Single-antibody, targeted nanoparticle delivery of camptothecin.

Abstract

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 mm(3)) when compared to irinotecan at 80 mg/kg (mean tumor volume of 575 mm(3)) and CPT at 8 mg/kg (mean tumor volume of 808 mm(3)) 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 mm(3) 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.

• Authors: Han Han, Mark E Davis
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 10 Issue 7 Pg. 2558-67 (Jul 01 2013) ISSN: 1543-8392 [Electronic] United States
• PMID: 23676007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal, Humanized
• Drug Carriers
• Polymers
• Sugar Acids
• galactaric acid
• Trastuzumab
• Camptothecin

Topics

• Animals
• Antibodies, Monoclonal, Humanized (chemistry)
• Camptothecin (chemistry)
• Chromatography, High Pressure Liquid
• Drug Carriers (chemistry)
• Female
• Humans
• Mice
• Mice, Nude
• Nanoparticles (chemistry)
• Polymers (chemistry)
• Sugar Acids (chemistry)
• Trastuzumab