INTELLECTUAL MERIT: The design and synthesis of functional self-assembling systems capable of encapsulating, storing, and delivering small hydrophobic molecules/therapeutics is becoming increasingly important. A majority of the delivery vehicles are derived from lipids and synthetic polymers. However, self-assembling peptides/proteins are emerging as potential materials that can be readily manipulated for therapeutic delivery. This work aims to tailor genetically engineered protein block polymers for the delivery of small hydrophobic molecules/therapeutics. The fabrication of multi-functional, nanoscaled protein-based delivery agents for the dual delivery of doxorubicin (dox) and curcumin (ccm) to cancer cells is proposed. The engineered protein materials can: (1) be targeted via hyperthermia conditions, concentrating the agents at the localized disease site, (2) bind/encapsulate dox and ccm without the need for further chemical alteration of the delivery agent or the therapeutic agent, (3) be retained at the cancer site due to the enhanced permeation retention (EPR) effect, and (4) be decorated with cancer targeting peptide sequences for active targeting of breast cancer cells. The central hypotheses to be tested are that (1) appropriate combinations of protein domains will enable supramolecular assembly in the hyperthermia temperature range and (2) tailoring small molecule-binding abilities and cancer specific targeting domains into a single construct will enable the controlled delivery of desired chemical agents to treat breast cancer as a model. Critical features of the proposed delivery vehicle are that the modular nature of these protein materials enables integration of the above domains into a single polymer chain and that their ability to self-assemble allows dual drug encapsulation as well as control over the delivery and targeting ligand presentation. This will be accomplished by exploiting the most powerful methods of molecular biology and protein engineering. The insight gleaned from these studies may be used to identify common themes or predictable rules towards engineering protein-derived materials with tunable properties for therapeutic delivery.
BROADER IMPACTS: The proposed work may lead to encapsulating vehicles capable of selectively delivering anticancer, and other, therapeutic agents. This project will train the next generation scientists and engineers to integrate tools from biology, chemistry, and engineering to address the biomedical challenge of targeted drug delivery. The educational and outreach components of this proposal fall into distinct but interrelated activities. In addition to teaching and mentoring graduate students and postdocs, the PI has and continues to supervise both undergraduates and high-school students from the Youth in Engineering and Science (YES) program in laboratory research. The PI will continue, in partnership with the Urban Assembly Institute for Math and Science for Young Women (UAI), to develop a tiered mentoring outreach program that provides classroom support for teachers and infuses technology into the curriculum through modern, engaging modules. This program integrates modern technology and interdisciplinary science for young students and teachers in the Brooklyn schools. Additional hands-on, technologically advanced modules will be developed together with undergraduate fellows. For example, they have developed an iPad app "Lewis Dots" that enables the molecular visualization of chemical structures that, together with blog-based learning approaches, has been implemented in the UAI classroom.
