Development of smart optical nanoagents for cancer immunotheranostics

Abstract

Cancer is a complicated and dynamic system composed of tumor cells and stromal cells. These cells crosstalk with each other, which impacts the tumor progression and antitumor therapeutic responses. Tumor immunotherapy, a regimen that uses exogenous immunomodulatory agents to activate endogenous stromal cells of host immunity to combat tumor, has been developed since 1980s. These agents include antibodies and cytokines (such as anti-programmed death ligand 1 antibody), small molecule agents (such as toll-like receptor activator imiquimod), and live cells (such as chimeric antigen receptor-T cell). These agents either directly boost cytotoxic T cells, the main immune fighter on tumor, or improve the immunosuppressive microenvironment to assist T cells activation and maintain their potency. However, current immunotherapy has some key drawbacks such as off-target toxicity, limited patients’ response, and inappropriate therapeutic intervention.

This thesis aimed to discuss nanoplatforms with rational design and precisely controlled therapeutic effects on tumor for augmented antitumor immunotherapy yet reduced normal tissue toxicity. Three different nanomedicines were sequentially developed: 1) SPNE, a nanoengager comprising second-near infrared photothermal semiconducting polymer and tumor cell/dendritic cell membrane coating; 2) ASPA, a nanoantagonist assembled by semiconducting polymer conjugated with an adenosine receptor inhibitor via thermo-labile linker; and 3) SCAN, a nanotheranostic agent made of activatable sonosensitizer, substrates, or immunomodulatory agents. Those nanoagents exert immunomodulation via two aspects: first, inducing immunogenic cell death through localized photothermal or sonodynamic therapy, thus recruiting intratumoral infiltration of immunocytes; second, regulating immunocytes functions to bolster antitumor immunocytes such as dendritic cells and T cells, or dampen pro-tumoral immunocytes such as M2-like macrophages and regulatory T cells. Owing to the local irradiation with laser or ultrasound, only tumor is damaged and to be targeted with immunocytes; moreover, prodrug designs and imaging-guided dose adjustment for immunomodulatory agents further guarantee their functions unleashed only in tumor region. These features substantially spare the normal tissue damage. Consequently, these agents achieve efficient primary and distant tumor inhibition, robust immune activation, long-lasting immunological memory, metastasis prevention, and survival extension on murine models. In summary, these strategies showcase clinical promises for cancer immunotherapy.