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Principal Investigator: Haifa Shen
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2021
Award: $463,570
Funding agency: National Cancer Institute
The tumor vasculature is generally considered as leaky, and thus allows accumulation of big molecules and
particles within a certain size range to penetrate and retain. Consequently, many cancer drugs have been
packaged into simple nanoparticles or composite drug particles in order to improve accumulation in the tumor
tissue and reduce toxicity to the normal organs. Yet there are multiple biological barriers that the particulate
drugs will encounter en route to the tumor such as the myeloid cells with a high phagocytic potential for the
drug particles in circulation and in organs of the mononuclear phagocyte system. In addition, the dense tumor
tissue is filled with extracellular matrix and tumor-associated myeloid cells. It is unclear how the particulate
drugs escape entrapment by the phagocytic cells at the system level and, for the particles that have arrived to
the tumor tissue, how they penetrate the multiple biological barriers inside the tumor and reach the cancer cells.
In this study, we will package doxorubicin in liposomes, micelles and composite particles, and apply them as
model drugs to study the mechanism of intratumoral transport of particulate drugs. We hypothesize that
myeloid cell-mediated transport is an important route of tumor entry and intratumoral distribution of the
particulate drugs. The overall study is divided into three specific aims. In the Aim 1 study, we will examine cell-
mediate tumor entry of particulate drugs. In the Aim 2 study, we will analyze the process of intratumoral
passage of drug particles. In the Aim 3 study, we will investigate potential impact on tumor microenvironment
and anti-tumor immunity as a result of effective intratumoral transport of particulate drugs. Knowledge
generated from this study will provide guidance on design and development of future particulate cancer drugs
with better therapeutic efficacy and low-to-no side effects.
Terms: <14-Hydroxydaunomycin><Adriamycine><Albumins><Alpha Particle Radiation><Alpha Particles><Alpha Radiation><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Asotax><Binding Proteins><Biological><Biotech><Biotechnology><Blood Circulation><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood monocyte><Bloodstream><Body Tissues><Breast Cancer Model><Breast Melanoma><Breast tumor model><Bristaxol><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell surface><Cell-Extracellular Matrix><Cells><Circulation><Development><Doxorubicin><Doxorubicina><Drug Efflux><Drug Modelings><Drug Therapy><Drug Transport><Drugs><ECM><Encapsulated><Extracellular Matrix><Fibroblasts><Follow-Up Studies><Followup Studies><Future><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Injectable><Intracellular Communication and Signaling><Intravenous><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Liposomal><Liposomes><Lymphatic cell><Lymphocyte><Lymphocytic><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Marrow monocyte><Marrow platelet><Mediating><Medication><Metastatic breast cancer><Mice><Mice Mammals><Micelles><Modeling><Modification><Mononuclear><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><Nature><Neoplastic Disease Chemotherapeutic Agents><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ><Paclitaxel><Paclitaxel (Taxol)><Particulate><Patients><Pattern><Pegylated Liposomal Doxorubicin><Permeability><Phagocytes><Phagocytic Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Plasma Proteins><Platelets><Play><Polymers><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Praxel><Process><Protein Binding><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Role><Route><S-Liposomal Doxorubicin><Si element><Signal Transduction><Signal Transduction Systems><Signaling><Silicon><Solid Neoplasm><Solid Tumor><Stealth Liposomal Doxorubicin><Sterically Stabilized Liposome><Surface><System><TNBC><Taxol><Taxol A><Taxol Konzentrat><Testing><Thrombocytes><Tissues><Toxic effect><Toxicities><Travel><Treatment Efficacy><Tumor Cell><Tumor Immunity><Tumor Tissue><Tumor-Specific Treatment Agents><Vesicle><amebocyte><anti-cancer drug><anti-cancer therapy><anti-tumor immune response><anti-tumor immunity><anticancer agent><anticancer drug><anticancer therapy><antitumor immune response><antitumor immunity><base><biological signal transduction><bound protein><cancer cell><cancer immunity><cancer microenvironment><cancer therapy><cancer-directed therapy><design><designing><developmental><drug distribution><drug treatment><drug/agent><efflux pump><fighting><improved><interstitial><intervention efficacy><lipid nanoparticle><lung metastatic><lymph cell><macrophage><malignancy><mammary cancer model><mammary tumor model><monocyte><mouse model><multi-drug resistant><multidrug resistant><murine model><nano particle><nano particle drug><nano-sized particle><nanoparticle><nanoparticle drug><nanosized particle><neoplasm/cancer><neoplastic cell><neutrophil><particle><pressure><pulmonary metastatic><side effect><social role><therapeutic efficacy><therapy efficacy><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor microenvironment><α Particles>