Mechanism of Intratumoral Transport of Particulate Drugs

颗粒药物的瘤内转运机制

• 批准号: 10053718
• 负责人: Haifa Shen
• 金额: $ 46.36万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/10053718
• 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

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.

肿瘤脉管系统通常被认为是泄漏的，因此可以积聚大分子和 一定尺寸范围内的颗粒以穿透和保留。因此，许多癌症药物已经 包装成简单的纳米颗粒或复合药物颗粒，以改善肿瘤的积累 组织并降低对正常器官的毒性。然而，有颗粒物有多个生物障碍 药物将在前往肿瘤的途中遇到，例如具有较高吞噬潜力的髓样细胞 循环和单核吞噬细胞系统的器官中的药物颗粒。另外，密集的肿瘤 组织充满细胞外基质和肿瘤相关的髓样细胞。目前尚不清楚颗粒 药物在系统水平上逃脱被吞噬细胞的夹带，对于已经到达的颗粒 肿瘤组织，它们如何穿透肿瘤内的多个生物屏障并到达癌细胞。 在这项研究中，我们将在脂质体，胶束和复合颗粒中包装阿霉素，并将其应用于 模拟药物以研究颗粒药的肿瘤内转运的机制。我们假设这一点 髓样细胞介导的转运是肿瘤进入和肿瘤内分布的重要途径 颗粒药。总体研究分为三个特定目标。在AIM 1研究中，我们将检查细胞 - 介导颗粒药的肿瘤进入。在AIM 2研究中，我们将分析肿瘤内的过程 药物颗粒的通过。在AIM 3研究中，我们将研究对肿瘤微环境的潜在影响 由于颗粒药的有效肿瘤内转运，抗肿瘤的免疫力。知识 这项研究产生的将为未来颗粒癌药物的设计和开发提供指导 具有更好的治疗功效和低对副作用。