<p>Immunotherapy has significantly improved cancer treatment. However, many tumors are resistant to current immunotherapy due to the highly immunosuppressive tumor microenvironment (TME). Tumor cells can evade immune activation by externalizing phosphatidylserine (PS) on cell surface to trigger anti-inflammatory signals and induce immune tolerance. Recent studies show that PS is upregulated in TME and further increased after chemotherapy. For effective immunotherapy of tumors, the exposed PS needs to be blocked to relieve immunosuppressive TME and sensitize tumors to immune stimulants. </p>
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<p>In this study, PS exposure level increased after the chemotherapy Doxil treatment on B16F10 melanoma cells, and the PS exposure reduced the response of antigen-presenting cells (APCs) to immune stimulants such as lipopolysaccharide. Dipicolylamine-Zn (DPA-Zn) shielded the PS exposure resulting from doxorubicin (DOX) treatment and reduced immunosuppressive interaction between tumors and APCs. The PS blockade by DPA-Zn improves the tumor response rate immune stimulants such as GM-CSF, STING agonist cyclic dinucleotides (CDN), anti-PD-L1 antibody. Among the combination at the tested doses, Doxil + DPA-Zn + CDN was the optimal combination that enhanced anti-tumor effect most significantly and prolonged the survival time in immune-cold B16F10 melanoma model. However, the anti-tumor efficacy was limited, which is attributed to poor tumor retention of CDN and DPA-Zn. </p>
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<p>To prolong the intratumoral release of DPA-Zn and CDN and maximize the anti-tumor immunity, CDN was formulated as liposomes (CDN@lip), which significantly delayed the release of CDN in vitro and improved anti-tumor efficacy compared with free CDN formulation. Alginate hydrogel showed the potential to sustain release of DPA-Zn. DPA-Zn was loaded in the alginate hydrogel via electrostatic interaction, and the release rate was controlled by additional zinc gluconate. However, zinc caused detrimental effects on skin and can cause mice death at a high dose. To avoid the side effect of subcutaneously administered Zn, the dose of DPA-Zn in alginate hydrogel was readjusted based on the maximum tolerated dose study, and zinc gluconate was replaced with CaSO4.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/23721162 |
| Date | 20 July 2024 |
| Creators | Jianping Wang (16625592) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | In Copyright |
| Relation | https://figshare.com/articles/thesis/PHOSPHATIDYLSERINE_TARGETING_FOR_ENHANCING_CHEMOIMMUNOTHERAPY_OF_CANCER/23721162 |
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