Controlled co-delivery nanocarriers based on mixed micelles formed from cyclodextrin-conjugated and cross-linked copolymers.

The combination of multiple drugs within a single nanocarrier can provide significant advantages for disease therapy and it is desirable to introduce a second drug based on host-guest interaction in these co-delivery systems. In this study, a core-stabilized mixed micellar system consisting of β-cyclodextrin-conjugated poly(lactic acid)-b-poly(ethylene glycol) (β-CD-PLA-mPEG) and DL-Thioctic acid (TA) terminated PLA-mPEG (TA-PLA-mPEG) was developed for the co-delivery of DOX and fluorescein isothiocyanate labeled adamantane (FA). DOX can be loaded within the hydrophobic segment of PLA and FA may form stable complexation with β-CD in the core. The mixed micelles (MM) are based on well-accepted medical materials and can be easily cross-linked by adding 1,4-dithio-D,L-threitol (DTT), which can enhance the stability of the system. Drug-loaded MM system was characterized in terms of particle size, morphology, drug loading and in vitro release profile. Cytotoxicity test showed that blank MM alone showed negligible cytotoxicity whereas the drug-loaded MM remained relatively high cytotoxicity for HeLa cancer cells. Confocal laser scanning microscopy (CLSM) demonstrated that the MM could efficiently deliver and release DOX and FA in the same tumor cells to effectively improve drugs' bioavailability. These results suggested that the core-stabilized MM are highly promising for intracellular co-delivery of multiple drugs.