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Tumor size-dependent abscopal effect of polydopamine-coated all-in-one nanoparticles for immunochemo-photothermal therapy of early- and late-stage metastatic cancer.

ABSTRACT: Metastatic cancer is a persistent clinical enigma, which requires combination of several treatment modules. Here, we developed an all-in-one nanomedicine strategy to systemically co-deliver photosensitive, chemotherapeutic, and immunomodulating agents for effective immunochemo-photothermal therapy (PTT) to inhibit both primary tumor and distal metastatic tumor. Two types of polydopamine (dp)-coated nanoparticles (NPs) (N/PGEM/dp-5 and N/PGEM/dp-16) co-loaded with gemcitabine (GEM) and NLG919, a potent indoleamine-2, 3-dioxygenase (IDO) inhibitor, were prepared. N/PGEM/dp-16 NPs with a thicker dp coating layer showed higher photothermal conversion ability, more favorable biodistribution profile and better tumor inhibition effect compared to N/PGEM/dp-5 NPs with a thinner coating layer. Combination with laser irradiation further enhanced the tumor inhibition effect of N/PGEM/dp-16 NPs. In an "early metastatic" pancreatic cancer PANC02 model with small distal tumors, introduction of NLG and dp coating improved the inhibition effect on both primary and distal tumors. Compared to N/PGEM/dp-16, N/PGEM/dp-16 plus laser irradiation further enhanced the inhibition effect on primary tumor, but didn't improve the abscopal antitumor effect. When the initial volume of distal tumor was sufficiently large in a "late metastasis" model, a more dramatic abscopal antitumor effect was achieved, resulting in a significant growth inhibition of both primary tumor and the unirradiated distal tumor. Furthermore, laser irradiation can amplify the immunochemo-NPs-mediated innate and adaptive immune responses in both tumors. This work demonstrated a distal tumor-size dependent abscopal effect, and provided a perspective for future design of more effective immunochemo-PTT nano-formulations for early- and late-stage metastatic tumors.

SUBMITTER: Sun J

PROVIDER: S-EPMC8466812 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Photothermal therapy (PTT) can be an effective antitumor therapy, but it may not completely eliminate tumor cells, leading to the risk of recurrence or metastasis. Here we describe nanocarriers that allow combination therapy involving PTT and immunotherapy. Nanocarriers are prepared by coating Al2O3 nanoparticles with non-toxic, biodegradable polydopamine, which shows high photothermal efficiency. A near-infrared laser irradiation can kill the majority of tumor tissues, resulting in the release of tumor-associated antigens. The Al2O3 within the nanoparticles, together with CpG, acts as an adjuvant to trigger robust cell-mediated immune responses that can help eliminate the residual tumor cells and reduce the risk of tumor recurrence. Methods: The characteristics and photothermal performance of polydopamine-coated Al2O3 nanoparticles were examined after one-step preparation. Then we studied their internalization, photothermal toxicity and immunostimulatory activity in vitro. For in vivo experiments, these nanocarriers were injected directly into B16F10 melanoma allografts in mice to ensure specific localization. After photothermal irradiation on day 0, mice were subcutaneously injected with CpG adjuvant on day 1, 3 and 5. Tumor volumes and number of living mice were recorded every two days. Moreover, various immune responses induced by our combined therapy were tested for mechanism research. Results: 50% of mice after our combined treatment successfully achieved the goal of tumor eradication, and survived for 120 days, which was the end point of the experiment. Mechanism studies demonstrated the combined therapy efficiently led to dendritic cell maturation, resulting in the secretion of antibodies and cytokines as well as the proliferation of splenocytes and lymphocytes for anti-tumor immunotherapy. Conclusion: Taken together, these results demonstrated the promise of our combined photothermal therapy and immunotherapy for tumor shrinkage, which merited further research.

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Tumor size-dependent abscopal effect of polydopamine-coated all-in-one nanoparticles for immunochemo-photothermal therapy of early- and late-stage metastatic cancer.

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