36] Linear polymers [33][34][35] Micelles [37,41] Polymersomes [38,40] Nanoparticles [39] Ortho ester [30][31][32] Micelles [42,43] Polymersomes [44] Imine [30][31][32]36] Micelles [45][46][47][48] Oxime [28,31,36] Nanoparticles [49] Micelles [50,51] Maleic acid amide derivatives [29,30,32] Micelles [41,52,54] Nanoparticles [53] Hydrazone [28][29][30][31][32]36] Linear polymers [55][56]…”

Smart polymeric nanocarriers for small nucleic acid delivery

“…Similarly, the pH in the late endosome (pH ~5.5) is known to be significantly lower than pH in the extracellular milieu (pH 7.4) and the cytoplasm (pH 7.2) (37). Therefore, cross-linking via acid-labile bonds, such as an acetal group (38), is also useful for the fabrication of acidic pH-responsive nanocarriers that can preferentially release payloads within the late endosome.…”

pH‐Responsive Polymers as Gene Carriers

“…This could be overcome by the incorporation of endosome active components such as DMMAn-Mel (melittin modified with dimethylmaleic anhydride) or PBAVE (an amphipathic poly(butyl and vinyl ether)). Knorr et al [23] synthesized two different acetalbased linkers OEI-MK ( Figure 2b) and OEI-BAA ( Figure 2c) by cross-linking oligoethylenimine (OEI) units into larger acidhydrolyzable polymers 2,2-bis(N-maleimidoethyloxy) propane (MK) and 1,1-bis-(2-acryloyloxy ethoxy)-[4-methoxyphenyl]methane) (BAA), respectively. The acetone ketalcontaining linker MK was introduced as a reversible protein crosslinking agent, and BAA was applied in acid-cleavable polymer particles.…”