Pendent Chain Functionalized Polyacetals That Display pH-Dependent Degradation:  A Platform for the Development of Novel Polymer Therapeutics

Abstract

The synthetic polymers that are used to prepare polymer therapeutics reaching clinical use are predominantly nonbiodegradable, and this severely limits the molecular weight range that will give certainty of safe elimination. The aim of this study was to synthesize water-soluble, biocompatible, amino-functionalized polyacetals that would display pH-dependent degradation and, moreover, be suitable for drug conjugation. To test the feasibility of the synthetic procedure, polyacetals were first prepared by the reaction of a diol (e.g., poly(ethylene glycol) (PEG)) and a divinyl ether (e.g., tri(ethylene glycol) divinyl ether) using an acid catalyst. Using PEG3400, these polyacetals had a M w of 36 000−43 000 g/mol (M w/M n = 1.6−1.8) and displayed pH-dependent degradation. An enhanced rate of hydrolysis was seen at pH 5.5 (41% M w loss in 25 h) compared to pH 7.4 (10% M w loss in 73 h). The polymers and their degradation products were nontoxic toward B16F10 cells in vitro (IC50 > 5 mg/mL), and they were also nonhemolytic (rat red blood cells). Several approaches were examined to produce amino-functionalized polyacetals. It was found that modification of either the divinyl ether or PEG monomer was not the best strategy. However, terpolymerization, for example using the hydrolytically stable diol 9-fluorenylmethyloxycarbonyl (Fmoc)-serinol, PEG3400, and tri(ethylene glycol) divinyl ether, did produce functionalized polyacetals of M w 20 000−77 000 g/mol and M w/M n = 1.8−2.0. Varying the ratios of diol monomer gave a family of polymers containing different amounts of pendent group. One of these amino-polyacetals was used to prepare a polymer containing 125I-labeled Bolton−Hunter reagent (74 μCi/mg), introduced to facilitate a preliminary biodistribution study after intravenous administration to rats. The polyacetals showed no preferential accumulation in the major organs (at 1 h; liver (4.2 % dose), lung (0.7%), and kidney (1.1%)), and the log blood clearance with time was linear over 24 h. These novel, biodegradable polyacetals have potential for further development as polymer therapeutics and more generally as a new family of biodegradable polymers.

Nanostructured materials for applications in drug delivery and tissue engineering

“…To be suitable for therapeutic applications, such chemistries must be amenable to industrial-scale development [18]. Scientists continue to explore new biodegradable polymers that exhibit more sophisticated three-dimensional structures [25] and are better suited to frequent parenteral administration [26].…”

Polymeric micelles: authoritative aspects for drug delivery

“…Accordingly, a pentablock copolymer was synthesized by the coupling of pHsensitive poly(β-amino ester) to thermosensitive biodegradable PCL-PEG-PCL [328]. An interesting dual-stimuli-responsive polymer has been based on acid-labile acetal linkages that provide an effective mechanism of polymer biodegradation in an acidic medium.…”

Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

“…Our recent studies have explored dextrin, a natural polymer degraded by amylase (Hreczuk-Hirst et al 2001), and pendant chain functionalised polyacetals that display pH-dependent degradation after internalisation into the endosomal or lysosomal compartment (Tomlinson et al 2002(Tomlinson et al , 2003. These polymers can incorporate the drug (e.g.…”