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Principal Investigator: Ninh La-Beck
Organization: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
Fiscal Year: 2024
Award: $463,889
Funding agency: National Cancer Institute
ABSTRACT
Drug delivery using liposomes increases tumor drug accumulation while sparing normal tissue. Several liposomal
chemotherapies are approved to treat cancer. Unfortunately, lipid nanoparticles such as liposomes interact with
the immune system and their impact on the tumor immunologic milieu is largely unknown. We have reported that
liposomes composed of phospholipids and cholesterol, similar to those used in patients, doubled tumor size in
mice by suppressing the immune response against tumors. We recently identified macrophages as the cells that
are responsible for these detrimental effects. In this proposal, we seek to identify the precise molecular
mechanisms. Our preliminary data show that liposomal cholesterol is metabolized into oxysterols that are known
to alter the function of macrophages. Based on this, we theorize that liposomal oxysterols cause macrophages
to suppress antitumor immunity and enhance tumor growth. Notably, oxidized metabolites of beta-sitosterol (a
plant sterol) lack the protumoral inflammatory activity of oxysterols, suggesting that more efficacious liposomal
drug formulations can be developed using analogs of cholesterol. The objectives of this proposal are to
understand the metabolism of liposomal cholesterol and to develop cholesterol analogs without tumorigenic
effects for liposomal drug formulation. We will dissect the metabolism pathways by conducting time-dependent
studies in immune cells and in mouse models. To identify the metabolic and cell signaling pathways that are
involved, we will conduct mechanistic studies in wildtype and knockout mice, and donor human immune cells.
Finally, we will design and test the immunological and anticancer effects of cholesterol analogs in immune cells
and in mouse models of cancer. Our team has unique combined expertise necessary for successful completion
of this project. This proposal is expected to have a positive impact by addressing critical gaps in current
understanding of the role of the immune system in liposomal drug pharmacology and the role of oxidized sterols
in cancer. This is likely to lead to new therapeutic targets and drug formulation strategies with potential to
significantly advance both cancer drug delivery and immunotherapy.
Terms: <14-Hydroxydaunomycin><27-hydroxycholesterol><5-cholestene-3 beta,27-diol><Address><Adriamycine><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Attenuated><Beta-Sitosterol><Blood Cells><Cancer Drug><Cancer Model><Cancer Patient><Cancer Treatment><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cholesterol><Cholesterol Homeostasis><Clinical><Clinical Trials><Cytotoxic Chemotherapy><Cytotoxic Therapy><D12S1644><Data><Development><Disease><Disorder><Doxorubicin><Doxorubicin Liposome><Doxorubicina><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drug Formulations><Drug Kinetics><Drug toxicity><Drugs><Dysfunction><Encapsulated><Enzyme Gene><Enzymes><FDA approved><Failure><Functional disorder><Health><Hedgehog (Hh) signal transduction pathway><Human><Hydroxycholesterols><Hydroxyl Daunorubicin><Hydroxylases><Hydroxyldaunorubicin><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-4-STAT><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Interferon><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune mediated therapy><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunologic Tests><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological Tests><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Inflammatory><Interferon Gamma><Interferon Type II><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Liposomal><Liposomal Doxorubicin><Liposomal-Encapsulated Doxorubicin><Liposomes><Macrophage><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediator><Medication><Membrane><Meta-Analysis><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mixed Function Oxidases><Mixed Function Oxygenases><Modeling><Modern Man><Molecular><Monooxygenases><Murine><Mus><Mφ><Neoplastic Disease Chemotherapeutic Agents><Normal Tissue><Normal tissue morphology><Null Mouse><Pathogenesis><Pathway interactions><Patients><Peripheral Blood Cell><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Phosphatides><Phospholipids><Physiopathology><Phytosterols><Plant Sterols><Production><Progression-Free Survivals><Property><Reporting><Role><STAT3><STAT3 gene><STAT6><STAT6 gene><STAT6B><STAT6C><Safety><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Sterols><Subcellular Process><Testing><Therapeutic><Therapeutic Effect><Time><Translating><Tumor Antigens><Tumor Immunity><Tumor-Associated Antigen><Tumor-Specific Treatment Agents><Wild Type Mouse><Work><analog><anti-cancer><anti-cancer drug><anti-cancer therapeutic><anti-cancer therapy><anti-tumor immunity><antigen-specific T cells><antitumor immunity><attenuate><attenuates><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cancer antigens><cancer immunity><cancer infiltrating T cells><cancer therapy><cancer-directed therapy><chemotherapy><cholest-5-ene-3 beta,27-diol><cholesterol analog><cholesterol metabolism><design><designing><developmental><drug/agent><fat metabolism><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><host response><immune function><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><inhibitor><interleukin-4 Stat><lFN-Gamma><lipid based nanoparticle><lipid metabolism><lipid nanoparticle><liposomal delivery><liposomal formulation><liposomal preparation><liposome delivery><malignancy><membrane structure><mouse model><murine model><nanoparticle drug><neoplasm/cancer><new anti-cancer agent><new anticancer agent><new anticancer drug><new antineoplastic><new cancer drug><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel anti-cancer agent><novel anti-cancer drug><novel anticancer agent><novel anticancer drug><novel antineoplastic><novel cancer drug><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><objective response rate><pathophysiology><pathway><pharmacologic><randomized, clinical trials><response><screening><screenings><smoothened signaling pathway><social role><theories><tumor><tumor growth><tumor infiltrating T cells><tumor-specific antigen><tumorigenic><wildtype mouse>