Ho T, Guidolin K, Makky A, Valic M, Ding L, Bu J, Zheng M, Cheng MHY, Yau J, Chen J, Zheng G

Angewandte Chemie

DOI: 10.1002/anie.202218218

Nanoparticles’ uptake by cancer cells upon reaching the tumor microenvironment is often the rate-limiting step in cancer nanomedicine. Herein, we report that the inclusion of aminopolycarboxylic acid conjugated lipids, such as EDTA- or DTPA hexadecylamide lipids in liposome-like porphyrin nanoparticles (PS) enhanced their intracellular uptake by 25-fold, which was attributed to these lipids’ ability to fluidize the cell membrane in a detergent-like manner rather than by metal chelation of EDTA or DTPA. EDTA-lipid incorporated-PS (ePS) take advantage of its unique active uptake mechanism to achieve >95% photodynamic therapy (PDT) cell killing compared to <5% cell killing by PS. In multiple tumor models, ePS demonstrated fast fluorescence-enabled tumor delineation within minutes post-injection and increased PDT potency (100% survival rate) compared to PS (60%). This study offers a new nanoparticle cellular uptake strategy to overcome challenges associated with conventional drug delivery.