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.

Public Health Relevance

The majority of drug molecules end up in the normal organs rather than in the tumor, making most cancer drugs very toxic to the body but not so potent to fight cancer. Consequently, more and more cancer drugs are being packaged into nanoparticles, which changes the drug distribution pattern and reduces toxicity, but still does not significantly improve therapeutic efficacy in many cases. In this application, we perform studies to systematically analyze the process of particulate drug entry into the tumor and drug distribution inside the tumor tissue, and to identify key factors that facilitate these processes. Knowledge generated from this study will greatly improve design of future cancer drugs with high therapeutic efficacy and low toxicity so as to better serve the patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Alley, Michael C
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Methodist Hospital Research Institute
United States
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