Journal
MOLECULAR PHARMACEUTICS
Volume 11, Issue 5, Pages 1651-1661Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp5000373
Keywords
cross-linked multilamellar liposomal vesicle; combination therapy; doxorubicin; paclitaxel; synergy; dose ratios; nanomedicine
Funding
- National Institutes of Health grants [R01AI068978, R01CA170820, P01CA132681]
- Joint Center for Translational Medicine
- National Cancer Institute [P30CA014089]
- Ming Hsieh Institute for Research on Engineering Medicine for Cancer
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Combining chemotherapeutics is a promising method of improving cancer treatment; however, the clinical success of combination therapy is limited by the distinct pharmacokinetics of combined drugs, which leads to nonuniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single cross-linked multilamellar liposomal vesicle (cMLV) to precisely control the drug ratio that reaches the tumor in vivo. The stability of cMLVs improves the loading efficiency and sustained release of doxorubicin (Dox) and paclitaxel (PTX), maximizing the combined therapeutic effect and minimizing the systemic toxicity. Furthermore, we show that the cMLV formulation maintains specific drug ratios in vivo for over 24 h, enabling the ratio-dependent combination synergy seen in vitro to translate to in vivo antitumor activity and giving us control over another parameter important to combination therapy. This combinatorial delivery system may provide a new strategy for synergistic delivery of multiple chemotherapeutics with a ratiometric control over encapsulated drugs to treat cancer and other diseases.
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