Rational Design of a Tumor Targeting and Penetrating Nanoparticle for Drug Delivery

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My research program focuses on engineering innovative nanoparticles (NPs) for use if targeting drugs to tumors. NPs preferentially accumulate in tumors via the enlarged vascular gap but do not leak out through the tightly sealed capillary presented in most normal tissues. After traveling through the circulatory system and reaching the tumor tissue, the NPs need to move from the blood vessels to interact with tumor cells, where they must release their cargo drug for biological activity. NPs can be chemically engineered to control their properties such as particle size, charge, the presentation of a targeting ligand, and drug release kinetics. These physical properties affect the penetration of NPs in tumors, the intracellular uptake of NPs by tumor cells, and the biological activity. For example, smaller NPs exhibit improved tumor penetration compared to their larger counterparts. Ligand-conjugated NPs display increased uptake by the tumor cells; however, the effect of ligand on tumor penetration requires better understanding. Additionally, NPs that exhibit triggered-release mechanisms (i.e., burst release in tumors) show enhanced activity, but certain cell-cycle dependent drugs, such as anti-tubulin agents, may prefer sustained release. The fundamental knowledge of this field needs to be strengthened to fully understand how physical properties of various types of NPs impact their drug delivery, and the knowledge will eventually lead to rational design of an improved NP system. My lab has engineered a proprietary polysaccharide-based NP system to target a water insoluble anti-tubulin drug to tumors. In the next five years, my research program will focus on controlling the physical properties of this NP system by chemical engineering, and examining how these properties affect the drug delivery. Particularly, we will focus on how the density of a targeting ligand at the NP surface impacts the tumor penetration and cellular internalization. We will study how drug release kinetics influences the drug delivery of this NP system. We will engineer the NP constructs that contain various combinations of ligand density and release kinetics, and examine how these two factors interact to impact the drug delivery. The short term goal of this program is to gain new knowledge about chemical engineering of this new NP system to control the physical properties and to identify the major NP designing factors that affect the drug delivery. The knowledge gain from this type of mechanistic study might be applied to other NP systems and is highly appreciated by the drug delivery and NP engineering fields, as it will eventually lead to rational design of an improved NP system for drug targeting to tumors, which is the long term goal of this program. This hypothesis driven research program focusing on mechanistic studies will offer comprehensive training opportunities in the junction of chemical engineering and biology.