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

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

<i>In Vitro</i> Efficacy of Paclitaxel-Loaded Dual-Responsive Shell Cross-Linked Polymer Nanoparticles Having Orthogonally Degradable Disulfide Cross-Linked Corona and Polyester Core Domains

Paclitaxel-loaded shell cross-linked polymeric nanoparticles having an enzymatically and hydrolytically degradable poly­(lactic acid) core and a glutathione-responsive disulfide cross-linked poly­(oligoethylene glycol)-containing corona were constructed in aqueous solution and investigated for their stimuli-responsive release of the embedded therapeutics and <i>in vitro</i> cytotoxicity. Paclitaxel release from the nanoparticles in PBS buffer was accelerated in the presence of glutathione at both pH 5.5 and pH 7.4, reaching <i>ca</i>. 65% cumulative drug release after 8 d, whereas only <i>ca</i>. 50% and 35% extents of release were observed in the absence of glutathione at pH 5.5 and pH 7.4, respectively. Enzyme-catalyzed hydrolysis of the nanoparticle core resulted in the degradation of <i>ca</i>. 30% of the poly­(lactic acid) core to lactic acid within 12 h, with coincidently triggered paclitaxel release of <i>ca</i>. 37%, as opposed to only <i>ca</i>. 17% release from the uncatalyzed nanoparticles at pH 7.4. While empty nanoparticles did not show any inherent cytotoxicity at the highest tested concentrations, paclitaxel-loaded nanoparticles showed IC₅₀ values that were similar to those of free paclitaxel at 72 h incubation with KB cells and were more efficacious at <i>ca</i>. 3-fold lower IC₅₀ value (0.031 μM vs 0.085 μM) at 2 h of incubation. Against human ovarian adenocarcinoma cells, the paclitaxel-loaded nanoparticles exhibited a remarkable <i>ca</i>. 11-fold lower IC₅₀ than a Taxol-mimicking formulation (0.0007 μM vs 0.008 μM) at 72 h of incubation. These tunable dual-responsive degradable nanoparticles show great promise for delivery of paclitaxel to tumor tissues, given their superior <i>in vitro</i> efficacies compared to that of free paclitaxel and Taxol-mimicking formulations