期刊
JOURNAL OF CONTROLLED RELEASE
卷 141, 期 1, 页码 13-21出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2009.08.006
关键词
Liposomes; Topotecan; ErbB2; Antibody targeting; Nanoparticles
资金
- NCI NIH HHS [P50 CA058207-150014, R01 CA118919, P50 CA058207] Funding Source: Medline
Topotecan (TPT), a highly active anticancer camptothecin drug, would benefit from nanocarrier-mediated site-specific and intracellular delivery because of a labile lactone ring whose hydrolysis inactivates the drug, poor cellular uptake resulting from both lactone hydrolysis and a titratable phenol hydroxyl, and the schedule-dependency of its efficacy due to its mechanism of action. We have encapsulated topotecan in liposomes using transmembrane gradients of triethylammonium salts of polyphosphate (Pn) or sucroseoctasulfate (SOS). Circulation lifetimes were prolonged, and the rate of drug release in vivo depended on the drug load (T-1/2 = 5.4 h vs. 11.2 h for 124 and 260 g TPT/mol PL, respectively) and the nature of intraliposomal drug complexing agent used to stabilize the nanoliposome formulation (T-1/2 = 11.2 h vs. 27.3 h for Pn and SOS, respectively). Anti-EGFR and anti-HER2-immunoliposomal formulations dramatically increased uptake of topotecan compared to nontargeted nanoliposomal topotecan and poorly permeable free topotecan in receptor-overexpressing cancer cell lines, with a corresponding increase in cytotoxicity in multiple breast cancer cell lines and improved antitumor activity against HER2-overexpressing human breast cancer (BT474) xenografts. We conclude that stabilization of topotecan in nanoliposomes significantly improves the targetability and pharmacokinetic profile of topotecan, allowing for highly active formulations against solid tumors and immunotargeting to cancer-overexpressing cell surface receptors. (C) 2009 Elsevier B.V. All rights reserved.
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