5R21EB006499-02 Final Status Report: “Cancer Targeting with Multi-Responsive Core/Shell Microgels” A. Specific Aims

A. Specific Aims The original grant proposal contained two specific aims. These aims remain unchanged at this point in the program. The overarching goals of the program relate to the development of multi-responsive/functional hydrogel nanoparticles for cancer cell targeting. This is to be accomplished in the following specific aims: Aim 1: To utilize doxorubicin-loaded, folate-modified, degradable core/shell microgels to target cells in vitro to specifically evade P-glycoprotein based multi-drug resistance. This aim will demonstrate that the core/shell microgel construct is effective in cellular targeting, that the designed degradation pathways enable cytosolic delivery of an anti-tumor agent (doxorubicin), and that the construct enables the evasion of multi-drug resistance that arises from P-glycoprotein overexpression. Aim 2: To develop multi-functional core/shell microgels that “display” folate in response to specific matrix metalloproteinase (MMP) activity. Taking advantage of elevated MMP activity proximal to tumor growth, these microgels will have “stealth” properties that allow for folate display, cell surface binding, and endocytosis only after exposure to elevated MMP activity. This will further reduce the potential for binding and uptake of the vehicles by healthy tissues.