Phenylboronic Acid Functionalized Resveratrol-based Nanomedicines with Enhanced Targeting for Synergistic Chemo-Photothermal Breast Cancer Therapy

Abstract

The combined application of photothermal therapy (PTT) and chemotherapy (CT) has emerged as a focal area to seek novel nanomedicines for enhanced cancer therapy.To date, there are burgeoning efforts directed toward the development of different carriers for codelivery of chemotherapeutic drugs and photosensitizers to give rise to potent anticancer nanomedicines with synergistic effects. Herein, phenylboronic acid-functionalized resveratrol (Res) oligomers were synthesized as nanocarriers in organic solvent via a Mannich condensation and with the addition of water, Res-based nanomedicines containing doxorubicin (Dox) and IR780 were conveniently achieved.3-Aminophenylboronic acid (3AP) and 4-Aminophenylboronic acid pinacol ester (4APE) were applied to prepare two kinds of nanomedicines, RsvDI and RevDI NPs. Physicochemical characterization revealed that both RsvDI and RevDI NPs exhibited spherical morphology, uniform particle size distribution, good colloidal stability, high encapsulation efficiency, and drug loading capacity. Photothermal performance evaluation confirmed that both nanomedicine formulations possessed excellent photothermal conversion efficiency. In vitro release studies demonstrated that Dox release was significantly enhanced under irradiation and acidic conditions, with RevDI NPs showing superior drug release kinetics. Cytotoxicity assays demonstrated that the active Res nanocarriers effectively inhibited the proliferation of multiple cancer cell lines while preserving the therapeutic efficacy of the encapsulated drugs.Cell uptake experiments further validated that both nanomedicines were efficiently internalized by tumor cells through the sialic acid-phenylboronic acid targeting mechanism and RevDI NPs, owing to their higher density of PBA groups, exhibited a better target enrichment effect. Animal studies demonstrated that the Res-based nanomedicines significantly enhanced the anti-cancer effects through the chemo-photothermal synergy, particularly RevDI NPs. The comparison using protected and unprotected PBA groups not only deepens the understanding of protective group mechanisms in nanocarrier design but also provides crucial experimental support for developing highly efficient and low-toxicity targeted nanomedicines.