This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In recent years, nanomaterials have made a huge impact on the field of drug delivery. Macromolecules are being used as scaffoldings to conjugate a variety of small molecules to create nanotherapeutics with specific functions. For example, poly(amidoamine) (PAMAM) dendrimers, synthetic starbranched polymers, have been conjugated to a targeting agent, an imaging agent, and a chemotherapy drug to create a targeted, trackable, chemotherapy delivery system. The debilitating drawback to producing such a nanotherapeutic is the lengthy total synthesis. From start to finish, each multi-functionalized polymer can take several months to produce. Although purification steps cannot be shortened, the reaction times of each conjugation may be shortened without sacrificing product quality. However, no detailed studies have been performed to determine optimal reaction times necessary for conjugation of the small molecules to the active arms of the dendrimer. Conventionally, 24-72 hours is the time period to produce an acceptable product, and this broad range of time indicates the lack of reaction optimization. For a multifunctional device requiring several conjugations, this lack of knowledge directly effects turnover time. However, if the chemical reactions were monitored throughout the synthesis, the time of completion could be determined for each conjugation and the efficiency of the total synthesis could be optimized. In addition, no catalysts have been reported to increase reaction rates of the amide bond formation between the dendrimers and their conjugates. The use of catalysts to increase reaction rates would improve reaction efficiency and make the targeted drug delivery device a more viable therapeutic option. Unfortunately, reaction analysis can be problematic since the nature of the material requires simultaneous characterization of a macromolecule and quantitative analysis of the small molecule conjugates.
We aim to develop a method to analyze the population distribution of dendrimers with varying numbers of small molecule conjugates in order to fully define reaction efficiency. Specifically, we plan to study how reaction time affects the average number of small molecules conjugated to dendrimers, as well as the distribution of intermediate reaction products that lead to this average. With this, we aim to optimize the synthesis of PAMAM dendrimer-small molecule conjugates using accepted methods and explore a variety of catalysts to improve reaction efficiency.
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