Mechanism of Intratumoral Transport of Particulate Drugs

颗粒药物的瘤内转运机制

• 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
• 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

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渗漏的，因此允许大分子和大分子的积聚。 在一定的尺寸范围内的颗粒渗透和保留。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中的积聚 组织，并减少对正常器官的毒性。然而，有多种生物屏障， 药物在到达肿瘤的途中会遇到诸如对肿瘤具有高吞噬潜力的骨髓细胞， 单核吞噬细胞系统的循环和器官中的药物颗粒。此外，高密度肿瘤 组织充满细胞外基质和肿瘤相关的骨髓细胞。目前尚不清楚颗粒物是如何 药物在系统水平逃脱吞噬细胞的捕获，对于已经到达的颗粒， 肿瘤组织，它们如何穿透肿瘤内的多种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，以研究颗粒药物的肿瘤内转运机制。我们假设 骨髓细胞介导的转运是肿瘤进入和肿瘤内分布的重要途径， 微粒药物总体研究分为三个具体目标。在Aim 1研究中，我们将检查细胞- 介导颗粒药物进入肿瘤。在目标2研究中，我们将分析肿瘤内 药物颗粒的通过。在目标3研究中，我们将研究对肿瘤微环境的潜在影响 以及由于颗粒药物的有效肿瘤内转运而产生的抗肿瘤免疫。知识 这项研究产生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至无副作用。

项目成果

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

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。

• DOI: 10.21769/bioprotoc.4030
• 发表时间: 2021
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Goel,Shreya;Ferrari,Mauro;Shen,Haifa
• 通讯作者: Shen,Haifa

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)
• 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