Non-technical: This award by the Biomaterials program in the Division of Materials Research to Wayne State University is to develop polymer based nanomaterials to attach cancer drugs with reduced toxicity and multidrug resistance. Doxorubicin (DOX) is a leading anticancer drug, having a broad range of activity against both solid and 'soft' tumors. In spite of its immense acceptability, DOX causes a series of side effects, especially its toxicity to the heart. Another major challenge in clinical oncology is the almost universal development of multidrug resistance (MDR), which also affects DOX. In this work, the investigator proposes the development of dendrimeric DOX nanoformulations that have a high concentration of the drug, while possessing reduced toxicity to healthy tissues, and thus decreased side effects, while maintaining its activity against tumors. The PI expects to integrate the outcomes from this work in educational activities involving undergraduate and graduate students, and postdoctoral scholars, in lecture and laboratory classes, and also through a Nanoengineering Certificate Program currently funded by NSF at the campus. The PI will use this opportunity to continue to mentor both graduate and undergraduate students, and disseminate the work to international audiences through collaborative efforts. The relevance and transformative potential of this application comes from the fact that, upon its successful completion, the nanostructures developed here may serve as an alternative strategy in the treatment of a broad range of clinically relevant malignances that afflict over millions of people in the US alone.
The overall objective of this work is to design dendrimeric DOX (DDox) nanoplatforms for cancer therapy. The proposed DDox nanoplatforms will be assembled with DOX, the active pharmaceutical ingredient (API) as the monomer, and will have combined chemically- and biologically-triggered depolymerization linkers for spatially controlled intracellular disassembly of DOX. Importantly, the DDox structures are designed to contain functional terminal groups that will serve as anchoring points for the conjugation of ligands that can be used, for example, in cellular and organelle targeting, or for combination therapies, so as to transform the DDox nanostructures in true platforms for the treatment of malignant tumors. The researcher will evaluate the effectiveness of these DDox nanostructures to induce cell death in an in vitro carcinoma model. The researcher will follow the rate and extent of internalization of these nanocarriers, the endocytic pathways, disassembly of DOX and co-localization with their target organelles. The information collected will be correlated with the structure and functional properties of the nanoplatforms and their ability to induce apoptosis so as to design optimum DDox platform for cancer treatment. The investigator plans to take an active role in the education of undergraduates, and area high-school and post-graduate students, besides the involvement and training of graduate students. These activities will be achieved through the instruction of key courses including 'Nanocarrier-based Cellular Drug Delivery' and the execution of a recently funded NSF-NEU program titled "Development of an Undergraduate Certificate Program in Nanoengineering for Training the Workforce of Tomorrow." In addition, the researcher plans to continue fostering collaborations with the partners in the US and abroad, to further enhance the translational potential of the knowledge obtained in this application.
