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Principal Investigator: Michelle S Bradbury
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2023
Award: $64,250
Funding agency: National Cancer Institute
Project Summary: Enormous strides continue to be made in the design of nanoparticles as highly specialized
therapeutics for achieving superior outcomes over standard pharmacological agents, the latter often associated
with significant toxicity that limits treatment efficacy. While cancer immunotherapies have revolutionized the
treatment of disease and shown therapeutic benefits in hard-to-treat cancers, these agents are limited, for
example, by immune-related adverse events and off-target effects in immunosuppressive microenvironments.
Novel, emerging anti-cancer strategies are therefore critically needed to overcome these limitations and improve
durable response rates in combination with immune therapies. One promising strategy exploits the unique “self-
therapeutic” capabilities of the nanomaterials themselves – the treatment of tumors without the need for cytotoxic
drugs. These capabilities are governed by the intrinsic physico-chemical properties of these materials, which can
lead to disruption of signal transduction pathways, cell cross-talk or invasion, and/or induced cell death programs
within the tumor microenvironment (TME) – providing unprecedented opportunities for combating disease. We
have developed specialized ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots),
with intrinsic therapeutic capabilities enabling a distinct combination of activities that (1) selectively and directly
induce cancer cell death through the iron-dependent mechanism of ferroptosis and (2) modulate immune cells
directly by priming T cells and polarizing macrophages toward a pro-inflammatory phenotype. As CD8+ T cells
are known to also regulate ferroptosis during immunotherapy, such effects are expected to synergize with those
induced by C' dots. A long-term goal of this proposal is to determine critical C' dot physico-chemical parameters
responsible for maximizing responses to these intrinsic therapeutic activities. In Aim I, we will examine the extent
to which changes in the structural properties of PEG-coated C' dots, plain or modified to specifically bind to
melanocortin-1 receptor (MC1-R; a well-established target overexpressed by our syngeneic murine models and
human melanomas), influence therapeutic efficacy in syngeneic melanoma models by modulating ferroptosis
and the tumor microenvironment, in the presence and absence of checkpoint blockade. In Aim II, we will probe
underlying mechanisms driving regulation of immune cell phenotype and/or induction of ferroptosis in vitro. The
successful completion of the project will provide critical insights into (i) key structural parameters modulating the
combined self-therapeutic activities of these particles related to their induction of ferroptosis and priming the
tumor immune microenvironment; (ii) whether critical differences exist in particle characteristics needed to
optimize these distinct activities; (iii) mechanisms underpinning these activities; and (iv) therapeutic strategies
that maximize potent anti-tumor effects in syngeneic melanoma models by administering therapeutic doses of
particles in tandem with checkpoint inhibitors (anti-PD-1 and anti-CTLA-4).
Terms: <Affinity><Antitumor Response><Automobile Driving><Binding><Biology><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Induction><Cancer Treatment><Cancerous><Cancers><Cell Body><Cell Death><Cell Death Induction><Cells><Characteristics><Checkpoint inhibitor><Chemicals><Cristobalite><Cytotoxic agent><Cytotoxic drug><Data><Dimensions><Disease><Disorder><Dose><Drugs><Encapsulated><Exclusion Chromatography><Exhibits><Fatty Acid Hydroperoxides><Fe element><Fluorescence Agents><Fluorescent Agents><Fluorescent Dyes><Gel Chromatography><Gel Filtration><Gel Filtration Chromatography><Gel Permeation Chromatography><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Goals><HPLC><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Human><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><In Vitro><Inflammatory><Inflammatory Response><Intravenous><Invaded><Iron><Lead><Lesion><Link><Lipid Hydroperoxide><Lipid Peroxides><Lipoperoxides><MC1 Receptor><Macrophage><Malignant Cell><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Medication><Melanocortin 1 Receptor><Melanocyte Melanocortin Receptor><Melanoma Cell><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Mφ><Necrosis><Necrotic><Outcome><Pathway interactions><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Population><Process><Property><Recombinant DNA Technology><Research><Research Design><Sand><Series><Signal Transduction Pathway><Silica><Silicon Dioxide><Study Type><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Therapeutic><Therapeutic Effect><Time><Toxic effect><Toxicities><Translations><Transplantation><Treatment Efficacy><Tridymite><aCTLA-4><aCTLA4><aPD-1><aPD1><anti programmed cell death 1><anti-CTLA-4><anti-CTLA4><anti-PD-1><anti-PD1><anti-cancer><anti-cancer activity><anti-cancer immunotherapy><anti-cancer therapeutic><anti-cancer therapy><anti-programmed cell death protein 1><anti-tumor effect><anti-tumor immune response><anti-tumor response><antiPD-1><antiPD1><anticancer><anticancer activity><anticancer immunotherapy><anticancer therapeutic><anticancer therapy><antitumor effect><antitumor immune response><aqueous><cancer cell><cancer immunotherapy><cancer microenvironment><cancer regression><cancer therapy><cancer-directed therapy><carcinogenesis><check point blockade><checkpoint blockade><combat><cytokine><design><designing><driving><drug/agent><experiment><experimental research><experimental study><experiments><fluorescent dye/probe><genetically engineered><genome mutation><heavy metal Pb><heavy metal lead><host response><immune check point blockade><immune check point inhibitor><immune checkpoint blockade><immune microenvironment><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immune-mediated adverse events><immune-related adverse events><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><inhibitor><insight><intervention efficacy><intravenous administration><lipid peroxide><malignancy><melanoma><mouse model><murine model><nano materials><nano particle><nano-sized particle><nanomaterials><nanoparticle><nanosized particle><nanotherapeutic><necrocytosis><neoplasm/cancer><novel><overexpress><overexpression><particle><pathway><pharmacologic><programs><recruit><response><response to therapy><response to treatment><small molecule><study design><synergism><therapeutic efficacy><therapeutic response><therapy efficacy><therapy response><thymus derived lymphocyte><translation><transplant><treatment response><tumor><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4><αPD-1><αPD1>