Functional Choline Phosphate Lipids for Enhanced Drug Delivery in Cancer Therapy

Liposome formulations by zwitterionic lipids (e.g., phosphatidyl choline (PC)) have been widely applied in the clinical translation of nanomedicines. However, poor bioorthogonality in the PC lipid backbone and limited cellular uptake potency significantly impede the development of a therapeutic strategy. Herein, we synthesized a novel bioorthogonal zwitterionic lipid named choline phosphate (CP), with reversed PC charge orientation via a phospholane derivative ring-opening reaction. CP lipids can assemble into liposomes with excellent biocompatibility and stable physical and chemical properties similar to PC liposomes. Due to supramolecular ionic pair interactions with the cell membrane, doxorubicin (Dox)-loaded CP liposomes (CP-Dox) were preferentially taken up and accumulated in cells compared to PC-Dox, which significantly enhanced the cytotoxicity in cancer cells and inhibited tumor growth. Furthermore, we determined the bioorthogonality of the CP lipids by conjugating folate in situ using a "click" reaction, which showed specificity in targeting treatment for breast cancer. Our studies provide a new proof of concept that functional liposomes can be designed at the molecular level. We also expect that CP lipids may have potential in other applications, including biosensors, antifouling coatings, cell membrane mimetic engineering, and artificial cells.