Anti-HER2 immunoliposomes: Enhanced efficacy attributable to targeted delivery

被引:0
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作者
Park, JW
Hong, KL
Kirpotin, DB
Colbern, G
Shalaby, R
Baselga, J
Shao, Y
Nielsen, UB
Marks, JD
Moore, D
Papahadjopoulos, D
Benz, CC
机构
[1] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA
[3] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94115 USA
[4] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
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R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Anti-HER2 immunoliposomes combine the tumor-targeting of certain anti-HER2 monoclonal antibodies (MAbs) with the pharmacokinetic and drug delivery capabilities of sterically stabilized liposomes. We previously showed that anti-HER2 immunoliposomes bind efficiently to and internalize in HER2-overexpressing cells in vitro, resulting in intracellular drug delivery. Experimental Design: Here we describe the pharmacokinetics and therapeutic efficacy of anti-HER2 immunoliposomes containing doxorubicin (dox) in a series of animal models. Results: Immunoliposomes displayed long circulation that was identical to that of sterically stabilized liposomes in single- and multiple-dose studies in normal rats. Anti-HER2 immunoliposome-dox produced marked therapeutic results in four different HER2-overexpressing tumor xenograft models, including growth inhibition, regression, and cures. These results demonstrated that encapsulation of dox in anti-HER2 immunoliposomes greatly increased its therapeutic index, both by increasing antitumor efficacy and by reducing systemic toxicity. Immunoliposome-dox was significantly superior to all other treatment conditions tested, including free dox, liposomal dox, and anti-HER2 MAb (trastuzumab). When compared with liposomal dox in eight separate therapy studies in HER2-overexpressing models, immunoliposome delivery produced significantly superior antitumor efficacy in each study (P < 0.0001 to 0.04). Anti-HER2 immunoliposome-dox containing either recombinant human MAb HER2-Fab' or scFv C6.5 yielded comparable therapeutic efficacy. Cure rates for immunoliposome-dox reached 50% (11 of 21) with optimized inmunoliposomes and Matrigel-free tumors and overall was 16% (18 of 115) versus no cures (0 of 124) with free dox or liposomal dox. Finally, anti-HER2 immunoliposome-dox was also superior to combinations consisting of free MAb plus free dox or free MAb plus liposomal dox. Conclusions: Anti-HER2 immunoliposomes produced enhanced antitumor efficacy via targeted delivery.
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页码:1172 / 1181
页数:10
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