Mechanism of Intratumoral Transport of Particulate Drugs

肿瘤的血管系统通常被认为是渗漏的，因此允许大分子和 一定大小范围内的颗粒能够穿透和保留。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，以改善在肿瘤中的蓄积 组织，减少对正常器官的毒性。然而，存在着多个生物屏障，颗粒物 药物会在到达肿瘤的途中遇到，例如具有高吞噬能力的髓系细胞 单核吞噬细胞系统中循环和器官中的药物颗粒。此外，致密的肿瘤 组织充满了细胞外基质和肿瘤相关的髓系细胞。目前尚不清楚颗粒物是如何 药物在系统水平上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，到达癌细胞。 在本研究中，我们将阿霉素包裹在脂质体、胶束和复合颗粒中，并将其应用于 研究微粒药物在肿瘤内转运机制的模型药物。我们假设 髓系细胞介导的转运是肿瘤进入和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。在目标1研究中，我们将检查细胞- 介导颗粒状药物进入肿瘤。在目标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。 以及由于有效地在肿瘤内转运颗粒药物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 具有较好的治疗效果和较低甚至没有副作用。

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.