Ratiometric co-delivery of multiple chemodrugs in a single nanocarrier

Co-delivery of multiple anti-cancer drugs in a single nanoplatform has shown great promise in enhancing therapeutic efficacy and reducing adverse effects. However, the ratiometric dose control is pivotal, but often challenging in combinational nanomedicine. Here, we report the employment of cyclodextrin-bearing amphiphilic polymer conjugate micelles for ratiometric, non-covalent loading of three hydrophobic model drugs, curcumin (CUR), camptothecin (CPT), and doxorubicin (DOX) in one single nanocarrier. Each drug was physically encapsulated in the cyclodextrin-bearing polymer conjugate via guest-host complexation. All three drugs displayed a 1: 1 complexation behavior with the cyclodextrin, which corresponded to a drug loading of 6.0 +/- 0.1% (CUR), 7.5 +/- 0.1% (CPT), and 9.0 +/- 0.1% (DOX) (w/w). The apparent association constant between the conjugate and drug was 2803.7 +/- 87.0 (CUR), 3699.4 +/- 123.3 (CPT), and 6760.9 +/- 176.3 (DOX), respectively. Ratiometric co-assembly of three types of drug-loaded conjugates produced mixed micelles in a dose-and ratio-controlled manner. The hydrodynamic diameter of co-assembled spherical micelles was ca. 150 nm that was similar to the single-drug loaded micelles. The ratiometric co-delivery of three drugs via mixed micelles was demonstrated both in HepG2 cells in vitro and in a mice model in vivo compared to a mixture of free drugs, as evidenced by co-localization analysis. This work provides a facile way to realize ratiometric co-administration of multiple drugs.