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Mechanism of Intratumoral Transport of Particulate Drugs

颗粒药物的瘤内转运机制

基本信息

批准号：
9723053
负责人：
Haifa Shen
金额：
$ 46.49万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9723053
关键词：
Albumins Alpha Particles Antineoplastic Agents Binding Proteins Biological Biotechnology Blood Circulation Blood Platelets Breast Cancer Model Breast Melanoma Cell surface Cells Development Doxorubicin Drug Efflux Drug Modelings Drug Transport Encapsulated Extracellular Matrix Fibroblasts Follow-Up Studies Future Injectable Intravenous Knowledge Liposomes Lymphocyte Malignant Neoplasms Mediating Metastatic breast cancer Micelles Modeling Modification Mononuclear Multi-Drug Resistance Mus Myelogenous Myeloid Cells Nature Organ Paclitaxel Particulate Patients Pattern Permeability Phagocytes Pharmaceutical Preparations Pharmacotherapy Plasma Proteins Play Polymers Process Role Route Signal Transduction Silicon Solid Neoplasm Sterically Stabilized Liposome Surface System Testing Tissues Toxic effect Travel Treatment Efficacy Tumor Immunity Tumor Tissue Vesicle anti-tumor immune response base cancer cell cancer therapy design drug distribution efflux pump fighting improved interstitial lipid nanoparticle lung metastatic macrophage monocyte mouse model nanoparticle nanoparticle drug neoplastic cell neutrophil particle pressure side effect triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

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.

肿瘤的血管系统通常被认为是渗漏的，因此允许大分子和