Biological evaluation of PEG modified nanosuspensions based on human serum albumin for tumor targeted delivery of paclitaxel

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• 作者：Tingjie Yin^a ; ¹ ; Han Cai^a ; ¹ ; Jiyong Liu^b ; Bei Cui^a ; Lei Wang^a ; Lifang Yin^a ; Jianping Zhou^a ; ^{cpu_zhoujp@163.com" class="auth_mail" title="E-mail the corresponding author} ; Meirong Huo^a
• 关键词：Paclitaxel ; Pharmacokinetics ; Biodistribution ; Antitumor efficiency ; Safety
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：83
• 期：Complete
• 页码：79-87
• 全文大小：1190 K

文摘

Since its approval by the FDA, Abraxane™ has been established as a clinical standard of paclitaxel (PTX)-based therapy against a variety of cancers. Despite success, Abraxane™ is still limited by suboptimal biodistribution, unfavorable pharmacokinetics and chronic toxicities from chloroform used during preparation. Accordingly, a PTX-loaded nanosuspension based on human serum albumin (HSA) with PEG modifiers (PTX-PEG-HSA) has been developed to optimize the in-vivo biodistribution, pharmacokinetics and safety of PTX over traditional PTX-HSA nanosuspensions prepared using the accepted method for Abraxane™. Results of in-vivo pharmacokinetic (PK) studies indicated PTX-PEG-HSA achieved prolonged blood circulation, illustrated by an 8.8-fold and 4.8-fold increase in area-under-the-curve (AUC) of PTX over Taxol® and PTX-HSA, while the mean residence time (MRT) of PTX in PTX-PEG-HSA was increased by 3.2-fold and 1.5-fold, respectively. HSA mediated active targeting further suppressed non-specific distribution of PTX to normal tissues, which permitted enhanced antitumor efficacy in S180 mice over Taxol® and PTX-HSA. Safety of intravenously administered PTX-PEG-HSA was confirmed through lower hemolytic activity, a 2.2-fold and 1.2-fold increase in LD₅₀ (113.4 mg/kg) over Taxol® and PTX-HSA alongside the absence of local venous irritation. Studies herein suggest the therapeutic and clinical applicability of PTX-PEG-HSA for tumor specific therapy.