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

Abstract

Background—Combination cytotoxic agents in breast cancer carry dose-limiting toxicities. We hypothesize that nanocarrier-conjugated doxorubicin and cisplatin will 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 +cisplatin) at 50% or 75% MTD, and monitored for efficacy and toxicity over 12-weeks.

Results—Efficacy results for mice treated with HA-conjugated doxorubicin/cisplatin at 50% MTD include:[complete responses(CR)=5, partial responses(PR)=2, and stable disease(SD)=1]and for HA-conjugated dox/cis at 75% MTD:[CR=7,PR=1; all CR’s confirmed histologically]. In comparison, mice given standard dox/cis(50% MTD)demonstrated:[progressive disease(PD)=6, SD=1, and PR=1] and for standard dox/cis(75% MTD):[PD=5,SD=3; p<0.0001 on multivariate ANOVA]. At 75% MTD, standard drug-treated mice had significant weight loss compared to nanocarrier drug-treated mice(p<0.001).

Conclusion—Subcutaneous nanocarrier-delivery of doxorubicin and cisplatin demonstrated significantly improved efficacy with decreased toxicity compared to standard agent combination therapy at all doses tested achieving complete pathologic tumor response.