Codelivery of Doxorubicin and Paclitaxel By Crosslinked Multilamellar Liposome Enables Synergistic Antitumor Activity

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 non-uniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single crosslinked 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 hours, 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. Moreover, this delivery approach significantly overcomes MDR by reducing the expression of P-glycoprotein (P-gp) in cancer cells, thus improving antitumor activity in vivo. 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.