Abstract
Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA7K NPs showed faster DOX release kinetics than DOX-PLGA12K NPs in the physiological condition. DOX-PLGA7K NPs and DOX-PLGA12K NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA7K NPs and DOX-PLGA12K NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.
Highlights
Cancer immunotherapy strategies, which can inhibit tumor growth and prevent its recurrence with metastasis, have been widely developed for the effective treatment of tumors by stimulating the immune systems in the body [1,2]
We prepared DOX-PLGA7K NPs and DOX-PLGA12K NPs by using the single o/w emulsion method to compare their therapeutic potential based on their drug release behavior
The difference in DOX content between the DOX-PLGA7K NPs and DOX-PLGA12K NPs would be affected by the difference in the solubility and miscibility of the polymers, DOX, or solution during the formulation [22]
Summary
Cancer immunotherapy strategies, which can inhibit tumor growth and prevent its recurrence with metastasis, have been widely developed for the effective treatment of tumors by stimulating the immune systems in the body [1,2]. Various cancer immunotherapy strategies, including cytokine therapy, adoptive T-cell therapy, immune checkpoint blockade therapy, and cancer vaccines, have shown attractive results in clinics [3,4] Conventional cancer vaccines, such as peptides and protein antigens, are widely used to stimulate immune responses against the tumors. The timing of the treatment of the ICD-inducers and immunotherapies can provide an impact on the therapeutic efficacy In this point of view, sustained-release with single-inoculation therapy with PLGA NPs might provide advantages for priming and boosting of immune responses against tumors [20]. To confirm the DOX release kinetics after direct tumor injection, we monitored the DOX fluorescence changes in the tumor tissue of the CT-26 tumor-bearing mice after direct tumor injection of the DOX-HCl, DOX-PLGA7K NPs, and DOX-PLGA12K NPs. tumor growth inhibition and immune cell changes were observed. The immunological memory effect of the tumor-suppressed mice was evaluated by monitoring tumor growth after re-challenging of the CT-26 tumor cells
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