Fully Acid-Degradable Biocompatible Polyacetal Microparticles for Drug Delivery

Abstract

A library of polyurethanes and polyureas with different hydrophobicities containing the same acid-degradable dimethyl ketal moiety embedded in the polymer main chain have been prepared. All polymers were synthesized using an AA-BB type step-growth polymerization by reaction of bis(p-nitrophenyl carbamate/carbonate) or diisocyanate monomers with an acid-degradable, ketal-containing diamine. These polymers were designed to hydrolyze at different rates in mildly acidic conditions as a function of their hydrophobicity to afford small molecules only with no polymeric byproduct. The library of polymers was screened for the formation of microparticles using a double emulsion technique. The microparticles that were obtained degraded significantly faster at acidic pH (5.0) than at physiological pH (7.4) with degradation kinetics related to the hydrophobicity of the starting polymer. In vitro studies demonstrated the ability of the FITC-BSA loaded microparticles to be phagocytosed by macrophages resulting in a 10-fold increase in the protein uptake compared to a free protein control; in addition, the microparticles were found to be nontoxic at the concentrations tested of up to 1 mg/mL. The ease of preparation of the polymers coupled with the ability to tune their hydrophobicity and the high acid sensitivity of the microparticles identify this new class of materials as promising candidates for the delivery of bioactive materials.

Materials engineering for immunomodulation

“…Whereas simple degradable polyesters such as polylactic acid, polyglycolic acid and their co-polymers are degraded by acid-catalysed hydrolysis, the hydrolysis rates at even lysosomal pH are so slow that they are not very useful for endosomal delivery. For this reason, more acid-sensitive, hydrolytically sensitive links, such as orthoesters 52 and ketals 53 , have been sought. For example, particles crosslinked with ketal moieties have been developed for biomolecular delivery 53 , including vaccination 54 , through the targeting of endosomal release.…”

“…For this reason, more acid-sensitive, hydrolytically sensitive links, such as orthoesters 52 and ketals 53 , have been sought. For example, particles crosslinked with ketal moieties have been developed for biomolecular delivery 53 , including vaccination 54 , through the targeting of endosomal release. Endosomal release of CpG oligonucleotides has also been shown to be feasible using these materials chemistries 55 .…”

Core-crosslinked pH-sensitive degradable micelles: A promising approach to resolve the extracellular stability versus intracellular drug release dilemma

“…In particular, pH-responsive micelles have attracted great attention due to existence of mildly acidic pH in the tumor tissues as well as in the endo/lysosomal compartments of cells [26,27]. Over the past decade, different pH-responsive micelles have been developed based on acid-labile bonds such as ortho ester, hydrazone, cis-acotinyl, and acetal for enhanced intracellular drug release [28][29][30][31][32][33][34][35][36]. We recently reported that biodegradable micelles and polymersomes based on poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate) (PEG-b-PTMBPEC) block copolymers are prone to rapid hydrolysis thereby "actively" releasing drug under endo/lysosomal pH conditions [37,38].…”

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

“…Fig. 5 shows a library of acetyl containing acid cleavable polymers created by Fréchet and coworkers [65]. These forms of acid cleavable linkage, are also easy to incorporate into living polymerizations [66,67], the preparation method of choice for many gene vectors [68,69].…”