Polymer–lipid hybrid nanoparticles synchronize pharmacokinetics of co-encapsulated doxorubicin–mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast tumor

Effective combination chemotherapy requires the delivery of drugs of synergism to tumor sites while sparing normal tissues. Herein we investigated whether coencapsulation of doxorubicin and mitomycin C within polymer–lipid hybrid nanoparticles (DMPLN) achieved this goal via ratiometric drugs in an orthotopic murine breast tumor model with nanocarrier-modified biodistribution, pharmacokinetics, local bioavailability and toxicity. Fluorescence imaging revealed quickened and extended tumor uptake but reduced cardiac accumulation of DMPLN. Quantitative drug analysis demonstrated prolonged systemic circulation, increased tumor accumulation and sustained synergistic ratios of doxorubicin and mitomycin C delivered by DMPLN over 24 h. Higher levels of tumor cell apoptosis and reduced organ toxicity were obtained with DMPLN compared to free drug cocktails. DMPLN released DOX in tumors more efficiently than that from liposomal doxorubicin, as evidenced by a higher extent of the metabolite, doxorubicinol. These findings substantiate the importance of rational design of nanoparticles for synergistic drug combination therapy.From the Clinical EditorThe treatment of cancer usually involves using combination chemotherapeutic agents. In adopting a nanomedicine approach, one can in theory design combination therapy consisting of drugs of synergistic activities, with the aim to target tumor specifically while minimizing systemic toxicity. The authors in this study provided evidence for this rational design by co-encapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) in a breast cancer model.

The success of combination chemotherapy requires precise delivery of synergistic drugs to cancer cells while sparing normal tissues. Here we demonstrated that co-encapsulating doxorubicin and mitomycin C within polymer–lipid hybrid nanoparticles (DMPLN) altered their biodistribution, pharmacokinetics, and toxicity profiles. DMPLN prolonged systemic circulation, increased accumulation, and maintained synergistic molar ratios of doxorubicin and mitomycin C within tumors, leading to significantly enhanced antitumor efficacy as compared to co-administrated free drugs. DMPLN also dramatically reduced toxic metabolite of doxorubicin and drug associated organ toxicity.Figure optionsDownload high-quality image (208 K)Download as PowerPoint slide