This thesis describes the exploitation of nanotechnology-based multifunctional platforms for reinforcing cancer immunotherapy. In the first part, a short introduction is presented to go over the current advance and limitation in cancer immunotherapy. In the second part, a plug-and-play nanorization ...
This thesis describes the exploitation of nanotechnology-based multifunctional platforms for reinforcing cancer immunotherapy. In the first part, a short introduction is presented to go over the current advance and limitation in cancer immunotherapy. In the second part, a plug-and-play nanorization of coarse black phosphorus nanosheets platform is developed for combining targeting and chemo-photoimmunotherapy in colorectal cancer. Following surface modification with folate acid for tumor cell targeting and loading of doxorubicin as well as the PD-L1 siRNA, as prepared drug delivery system not only assures photothermal, and photodynamic effect after Nir irradiation, but also displays Nir-triggered doxorubicin and PD-L1 siRNA release for initiating chemotherapy and silencing of PD-L1 expression on tumor cells. Collectively, this novel black phosphorus nanorization system shows high tumor eradication efficiency in vivo by inducing efficient chemo-, photothermal-, photodynamic- and immune-therapies. These findings also predict an efficient combinational therapeutic strategy to enhance the efficacy of widely recognized chemo-phototherapies.
The third part of this thesis introduces the development of regulatory T cell targeted hybrid nanoparticles in combination with an anti-CTLA4 immune checkpoint for cancer immunotherapy. As the key regulator of an immune response, regulatory T cells also restraint the activation of the antitumor immune response into tumor microenvironment. Hence, modulating the immunosuppressive function of regulatory T cells by Treg cells-oriented nanoparticles can help to reboot the antitumor immune response against tumor and assist the effectiveness of immune checkpoint antibodies. In this part, tLyp1 peptide-conjugated PLGA hybrid nanoparticles are formulated for targeting and regulating the suppressive function of Treg cells in the tumor microenvironment. These nanoparticles present good stability as well as Treg cell orientation, and improve the efficacy of imatinib in downregulating Treg cell suppression by inhibiting the phosphorylation of STAT3 and STAT5. After intravenous injection for in vivo study, high tumor accumulation is monitored in the hybrid nanoparticles treating groups. In particular, enhanced tumor inhibition, reduced intratumoral Treg cells, and elevated intratumoral CD8+ T cells and prolonged survival rate are observed when combined with anti-CTLA4 checkpoint-blockade. This platform provides a groundwork for harnessing nanoparticle-based drugs to target and modulate Treg cell function in the tumor microenvironment and improves antitumor immunotherapy.
The last part of this thesis further addresses the limitation of Treg cell based immunotherapy using nanotechnology. To expand the application of Treg cell functional modulation and achieve total tumor eradication, layer by layer PLGA hybrid nanoparticles embracing photothermal, photodynamic effect and Treg cell regulation, are manufactured. The imatinib-loaded GITR-PLGA were formulated as a core and photosensitizer IR-780 were loaded outside the PLG/PLH layers, resulting in pH-sensitive release of IR-780 dye from layer by layer assembly to perform NIR-induced photothermal and photodynamic effects, and further release of imatinib-loaded GITR-PLGA core to mediate Treg cell-modulated antitumor immunotherapy. In the presence of the significant photothermal, photodynamic and activated immune response, this platform successfully abrogates tumor growth, diminish tumor recurrence, and extend the survival rates in vivo. Therefore, the proposed layer by layer nanoparticles offers a novel and versatile approach to address the limitation of Treg cell-induced cancer immunotherapy.
This thesis describes the exploitation of nanotechnology-based multifunctional platforms for reinforcing cancer immunotherapy. In the first part, a short introduction is presented to go over the current advance and limitation in cancer immunotherapy. In the second part, a plug-and-play nanorization of coarse black phosphorus nanosheets platform is developed for combining targeting and chemo-photoimmunotherapy in colorectal cancer. Following surface modification with folate acid for tumor cell targeting and loading of doxorubicin as well as the PD-L1 siRNA, as prepared drug delivery system not only assures photothermal, and photodynamic effect after Nir irradiation, but also displays Nir-triggered doxorubicin and PD-L1 siRNA release for initiating chemotherapy and silencing of PD-L1 expression on tumor cells. Collectively, this novel black phosphorus nanorization system shows high tumor eradication efficiency in vivo by inducing efficient chemo-, photothermal-, photodynamic- and immune-therapies. These findings also predict an efficient combinational therapeutic strategy to enhance the efficacy of widely recognized chemo-phototherapies.
The third part of this thesis introduces the development of regulatory T cell targeted hybrid nanoparticles in combination with an anti-CTLA4 immune checkpoint for cancer immunotherapy. As the key regulator of an immune response, regulatory T cells also restraint the activation of the antitumor immune response into tumor microenvironment. Hence, modulating the immunosuppressive function of regulatory T cells by Treg cells-oriented nanoparticles can help to reboot the antitumor immune response against tumor and assist the effectiveness of immune checkpoint antibodies. In this part, tLyp1 peptide-conjugated PLGA hybrid nanoparticles are formulated for targeting and regulating the suppressive function of Treg cells in the tumor microenvironment. These nanoparticles present good stability as well as Treg cell orientation, and improve the efficacy of imatinib in downregulating Treg cell suppression by inhibiting the phosphorylation of STAT3 and STAT5. After intravenous injection for in vivo study, high tumor accumulation is monitored in the hybrid nanoparticles treating groups. In particular, enhanced tumor inhibition, reduced intratumoral Treg cells, and elevated intratumoral CD8+ T cells and prolonged survival rate are observed when combined with anti-CTLA4 checkpoint-blockade. This platform provides a groundwork for harnessing nanoparticle-based drugs to target and modulate Treg cell function in the tumor microenvironment and improves antitumor immunotherapy.
The last part of this thesis further addresses the limitation of Treg cell based immunotherapy using nanotechnology. To expand the application of Treg cell functional modulation and achieve total tumor eradication, layer by layer PLGA hybrid nanoparticles embracing photothermal, photodynamic effect and Treg cell regulation, are manufactured. The imatinib-loaded GITR-PLGA were formulated as a core and photosensitizer IR-780 were loaded outside the PLG/PLH layers, resulting in pH-sensitive release of IR-780 dye from layer by layer assembly to perform NIR-induced photothermal and photodynamic effects, and further release of imatinib-loaded GITR-PLGA core to mediate Treg cell-modulated antitumor immunotherapy. In the presence of the significant photothermal, photodynamic and activated immune response, this platform successfully abrogates tumor growth, diminish tumor recurrence, and extend the survival rates in vivo. Therefore, the proposed layer by layer nanoparticles offers a novel and versatile approach to address the limitation of Treg cell-induced cancer immunotherapy.
주제어
#pharmaceutics nanoparticles cancer immunotherapy multi-functional
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