A minimalist dendrimer nanodrug for autophagy inhibition-amplified tumor photothermo-immunotherapy

Development of a powerful photothermal agent to exert combinational photothermo-immunotherapy of tumors through autophagy inhibition remains challenging. Herein, we report an indocyanine green (ICG)modified dendrimer nanomedicine formulation encapsulated with an autophagy inhibitor chloroquine (CQ) for synergistic autophagy inhibition-enhanced photothermo-immunotherapy. Poly(amidoamine) dendrimers of generation 5 (G5) were covalently conjugated with ICG, full acetylated to neutralize their remaining amine termini, and physically loaded with CQ. The created G5. NHAc-ICG/CQ (GIC) complexes display desired colloidal stability, cytocompatibility and photothermal conversion efficiency (39.7%), and can induce apoptosis and immunogenic cell death of cancer cells under laser irradiation in coordination with autophagy inhibition, thereby promoting maturation of dendritic cells and subsequent tumoral infiltration of activated CD4+/CD8+ T cells. The incorporated autophagy inhibitor CQ also enhances the antitumor efficacy through NF-& kappa;B pathway activation to remodel the tumor microenvironment through repolarization of the tumor-associated macrophages to anti-tumor M1 type. With the combination of programmed cell death ligand 1 antibody-elicited immune check-point blockade, the developed GIC nanodrug enables effective restriction of the growth of both primary and distal tumors with amplified antitumor immune response. The developed GIC nanodrug with the minimalist composition displays a promising translation potential for autophagy inhibition-enhanced photothermo-immunotherapy of different tumor types.

Automated summary

In this study, an indocyanine green (ICG) modified dendrimer nanomedicine loaded with an autophagy inhibitor chloroquine (CQ) was developed for enhanced photothermo-immunotherapy. The G5.NHAc-ICG/CQ (GIC) complexes showed good stability, cytocompatibility, and high photothermal conversion efficiency. Under laser irradiation, the GIC complexes inhibited autophagy, induced apoptosis and immunogenic cell death, promoted dendritic cell maturation and the infiltration of activated CD4+/CD8+ T cells into tumors.