CAREER: Multimodal Biomaterials for Sequential Delivery of Diverse Immunotherapeutic Cargos

University Of Mississippi, University MS

Investigators

Abstract

This project is jointly funded by Biomaterials program, and the Established Program to Stimulate Competitive Research (EPSCoR). CAREER: MULTIMODAL BIOMATERIALS FOR SEQUENTIAL DELIVERY OF DIVERSE IMMUNOTHERAPEUTIC CARGOS Non-Technical Summary: The human immune system is diverse beyond compare and capable of responding to all types of challenges with precise control over the timing and area of the response. However, immunotherapies – one of the most promising types of medicines in the 21st century – are typically given all at once as single therapies, without regards to the spatial and dynamic considerations of delivery. Additionally, materials capable of controlling the timing or sequence of delivery of immunotherapies are lacking. The current project seeks to overcome these shortcomings and radically improve our ability to program immune responses. To do so, new biomaterials that can deliver a diverse range of immunotherapeutic agents in precise sequences will be generated. If successful, the project will produce innovative new polymeric technologies with applications ranging from vaccine development to immuno-oncology, having the potential to significantly improve healthcare in the US. Outreach and educational programs that build from these research efforts will include: incorporation of the research findings into undergraduate teaching, recruitment and exposure of students, including from underrepresented groups, to research through a Nanoengineering Research Experience for Undergraduates (REU), and establishment of a STEM Excursion Program where North Mississippi high school students visit the University of Mississippi to learn about the growing field of Nanobiotechnology, while undergraduate researchers serve as mentors/role models to solidify their identity in STEM. Technical Summary: Existing immunotherapies involve either a single agent or multiple agents given in combination. However, due to both the complex nature of the immune response and the diverse physicochemical nature of immunotherapeutic agents, it is incredibly challenging to design combination immunotherapies with the spatiotemporal control of delivery needed to program holistic immune responses. Moreover, materials capable of sequentially delivering immunotherapeutic agents from diverse chemical classes with control over the timing and order of release are lacking. Thus, the central research goal of this project is to develop a new class of multimodal biomaterials capable of 1) delivering diverse immunotherapeutic agents from a single material and 2) programming sequential drug release to recruit, train, and sustain the immune system during response. The first objective of this proposal is to generate a new class of glycopolymer-corona nanoparticles (NPs) that can train the immune response by co-delivering antigen and adjuvant to the same antigen-presenting cell (APC) with precise targeting of each component to the appropriate subcellular location of interest. Importantly, glycopolymer coronas will circumvent the use of poly(ethylene glycol), which is responsible for negative reactions in some patients, target the NPs to precise subsets of APCs, and inherently enable cryoprotection and lyophilization of the NPs. The second design objective of this proposal is to generate multilayered films which surface erode and release cargo sequentially at pre-programmed rates. The films will be composed of poly(2-vinyl-4,4-dimethylazlactone) (PVDMA), which undergoes ring-opening reactions in the presence of nucleophiles such as primary amines to produce hydrolytically-stable amide bonds or alcohols to yield hydrolyzable ester linkages. Thus, by post-polymerization modification, we will produce crosslinked polymer networks with control over the crosslinking density, swelling and erosion rates, and scaffold hydrophobicity. The resulting multilayered films will be engineered with three distinct phases of release: 1) recruitment phase to attract APCs, 2) training phase to deliver antigen and adjuvant to APCs, and 3) sustainment phase to boost immunogenicity and maintain a robust immune response. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.