Synthesis and properties of a biodegradable polymer-drug conjugate: Methotrexate-poly(glycerol adipate)

Abstract

Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX. The MTX-PGA conjugate self-assembled into nanoparticles with size dependent on the amount of conjugated MTX and the pH of medium. Change in particle size was attributed to steric hindrance and bulkiness inside the nanoparticle core and dissociation of free functional groups of the drug. The MTX-PGA nanoparticles were physically stable in media with pH range of 5-9 and ionic strength of up to 0.15 M NaCl and further chemically stable against hydrolysis in pH 7.4 medium over 30 days but enzymatically degradable to release unchanged free drug. Although 30%MTX-PGA nanoparticles exhibited only slightly less potency than free MTX in 791T cells in contrast to previously reported human serum albumin-MTX conjugates which had >300 times lower potency than free MTX. However, the MTX nanoparticles showed 7 times higher toxicity to Saos-2 cells than MTX. Together with the enzymic degradation experiments, these results suggest that with a suitable biodegradable polymer a linker moiety is not a necessary component. These easily synthesised PGA drug conjugates lacking a linker moiety could therefore be an effective new pathway for development of polymer drug conjugates.

Polyglycerol Hyperbranched Polyesters: Synthesis, Properties and Pharmaceutical and Biomedical Applications

“…Zhang PGAd is a biodegradable polyester [56] which exhibits a high biocompatibility. Additionally, it can be degraded by human enzymes, producing non-toxic removable metabolites [57]. For these reasons, it has found many applications as a carrier for drug delivery.…”

“…Suksiriworapong et al reported a PGAd-anticancer drug conjugate with methotrexate (MTX) with MTX% amount up to 27.5 mol %, which was prepared by a simple carbodiimide coupling reaction in DMSO [57]. It was found that MTX-PGAd conjugate self-assembled into nanoparticles whose size depended on the amount of conjugated MTX and the pH of medium.…”

Exploring the enzymatic degradation of poly(glycerol adipate)

“…Previously, the release of methotrexate from a PGA-drug conjugate has been studied in the presence of porcine carboxylesterase. The enzyme was seen to increase the release of methotrexate compared with buffer alone over a period of seven days [12]. This work suggested the polymer was susceptible to enzymatic degradation but did not focus on the nature of this degradation in detail or examine the degradation products.…”

“…Previously, this has been demonstrated through functionalisation of PGA with N-acyl amino acids via Steglich Esterification [8]. Additionally, the drug molecules indomethacin [11], methotrexate [12] and ibuprofen [13] have been successfully coupled to the polymer backbone. The low toxicity of PGA coupled with the ease with which it can be synthesised, functionalised with drug molecules and formulated into nanoparticles means it shows great potential as a polymeric platform for both targeted and systemic drug delivery.…”

Starch/Poly (Glycerol-Adipate) Nanocomposite Film as Novel Biocompatible Materials

“…The reaction temperature is optimally performed at 50 • C to produce a highly linear polymer backbone motif with negligible branching [14][15][16][17]. Since the hydroxyl moieties are positioned in the outer shell of the nanoparticles (NPs), PGA will create low-force interactions with starch.…”