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IR820-loaded PLGA nanoparticles for photothermal therapy of triple-negative breast cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) accounts for 15-25% of breast cancer cases and lacks expression of the three most common receptors seen on other subtypes of breast cancer. This lack of expression makes TNBC unsusceptible to currently available targeted or hormonal therapies, so new treatment strategies are desperately needed. Photothermal therapy (PTT), which utilizes nanoparticles (NPs) embedded in tumors as exogenous energy absorbers to convert externally applied near-infrared (NIR) light into heat to ablate cancer cells, has shown promise as an alternative strategy. However, it typically uses gold-based NPs that will remain in the body for extended period of time with unknown long-term health effects. To enable PTT with biodegradable, polymeric NPs, we encapsulated the NIR-absorbing dye IR820 in poly(lactic-co-glycolic acid) (PLGA) NPs. We characterized the physicochemical properties of these IR820-loaded PLGA NPs and evaluated their performance as PTT agents using both in vitro and in vivo models of TNBC. The results demonstrate that these NPs are potent mediators of PTT that induce cell death primarily through apoptosis to effectively hinder the growth of TNBC tumors. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1702-1712, 2019.

SUBMITTER: Valcourt DM

PROVIDER: S-EPMC7153575 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Project description:The present work was an endeavor to shed light on how mild photothermia possibly synergizes with immune checkpoint inhibition for tumor therapy. We established mild photothermal heating protocols to generate temperatures of 43 °C and 45 °C in both in vitro and in vivo mouse 4T1 triple-negative breast cancer (TNBC) models using polyglycerol-coated carbon nanohorns (CNH-PG) and 808 nm laser irradiation. Next, we found that 1) CNH-PG-mediated mild photothermia (CNH-PG-mPT) significantly increased expression of the immune checkpoint PD-L1 and type-1 macrophage (M1) markers in the TNBC tumors; 2) CNH-PG-mPT had a lower level of anti-tumor efficacy which was markedly potentiated by BMS-1, a PD-L1 blocker. These observations prompted us to explore the synergetic mechanisms of CNH-PG-mPT and BMS-1 in the context of tumor cell-macrophage interactions mediated by PD-L1 since tumor-associated macrophages (TAMs) are a major source of PD-L1 expression in tumors. In vitro, the study then identified two dimensions where BMS-1 potentiated CNH-PG-mPT. First, CNH-PG-mPT induced PD-L1 upregulation in the tumor cells and showed a low level of cytotoxicity which was potentiated by BMS-1. Second, CNH-PG-mPT skewed TAMs towards an M1-like anti-tumor phenotype with upregulated PD-L1, and BMS-1 bolstered the M1-like phenotype. The synergistic effects of BMS-1 and CNH-PG-mPT both on the tumor cells and TAMs were more pronounced when the two cell populations were in co-culture. Further in vivo study confirmed PD-L1 upregulation both in tumor cells and TAMs in the TNBC tumors following treatment of CNH-PG-mPT. Significantly, TAMs depletion largely abolished the anti-TNBC efficacy of CNH-PG-mPT alone and in synergy with BMS-1. Collectively, our findings reveal PD-L1 upregulation to be a key response of TNBC to mild photothermal stress, which plays a pro-survival role in the tumor cells while also acting as a brake on the M1-like activation of the TAMs. Blockade of mPT‑induced PD‑L1 achieves synergistic anti-TNBC efficacy by taking the intrinsic survival edge off the tumor cells on one hand and taking the brakes off the M1-like TAMs on the other. Our findings reveal a novel way (i.e. mild thermia plus PD-L1 blockade) to modulate the TAMs-tumor cell interaction to instigate a mutiny of the TAMs against their host tumor cells.

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IR820-loaded PLGA nanoparticles for photothermal therapy of triple-negative breast cancer.

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