Self-Delivered Nanomedicines for Cancer Photodynamic Therapy and Immunotherapy

自遞送納米葯用於癌的光動力治療和免疫治療

Student thesis: Doctoral Thesis

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Award date17 Jun 2020

Abstract

Cancer is one of the most important threats to harm human health. Self-delivered nanomedicines for cancer therapy have shown great advantages in improving therapeutic efficacy and reducing side effects. At present, main treatments for cancer are surgery, chemotherapy and radiotherapy. However, these therapies have high recurrence rate and often strong side-effects. Photodynamic therapy (PDT) is a non-invasive therapy, with tumor targeting and can be applied repeatedly with no drug resistance. Immunotherapy is methods to stimulate and enhance the body's immune response to kill tumor cells and inhibit tumor growth. Developing immunotherapy and its combined therapy for enhancing treatment efficiency of tumor needs to be solved urgently in this field. In this thesis, our work focused on three aspects:

Firstly, monoclonal antibodies targeting the programmed cell death receptor and its ligand (PD-1/PD-L1) pathway have achieved recent clinical success in antitumor therapy, but the therapeutic antibodies exhibit several issues such as limited tumor penetration, immunogenicity, and costly production. With Bristol-Myers Squibb (BMS) patented chemical compound we prepared small molecule BMS-202 nanoparticles (NPs) using a reprecipitation method. The nanoparticles have advantages including passive targeting, hydrophilic and nontoxic features, and a high drug loading rate. BMS-202 is a small-molecule inhibitor of PD-1/PD-L1 interaction. Treating 4T1 tumor-bearing mice with BMS-202 NPs resulted in markedly slower tumor growth to the same degree as treatment with anti-PD-L1 monoclonal antibody (α-PD-L1). Consistently, the combination of Ce6 NPs with BMS-202 NPs or α-PD-L1 in parallel shows more efficacious antitumor and antimetastatic effects, accompanied by enhanced dendritic cell maturation and infiltration of antigen-specific T cells into the tumors. Thus, inhibition rates of primary and distant tumors reach > 90%. In addition, BMS-202 NPs are able to attack spreading metastatic lung tumors and offer immune-memory protection to prevent tumor relapse. These results indicate that BMS-202 NPs possess effects similar to α-PD-L1 in the therapies of 4T1 tumors. Therefore, this work reveals the possibility of replacing the antibody used in immunotherapy for tumors with BMS-202 NPs.

Secondly, the above results demonstrate for the first time that small molecule BMS-202 inhibitor can indeed be used for suppressing the PD-1/PD-L1 interaction in vivo, practical applications of such small molecule PD-1/PD-L1 inhibitors would obviously require more than a single example. Exploring more effective small molecule PD-1/PD-L1 inhibitors as well as relationship between structure and effect remains an important and urgent task. Therefore, we prepared water dispersible nanoparticles of four BMS small molecules (BMS-1, BMS-8, BMS-202 and BMS-1166) which were claimed to be able to be potentially useful for inhibiting the PD-1/PD-L1 interactions in vivo. Using these nanoparticles, we carried out the first systematic comparison of different small molecule PD-1/PD-L1 inhibitors for their cancer immunotherapy performance in vivo. Their performance differences are explained via their molecular structure differences. BMS-1 NPs was found to have the best performance and more importantly, for the first time, we show that the tumor inhibition rate of a small molecule PD-1/PD-L1 inhibitor (BMS-1, 70.3%) can considerably surpass that of α-PD-L1 antibody (62.9%). Based on the impressive immune checkpoint blockage (ICB) performance of BMS-1 NP, we further combine it with R837 nanoadjuvant to reverse immunosuppressive tumor microenvironment (TME) during cancer photodynamic immunotherapy. The combined therapy of BMS-1 NPs based ICB and R837 augmented PDT induced both upregulation of tumor-antagonizing immune cells such as CD8+ killer T cells, dendritic cells, and M1 macrophages as well as downregulation of tumor-promoting immune cells including marrow-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2 macrophages in the TME. This new approach demonstrates a tumor inhibition rate of 100% for primary tumor and a strong abscopal effect. A long-term immunological memory function can be generated to protect against tumor re-challenge after elimination of the initial tumors.

Finally, in PDT for tumor, the tissue penetration depth of light and the singlet oxygen (1O2) generation efficiency of photosensitizers (PSs) are the two main factors that determine the effectiveness of PDT. Therefore, we report a novel strategy to prepare a multifunctional upconversion nanophotosensitizer (UCPS) based on the host/guest nanoarchitecture. By a simple reprecipitation method, host/guest tetracene/pentacene nanorods (Tc/Pc NRs) were synthesized for enhancing triplet-triplet annihilation-upconversion (TTA-UC) or two-photon excited (TPE) emission and 1O2 generation efficiency upon 650 or 808 nm excitation. Tc/Pc NRs had higher 1O2 quantum yield (74%) than Tc NRs (28%) upon 650 nm laser irradiation. Proposed mechanism is that doping Pc molecules into Tc NRs induces “intermediate” states between S0 and S1, shortening the energy gap for more effective 1O2 generation and resulting in TTA-UC emission. Equally important, with 808 nm femtosecond (fs) laser excitation, Tc/Pc NRs showed an enhanced 1O2 generation efficiency. In addition, when the tumors in mice were exposed to the Tc/Pc NRs with 650 or 808 nm wavelength irradiation, the tumor inhibition rates achieved 99 % and 95 %, respectively. This work opens new perspectives for exploring novel nano UCPSs for biomedical applications.