Core cross-linked polyphosphoester micelles with folate-targeted and acid-cleavable features for pH-triggered drug delivery

To prevent the disassembly of drug-loaded micelles under the high dilution conditions of the bloodstream, one of the efficient methods is to achieve the cross-linkage inside the micellar core. In this study, we have developed a kind of novel folate-conjugated core cross-linked polyphosphoester micelle with acid-cleavable acetal groups (ACCL-FA). These polyphosphoester-based cross-linked micelles possessed a much smaller size and enhanced stability compared to the uncross-linked (UCL) counterpart, and also showed good biodegradability and low cytotoxicity. The in vitro release studies revealed that the doxorubicin (DOX)-loaded ACCL micelles showed excellent stability with minimal drug release under neutral conditions, and displayed fast micellar dissociation and drug release in the presence of acid or phosphodiesterase I (PDE I). Moreover, with the comparison of the in vitro antitumor activity for free DOX, the DOX-loaded ACCL micelles, the DOX-loaded ACCL-FA micelles and the DOX-loaded folate-conjugated acid-insensitive cross-linked (CCL-FA) micelles, it could be found that the DOX-loaded ACCL-FA micelles exhibited higher inhibition of the proliferation of KB cells. In addition, these FA-decorated ACCL micelles showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated core cross-linked biodegradable micelles are highly promising for targeted cancer chemotherapy.