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

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• 作者：Sandani Samarajeewa ; Ritu Shrestha ; Mahmoud Elsabahy ; Amolkumar Karwa ; Ang Li ; Ryan P. Zentay ; James G. Kostelc ; Richard B. Dorshow ; Karen L. Wooley
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：March 4, 2013
• 年：2013
• 卷：10
• 期：3
• 页码：1092-1099
• 全文大小：438K
• 年卷期：v.10,no.3(March 4, 2013)
• ISSN：1543-8392

文摘

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 in vitro 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 ca. 65% cumulative drug release after 8 d, whereas only ca. 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 ca. 30% of the poly(lactic acid) core to lactic acid within 12 h, with coincidently triggered paclitaxel release of ca. 37%, as opposed to only ca. 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 ICb>50b> values that were similar to those of free paclitaxel at 72 h incubation with KB cells and were more efficacious at ca. 3-fold lower ICb>50b> value (0.031 渭M vs 0.085 渭M) at 2 h of incubation. Against human ovarian adenocarcinoma cells, the paclitaxel-loaded nanoparticles exhibited a remarkable ca. 11-fold lower ICb>50b> than a Taxol-mimicking formulation (0.0007 渭M vs 0.008 渭M) at 72 h of incubation. These tunable dual-responsive degradable nanoparticles show great promise for delivery of paclitaxel to tumor tissues, given their superior in vitro efficacies compared to that of free paclitaxel and Taxol-mimicking formulations.<br>

Keywords:

paclitaxel; degradable; poly(dl-lactic acid); poly(dl-lactide); cell viability; disulfide cross-linker; polymeric nanoparticles