Photodynamic Therapy With Multi-Tasking Upconversion Nanoparticles In Combination With Immunotherapy Of Cancer

Recently,the combination of multiple therapeutic approaches has become one of the key strategies for cancer treatment.Photodynamic therapy(PDT),as an effective therapeutic approach,can kill cancer cells by utilizing photosensitizers to generate reactive oxygen species.Moreover,it has been reported that PDT can also promote tumor-specific immune responses.However,conventional PDT triggered by visible light has limited penetration depth,and PDT-triggered immune responses are not usually robust enough to eliminate tumors.Given the unique near-infrared(NIR)absorption property of upconversion nanoparticles(UCNPs)and aiming at employing NIR-triggered deep PDT to trigger effective cancer immunotherapy,herein,we design a multifunctional UCNP-based platform by co-loading chlorin e6(Ce6),a photosensitizer,and imiquimod(R837),a Toll-like-receptor-7(TLR-7)agonist as an immune adjuvant,onto polymer-coated UCNPs.In this work,we explored the immune response triggered by UCNP-Ce6-R837-based PDT and the combination with immunotherapy.The research results are as follows:1.Upconversion nanoparticles(UCNPs)are simultaneously loaded with Ce6 and R837.The obtained multi-tasking UCNP-Ce6-R837 nanoparticles under NIR irradiation with enhanced tissue penetration depth would enable effective photodynamic destruct of tumors to generate a pool of tumor-associated antigens,which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses.2.More significantly,PDT with UCNP-Ce6-R837 in combination with the cytotoxic T-lymphocyte-associated protein 4(CTLA-4)checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser,but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment.Furthermore,such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell re-challenging.3.After PDT treatment,the released tumor-associated antigens with the assistance by R837-containing UCNPs as immune-adjuvants could amply the anti-tumor immune responses.Meanwhile,anti-CTLA4 antibody would effectively hamper the immune-suppression activity of the Treg cells and increase the ratio of CTLs to Treg cells,favorable for promoting anti-tumor cellular immunity to attack tumors.This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA4 checkpoint-blockade,so as to effectively destruct primary tumors under light exposure,inhibit distant tumors that can hardly be reached by light,and prevent tumor re-occurrence via the immune memory effect.