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DiMaggio Project
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Reaction Rate Determination and Optimization Of PAMAM Dendrimer-Small
Molecule Conjugation: Improving The Efficiency Of Chemotherapeutic
Nanodevice Synthesis

Principal Investigator: Stassi DiMaggio, Ph.D. Assistant Professor, Department of Chemistry

Abstract

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.

Specific Aims

Herein, we describe the technical plan for determining the specific reaction completion time, analyzing product distribution, and optimizing the conditions of each conjugation step necessary to develop a targeted nanodevice for use in treating cancer. To this end, four tasks are proposed. They are:

  1. Perform simultaneous nanomaterial synthesis reactions and evaluation of the products using HPLC and NMR. Determine at what time interval the reaction was completed and determine distribution of products as a function reaction time and reagent stoichiometry.
  2. Analyze products for quality using HPLC, NMR, MALDI-ToF and Gel Permeation Chromatography (GPC) featuring light scattering, viscometer, refractometer and UV detectors to determine molecular weight and polydispersity.
  3. Optimize multifunctional nanodevice synthesis by monitoring conjugation reactions of small molecules to macromolecules under controlled reaction conditions.
  4. Synthesize monodisperse polymeric dendrimer conjugates using a catalysis based synthesis.

Presentations:

  1. J. Abair , L. McElrath , L. Preyan , P. Barrett and S. DiMaggio. Non-Viral Gene Targeting in C.elegans . LA ACS Undergraduate Research Poster Session, New Orleans, LA, September 30, 2009
  2. M. Thompson, A. Desai, S. DiMaggio Improving the Synthesis of a Chemotherapeutic Nanodevice LA ACS Undergraduate Research Poster Session, New Orleans, LA, September 30, 2009
  3. M. Thompson, A. Desai, S. DiMaggio Determining Reaction Rates and Product Distribution of Dendrimer Conjugation Reactions. LSU Triple X Undergraduate Research Symposium, Baton Rouge, LA, October 29, 2009
  4. J. Abair , L. McElrath , L. Preyan , P. Barrett and S. DiMaggio. Synthesis of Functionalized Dendrimers as Non-Viral Gene Delivery Systems. LSU Triple X Undergraduate Research Symposium, Baton Rouge, LA, October 29, 2009
  5. J. Abair , L. McElrath , L. Preyan , P. Barrett and S. DiMaggio. Synthesis of Functionalized Dendrimers as Non-Viral Gene Delivery Systems. 239th ACS National Meeting & Exposition, San Francisco March 21-25, 2010
  6. M. Thompson, A. Desai, S. DiMaggio Determining Reaction Rates and Product Distribution of Dendrimer Conjugation Reactions. 239th ACS National Meeting & Exposition, San Francisco March 21-25, 2010
  7. Stassi DiMaggio, Doug Mullen, Mark Banaszak Holl , James R. Baker, Jr , Reaction Rate Determination of PAMAM Dendrimer -Small Molecule Conjugation:  Improving the Efficiency of Chemotherapeutic Nanodevice Synthesis . LCRC Retreat Poster session, New Orleans, LA, March 2010.
  8. J. Abair , P. Barrett and S. DiMaggio Synthesis of Functionalized Dendrimers as Non-Viral Gene Delivery Systems. Festival of Scholars, New Orleans, LA, 2010
  9. M. Thompson, A. Desai, S. DiMaggio. Determining reaction rates and product distribution of dendrimer conjugation reactions.  Festival of Scholars, New Orleans, LA, 2010
 
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