Subcutaneous delivery of nanoconjugated doxorubicin and cisplatin for locally advanced breast cancer demonstrates improved efficacy and decreased toxicity at lower doses than standard systemic combination therapy in vivo

• Published in: The American journal of surgery 2011-12, Vol.202 (6), p.646-653
• Main Authors: Cohen, Stephanie M., M.D, Mukerji, Ridhwi, M.D, Cai, Shuang, Ph.D, Damjanov, Ivan, M.D., Ph.D, Forrest, M. Laird, Ph.D, Cohen, Mark S., M.D., F.A.C.S
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Biocompatibility; Breast cancer; Cancer; Cancer therapies; Cisplatin; Cisplatin - administration & dosage; Combination chemotherapy; Cytotoxic agents; Cytotoxicity; Disease Progression; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - administration & dosage; Drug delivery; Drug Delivery Systems; Drug therapy; Drug Therapy, Combination; Drugs; Effectiveness; Female; Humans; Hyaluronic acid; In vivo methods and tests; Injections, Subcutaneous; Locoregional therapy; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Maximum Tolerated Dose; Mice; Mice, Nude; Multivariate analysis; Nanocarriers; Nanostructure; Surgery; Therapy; Toxicity; Treatment Outcome; Variance analysis; Weight loss
• ISSN: 0002-9610; 1879-1883
• DOI: 10.1016/j.amjsurg.2011.06.027

Abstract Background Combination cytotoxic agents in breast cancer carry dose-limiting toxicities. The aim of this study was to test the hypothesis that nanocarrier-conjugated doxorubicin and cisplatin would have improved tumor efficacy with decreased systemic toxicity over standard drugs, even at lower doses. Methods Female Nu/Nu mice were injected in the breast with human MDA-MB-468LN cells and treated with either standard or nanocarrier-conjugated combination therapy (doxorubicin plus cisplatin) at 50% or 75% maximum tolerated dose (MTD) and monitored for efficacy and toxicity over 12 weeks. Results Efficacy results for mice treated with hyaluronan-conjugated doxorubicin and cisplatin at 50% MTD were as follows: 5 complete responses, 2 partial responses, and 1 case of stable disease. For hyaluronan-conjugated doxorubicin and cisplatin at 75% MTD, efficacy results were as follows: 7 complete responses, 1 partial response. All complete responses were confirmed histologically. In comparison, mice given standard doxorubicin and cisplatin at 50% MTD demonstrated progressive disease in 6, stable disease in 1, and partial response in 1. For standard doxorubicin and cisplatin at 75% MTD, there were 5 cases of progressive disease and 3 of stable disease ( P < .0001 on multivariate analysis of variance). At 75% MTD, standard drug–treated mice had significant weight loss compared to nanocarrier drug–treated mice ( P < .001). Conclusions Subcutaneous nanocarrier delivery of doxorubicin and cisplatin demonstrated significantly improved efficacy with decreased toxicity compared with standard agent combination therapy at all doses tested, achieving complete pathologic tumor response.