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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：
10531257
负责人：
Shu-Hsia Chen
金额：
$ 45.65万
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/10531257
关键词：
Albumins Antineoplastic Agents Binding Binding Proteins Biological Biotechnology Blood Platelets Breast Cancer Model Breast Melanoma Cell surface Cells Circulation Development Doxorubicin Drug Efflux Drug Modelings Drug Transport Encapsulated Extracellular Matrix Fibroblasts Follow-Up Studies Future Injectable Knowledge Liposomes Lymphocyte Macrophage 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 Penetration 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 cancer cell cancer therapy design drug distribution efflux pump fighting improved interstitial intravenous administration lipid nanoparticle lung metastatic 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

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systematic comparison of methods for determining the in vivo biodistribution of porous nanostructured injectable inorganic particles.

确定多孔纳米结构可注射无机颗粒体内生物分布的方法的系统比较。

DOI：
10.1016/j.actbio.2019.08.002
发表时间：
2019
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Nizzero,Sara;Li,Feng;Zhang,Guodong;Venuta,Alessandro;Borsoi,Carlotta;Mai,Junhua;Shen,Haifa;Wolfram,Joy;Li,Zheng;Blanco,Elvin;Ferrari,Mauro
通讯作者：
Ferrari,Mauro

Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages.

DOI：
10.1038/s41467-020-20140-0
发表时间：
2020-12-08
期刊：
Nature communications
影响因子：
16.6
作者：
Song M;Yeku OO;Rafiq S;Purdon T;Dong X;Zhu L;Zhang T;Wang H;Yu Z;Mai J;Shen H;Nixon B;Li M;Brentjens RJ;Ma X
通讯作者：
Ma X

Sensitizing non-small cell lung cancer to BCL-xL-targeted apoptosis.

DOI：
10.1038/s41419-018-1040-9
发表时间：
2018-09-24
期刊：
Cell death & disease
影响因子：
9
作者：
Shen Q;Li J;Mai J;Zhang Z;Fisher A;Wu X;Li Z;Ramirez MR;Chen S;Shen H
通讯作者：
Shen H

Synergistic Activation of Antitumor Immunity by a Particulate Therapeutic Vaccine.

DOI：
10.1002/advs.202100166
发表时间：
2021-06
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
0
作者：
Mai J;Li Z;Xia X;Zhang J;Li J;Liu H;Shen J;Ramirez M;Li F;Li Z;Yokoi K;Liu X;Mittendorf EA;Ferrari M;Shen H
通讯作者：
Shen H

Surface Engineering and Multimodal Imaging of Multistage Delivery Vectorsin Metastatic Breast Cancer.

转移性乳腺癌多级递送载体的表面工程和多模态成像。