A carrier-free multifunctional nano photosensitizer based on self-assembly of lactose-conjugated BODIPY for enhanced anti-tumor efficacy of dual phototherapy

Abstract Carrier-free multifunctional nano photosensitizers (NPSs) based on amphiphilic small molecules with a single photoactivable motif that combine targeted delivery, tumor microenvironment (TME) responsive release, and dual phototherapy with a single irradiation hold great potential to enhance efficacy, safety, and accuracy of cancer treatment as well as facilitate clinical translation. However, the fabrication of such NPSs is challenging. Herein, we report the synthesis of an amphiphilic small glycosylated BODIPY (BSL) molecule with the ability of self-assembly into NPS (BSL NPS). BSL NPS shows excellent biocompatibility, targetability to HepG2 cells via overexpressed galactose receptors on the cell membrane, and responsiveness to high level of glutathione (GSH) in TME. BODIPY released from intracellular BSL NPS by GSH generated reactive oxygen species and hyperthermia upon irradiation of 685 nm NIR laser resulted in significant enhanced cytotoxicity through the synergy of photodynamic and photothermal therapies. More importantly, in vivo experiments with BSL NPS using HepG2 tumor-bearing nude mice model demonstrated good biosafety, enrichment at tumors, and effective destruction of tumors. This work provides a good example of constructing carrier-free multifunctional NPSs based on one single glycosylated amphiphilic small molecule for dual phototherapy against cancers, which may eventually contribute to bridging the translational gap to the clinic.