Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 83, Issue -, Pages 79-87Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2015.12.019
Keywords
Paclitaxel; Pharmacokinetics; Biodistribution; Antitumor efficiency; Safety
Categories
Funding
- National Natural Science Foundation of China [81102397]
- Natural Science Foundation of Jiangsu Province [BK2012761]
- Qing Lan Project of Jiangsu Province [02432009]
- Innovative Project for Graduate Cultivation of Jiangsu Province [CXZZ11-0807]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGQ201107, JKPZ2013004]
- Ministry of Science and Technology of China [2009ZX09310004]
- Fostering Plan of University Scientific & Technological Innovation Team of Jiangsu Qing Lan Project
- National Basic Research Program of China (973 Program) [2009CB903300]
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Since its approval by the FDA, Abraxane(TM) has been established as a clinical standard of paclitaxel (PTX)-based therapy against a variety of cancers. Despite success, Abraxane(TM) 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 (TM). 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 (R) 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 (R) 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 (R) 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. (C) 2015 Elsevier B.V. All rights reserved.
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