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Single-Antibody, Targeted Nanoparticle Delivery of Camptothecin

Han, Han and Davis, Mark E. (2013) Single-Antibody, Targeted Nanoparticle Delivery of Camptothecin. Molecular Pharmaceutics, 10 (7). pp. 2558-2567. ISSN 1543-8384. PMCID PMC3795804. doi:10.1021/mp300702x.

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We have developed a new method for assembling targeted nanoparticles that utilizes the complexation between targeting agents that contain boronic acids and polymer–drug conjugates that possess diols. Here, we report the first in vivo, antitumor results of a nanoparticle formed via this new assembly methodology. A nanoparticle consisting of a mucic acid polymer conjugate of camptothecin (CPT), MAP–CPT, and containing on average one Herceptin antibody is investigated in nude mice bearing HER2 overexpressing BT-474 human breast cancer tumors. Nontargeted MAP–CPT and antibody-containing MAP–CPT nanoparticles of ca. 30–40 nm diameter and slightly negative zeta potential show prolonged in vivo circulation and similar biodistributions after intravenous tail vein injections in mice. The maximum tolerated dose (MTD) of the nontargeted and Herceptin-containing MAP–CPT nanoparticles is found to be 10 and 8 mg of CPT/kg, respectively, in mice. Mice bearing BT-474 human breast tumors treated with nontargeted MAP–CPT nanoparticles at 8 mg of CPT/kg show significant tumor growth inhibition (mean tumor volume of 63 mm3) when compared to irinotecan at 80 mg/kg (mean tumor volume of 575 mm3) and CPT at 8 mg/kg (mean tumor volume of 808 mm3) at the end of the study. Herceptin antibody treatment at 5.9 mg/kg results in complete tumor regressions in 5 out of 8 mice, with a mean tumor volume of 60 mm3 at the end of the study. Mice treated with MAP–CPT nanoparticles at 1 mg of CPT/kg do not show tumor inhibition. However, all mice receiving administrations of MAP–CPT nanoparticles (1 mg of CPT/kg) that contain on average a single Herceptin molecule per nanoparticle (5.9 mg of Herceptin equivalent/kg) show complete tumor regression by the end of the study. These results demonstrate that the antitumor efficacy of nanoparticles carrying anticancer drugs can be enhanced by incorporating on average a single antibody.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2013 American Chemical Society. Received: December 11, 2012; Revised: May 8, 2013; Accepted: May 15, 2013; Published: May 15, 2013. We thank Leonard Medrano, Aaron Gale, and Devin Wiley for assistance with animal work, tumor processing, and confocal microscopy, respectively. This project was financially supported by National Cancer Institute Grant CA 151819.
Funding AgencyGrant Number
NIHCA 151819
National Cancer InstituteUNSPECIFIED
Subject Keywords:targeted nanoparticles; Herceptin; camptothecin; antitumor efficacy; biodistribution
Issue or Number:7
PubMed Central ID:PMC3795804
Record Number:CaltechAUTHORS:20130809-092706142
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Official Citation:Single-Antibody, Targeted Nanoparticle Delivery of Camptothecin Han Han and Mark E. Davis Molecular Pharmaceutics 2013 10 (7), 2558-2567
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39830
Deposited By: Tony Diaz
Deposited On:09 Aug 2013 16:49
Last Modified:09 Nov 2021 23:47

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