The long-term research goal of this work is to create polymeric drug delivery platforms with broad applicability and a wide range of tunable release parameters using rationally designed affinities between the drug and polymer. The research objective of this CAREER proposal is to develop a mathematical model of an existing affinity-based platform, and to evaluate two new affinity-based systems, testing on a cancer model. Specifically, the research goals are to: 1) develop a mathematical model comparing previously studied cyclodextrin-adamantane affinities, and extend that model to a drug delivery platform multiplexing those affinities 2) evaluate the use of antibodies / antigens affinities to provide a greater breadth of unmodified protein drug delivery; and 3) evaluate the use of oligonucleotide affinities to allow for a more tunable delivery through use of single nucleotide additions and changes. Long-term educational objectives are to introduce concepts of drug delivery to the general public, integrate engineering concepts behind drug delivery mechanisms into graduate and undergraduate education, and achieve representational participation of under-represented groups in the field of Biomedical Engineering. The specific educational goals of this proposal are to include: 1) promote participation of women and under-represented minorities through outreach to local schools; 2) increase participation of undergraduates in drug delivery education and research through creation of a Drug Delivery curriculum sequence; and 3) make a graduate level education available to local industry, law students, etc. through creation of a non-thesis Master's program and use of web-based course materials.

Intellectual Merit: Although there is anecdotal evidence that molecular affinities between drug and polymer can delay the release of drug, these affinities have not been carefully modeled to examine how rational choice of drug and polymer can be exploited to customize drug release across a broad range of therapeutic agents and disease treatments. The novelty of this work is that at the completion of the proposed research the concept of affinity-based delivery will be applicable to many new categories of drugs and drug delivery including protein based drugs such as polypeptides or antibodies, as well as oligonucleotide drugs such as anti-sense DNA, or small interfering RNA (siRNA). This work will be transformative in assisting future researchers in tuning drug delivery rates to those much slower than currently available (using cyclodextrin multiplexing), those with a broader range of tunability (using oligonucleotides), and those with unmodified molecules such as full-length proteins. The proposed research has relevance to pharmaceutics and pharmacology, chemistry, biomaterials, and biocomputing, a newly emerging field in which well-tuned biochemical affinities are used to recreate mathematic or computational tasks at an atomic level.

Broader Impact: Although this work will only test affinity-based delivery for treatment of human disease, specifically cancer, better understanding of how molecules interact will be useful for other applications such as neutraceuticals, cosmetics, as well as environmental applications such as paints, coatings, marine anti-fouling mechanisms, etc. The proposed educational plan includes community outreach, as well as undergraduate and graduate enhancement through coursework and research experiences. New classes, web-based materials, an undergraduate education sequence, and a graduate non-thesis Master's track will introduce this field to a larger audience, bringing those interested to research jobs in industry or academia. Findings from this proposed research effort will be broadly disseminated through publications in peer-reviewed journals, discussions with collaborators, and student presentations at national meetings. In addition these findings will be made available on the web. Finally the proposed research will allow the investigator to continue his efforts at mentoring future scientists and engineers, particularly women and underrepresented minorities. This will be possible through outreach to local high schools, participation in the departmental NSF undergraduate research program, and in the outreach activities of the Layered Polymers Science and Technology Center at Case.

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Case Western Reserve University
United States
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