Institute of Biomedical Sciences

Title

Combined Nanoparticle-based Photothermal Therapy and Epigenetic Immunomodulation for Melanoma

Document Type

Poster

Abstract Category

Cancer/Oncology

Keywords

Nanoparticles, Photothermal Therapy, Epigenetic Therapy, Immunomodulation, Melanoma

Publication Date

Spring 5-1-2019

Abstract

Melanoma is a severe skin cancer that grows and spreads rapidly when undiagnosed and accounts for a majority of skin-cancer related deaths. Since many melanoma tumors are superficially accessible, nanoparticle-based photothermal therapy (PTT) may provide an effective treatment approach. To extend the local benefits of PTT to sites of melanoma dissemination, which is associated with a poorer prognosis, we propose to engage the immune system by using epigenetic drugs in combination with PTT. Several recent studies have described the antitumor immune effects of epigenetic drugs, including histone deacetylase (HDAC) inhibitors. Our approach comprises a single nanoparticle platform based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles that encapsulate indocyanine green (ICG), a photothermal agent, and Nexturastat A (NextA), an HDAC6 inhibitor, to administer the combined photothermal-epigenetic therapy to melanoma. We test the effects of the combined therapy (using ICG- NextA-PLGA nanoparticles; INAP) on melanoma in vitro and in vivo. INAPs were synthesized using an emulsion-evaporation synthesis scheme. INAP size distributions and stability were determined using dynamic light scattering. NextA encapsulation efficiency/drug loading was determined through UV-Vis spectrometry, and the photothermal heating characteristics were evaluated by illuminating the INAPs with an 808 nm NIR laser, measuring temperatures via a thermal camera. B16-F10 and B16-OVA melanoma cells treated with INAPs (± PTT) were assessed for viability, expression of NextA target proteins, and expression of immunogenic markers. In vivo studies assessed the effect of INAP-PTT on the expression of tumor-specific immune markers, tumor growth, and survival. Our optimized synthesis scheme yielded monodisperse and stable INAPs (200-300 nm, stable over 7 days) with 3-6% NextA drug loading. Illuminating INAPs with an NIR laser resulted in INAP concentration- and laser-power-dependent heating, achieving temperatures of 50-60°C. Functional assays demonstrated that encapsulated NextA retained effective HDAC6 inhibitory activity in INAP-treated melanoma cells. Further, INAP-PTT treatment resulted in increased MHC1 and MHC1/OVA expression in B16-OVA melanoma cells suggesting increased antigen presentation, important for breaking tumor tolerance. Finally, INAP-PTT generated slower tumor progression and increased survival in the B16-OVA murine melanoma model, suggesting the potential of the combined photothermal-epigenetic therapy to treat melanoma. Our study demonstrates the feasibility of using nanoparticles to combine disparate, yet complementary therapies such as PTT and epigenetic immunomodulation to treat melanoma. Ongoing studies are investigating the effects of the INAP-PTT on potentiating robust systemic antitumor immune responses, eliciting immunological memory, and validating our in vivo findings in other models of melanoma (B16F10 and SM1).

Open Access

1

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Presented at Research Days 2019.

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Combined Nanoparticle-based Photothermal Therapy and Epigenetic Immunomodulation for Melanoma

Melanoma is a severe skin cancer that grows and spreads rapidly when undiagnosed and accounts for a majority of skin-cancer related deaths. Since many melanoma tumors are superficially accessible, nanoparticle-based photothermal therapy (PTT) may provide an effective treatment approach. To extend the local benefits of PTT to sites of melanoma dissemination, which is associated with a poorer prognosis, we propose to engage the immune system by using epigenetic drugs in combination with PTT. Several recent studies have described the antitumor immune effects of epigenetic drugs, including histone deacetylase (HDAC) inhibitors. Our approach comprises a single nanoparticle platform based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles that encapsulate indocyanine green (ICG), a photothermal agent, and Nexturastat A (NextA), an HDAC6 inhibitor, to administer the combined photothermal-epigenetic therapy to melanoma. We test the effects of the combined therapy (using ICG- NextA-PLGA nanoparticles; INAP) on melanoma in vitro and in vivo. INAPs were synthesized using an emulsion-evaporation synthesis scheme. INAP size distributions and stability were determined using dynamic light scattering. NextA encapsulation efficiency/drug loading was determined through UV-Vis spectrometry, and the photothermal heating characteristics were evaluated by illuminating the INAPs with an 808 nm NIR laser, measuring temperatures via a thermal camera. B16-F10 and B16-OVA melanoma cells treated with INAPs (± PTT) were assessed for viability, expression of NextA target proteins, and expression of immunogenic markers. In vivo studies assessed the effect of INAP-PTT on the expression of tumor-specific immune markers, tumor growth, and survival. Our optimized synthesis scheme yielded monodisperse and stable INAPs (200-300 nm, stable over 7 days) with 3-6% NextA drug loading. Illuminating INAPs with an NIR laser resulted in INAP concentration- and laser-power-dependent heating, achieving temperatures of 50-60°C. Functional assays demonstrated that encapsulated NextA retained effective HDAC6 inhibitory activity in INAP-treated melanoma cells. Further, INAP-PTT treatment resulted in increased MHC1 and MHC1/OVA expression in B16-OVA melanoma cells suggesting increased antigen presentation, important for breaking tumor tolerance. Finally, INAP-PTT generated slower tumor progression and increased survival in the B16-OVA murine melanoma model, suggesting the potential of the combined photothermal-epigenetic therapy to treat melanoma. Our study demonstrates the feasibility of using nanoparticles to combine disparate, yet complementary therapies such as PTT and epigenetic immunomodulation to treat melanoma. Ongoing studies are investigating the effects of the INAP-PTT on potentiating robust systemic antitumor immune responses, eliciting immunological memory, and validating our in vivo findings in other models of melanoma (B16F10 and SM1).