Engineered biomaterials for photothermal therapy and immunotherapy

Abstract

In cancer treatment, surgery, chemotherapy or radiotherapy are the first option in the guideline for cancer treatment. However, those strategies remain limited efficacy in tumor eradication as well as the apparent side effects which are the burden for many cancer patients. Recently, photothermal therapy (PTT) has withdrawn an intensive investigation in the context of treating cancer. Light energy is the main source for heat generation in PTT. Various materials have been developed to harness the PTT in the way that burns tumor specifically but leave the normal tissue harmless. Besides, cancer immunotherapies have evidenced the potential effect in tumor treatment, even metastasis. The principle of cancer immunotherapy is to take advantage of immune system to fight against cancer. Currently, the approved immunotherapies based on the inactivation of immune checkpoint to reverse the immune suppression. On the other hand, cancer vaccine was also studied. Although robust and long-term tumor suppression was observed, single immunotherapy still suffers from limited efficacy in clinic. We, herein, engineered biomaterials as the novel drug delivery system that allow the precise and safe treatment using PTT. In addition, these materials are designed as drug delivery system boosting the immune response against cancer. In chapter 1, I overviewed the current status of photothermal therapy and application of photothermal therapy in cancer treatment. The relationship of photothermal therapy and immune activation. In additions, the current approached of immunotherapy in cancer treatment was also mentioned to provide the insight of limitation of this treatment. In chapter 2, I developed a nanoadjuvant system PDL1Ab-IQ/PN that takes advantage of combination of immune checkpoint blockade and photothermal therapy-mediated in situ cancer vaccine for solid tumor treatment. PDL1Ab-IQ/PN injection followed by near infrared (NIR) laser irradiation could completely ablate the primary tumor due to the improved accumulation of PDL1Ab-IQ/PN at tumor tissue. In addition, the binding between PDL1Ab-IQ/PN nanoadjuvant and heated-induced apoptosis tumor cells resembled of adjuvant-antigen system that generated in situ vaccine. Photothermal treatment induced immunogenic cell death and facilitate dendritic cells phagocyte the whole tumor cell-nanoadjuvant complex, thus successfully inducing a systemic antitumor-response. This systemic response, which was attributed mainly by cytotoxic T cells, suppressed the distant tumor growth in both subcutaneous and orthotopic tumor models. Furthermore, the systemic response could last long for 150 days to prevent the growth of re-challenged tumor, which imply the long-term prevention effect against tumor recurrence. In chapter 3, molecular engineering technique was used for sitespecific conjugation of antibodies to nanoparticles. We designed an anti-claudin 3 (CLDN3) antibody containing a single cysteine residue, h4G3cys, then linked it to the maleimide group of lipid polydopamine hybrid nanoparticles (LPNs). Because of their negatively charged lipid coating, LPNs showed high colloidal stability and provided a functional surface for site-specific conjugation of h4G3cys. The activity of h4G3cys was tested by measuring the binding of h4G3cys-conjugated LPNs (C-LPNs) to CLDN3- positive tumor cells and assessing its subsequent photothermal effects. C-LPNsspecifically recognized CLDN3-overexpressing T47D breast cancer cells but not CLDN3-negative Hs578T breast cancer cells. High binding of C-LPNs to CLDN3-overexpressing T47D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy. In chapter 4, PDA was exploited as coating material for DNA-microflower (DMF). The active PDA surface allowed conjugation of T cell stimulating antibodies on DMF in a facile manner. Due to the extreme large surface area inheriting from the unique surface topology of DMF, the Ab-DMF could serve as the effective T cell activator, compared to the control spherical activator prepared from polystyrene microparticles. The combination of PTT and Ab-DMF in our studies has provide a novel strategy that not only recruited T cell to the tumor by heat-induced immunogenic cell death but also amplified the number of cytotoxic T cells in tumor tissues. The dominant increase of cytotoxic T cell over regulatory T cell have been observed as the evidenced for effective tumor suppression. The combination of PTT and immunotherapy by our biomaterials synergized in eradicating solid tumor besides generating systemic anti-tumor systemic immune response.