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：
10310460
负责人：
Shu-Hsia Chen
金额：
$ 45.89万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310460
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 Myeloid Cells Myeloid-derived suppressor 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.

肿瘤脉管系统通常被认为是有渗漏的，因此允许大分子的积累和一定粒径范围内的颗粒能够渗透并截留。因此，许多抗癌药物被包装成简单的纳米颗粒或复合药物颗粒以改善在肿瘤中的积累组织并减少对正常器官的毒性。然而，颗粒物存在多种生物屏障药物在到达肿瘤的途中会遇到具有高吞噬潜力的骨髓细胞循环中和单核吞噬细胞系统器官中的药物颗粒。此外，致密肿瘤组织充满细胞外基质和肿瘤相关骨髓细胞。目前尚不清楚颗粒物如何药物在系统水平上逃脱吞噬细胞的捕获，并且对于已经到达的颗粒肿瘤组织，它们如何穿透肿瘤内部的多重生物屏障并到达癌细胞。在本研究中，我们将阿霉素包装在脂质体、胶束和复合颗粒中，并将其作为模型药物研究颗粒药物的瘤内转运机制。我们假设骨髓细胞介导的运输是肿瘤进入和瘤内分布的重要途径颗粒药物。总体研究分为三个具体目标。在目标 1 研究中，我们将检查细胞- 介导颗粒药物进入肿瘤。在Aim 2研究中，我们将分析瘤内药物颗粒的通过。在 Aim 3 研究中，我们将研究对肿瘤微环境的潜在影响颗粒药物有效的瘤内转运带来的抗肿瘤免疫。知识这项研究的结果将为未来颗粒抗癌药物的设计和开发提供指导具有更好的治疗效果和低甚至无副作用。