Synthesis and Characterization of Amphiphilic Dendron Coils – Potential Nanomicelle Precursors Jeromy T. Bentley, RET Fellow 2011 Naperville Central High School RET Mentor: Dr. Seungpyo Hong, PhD NSF-RET Program IntroductionAbstract Conclusion Hypothesis Materials and Methods Teaching Module Plan This study was supported by NSF Grant # EEC to Dr. Andreas Linninger, RET Program Director. I would also like to thank Dr. Seungpyo Hong my faculty research mentor and Ryan M. Pearson my graduate research mentor. I would also like to acknowledge the undergraduate and graduate students in Hong Lab for this experience. This work has been partially supported by the Vahlteich Research Funds of the University of Illinois College of Pharmacy awarded to Dr. Hong. Acknowledgements Results This year, an estimated 570,000 Americans are expected to die of cancer, more than 1,500 people a day. Nearly 1,600,000 new cases of cancer will be diagnosed in the U.S. in Cancer is the second most common cause of death in the US, exceeded only by heart disease. In the US, cancer accounts for nearly 1 of every 4 deaths. Most currently available chemotherapy treatments frequently accompany severe side effects due to high toxicity to normal cells and tissues, thus targeting tumor cells and tissues is a worthwhile endeavor. Passive targeting utilizes the enhanced permeability and retention (EPR) effect that is defined by leaky vasculature around tumors, resulting in the accumulation of the nanoscale delivery system at the tumor site. 3 In order to take advantage of the EPR effect, a nanoscale delivery system needs to be in the range of nm. The objective of the study was to synthesize a novel amphiphilic PEGylated dendron coil capable of self-assembling to form nanomicelles less than 200 nm. 1. Duncan, R. The Dawning Era of Polymer Therapeutics. Nature Reviews Drug Discovery. 2003, 2, American Cancer Society. Cancer Facts & Figures Atlanta: American Cancer Society; Peer et al., Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech. 2007, 2, Dendritic polymers are highly branched structures, with complex architectures and well-defined spatial location of functional groups. They can be used in applications such as targeted drug-delivery, surface engineering, and as biomimetic materials 1. A dendritic hybrid called a dendron coil was synthesized and PEGylated. Proton NMR indicates this process was successful. This PEGylated dendron coil will be further evaluated to observe the self-assembled structures which can form and tested for its drug delivery potential. The results presented here are the first steps towards developing a novel drug delivery system with passive targeting potential through size control. Scheme 1: Ring opening polymerization of D,L Lactide. Stannous Octoate (Sn(oct) 2 ); 2-ethyl-1- butanol (EB); Polylactide (PLA). Scheme 2: Synthesis of azido-functionalized PLA8.5K. PLA8.5K was first brominated using 2- bromoethyl isocyanate (BEI) followed by reaction with sodium azide (NaN 3 ) to yield PLA8.5K-N 3. Dibutyltindilaurate (DBTDL). Scheme 3: Synthesis of PLA8.5K-G3 Dendron via ‘Click’ Chemistry. Copper Bromide (CuBr); N, N, N’, N”,N”-Pentamethyldiethylenetriamine (PMDETA). Scheme 4: PEGylation of G3 dendron. p-nitrophenyl chloroformation (p-NPC); triethylamine (TEA). Figure 1: 1 H-NMR characterization of end-group modification of polylactide (PLA). Modification of the end-group of PLA was followed by the observance of the appearance of proton signals adjacent to the attempted modification. PLA-OH was converted to PLA-Br which was then converted to PLA-N 3. Characteristic proton signals are labeled. Figure 2: 1 H-NMR characterization of ‘click’ chemistry between PLA-N 3 and G3 dendron bearing a focal acetylene group. Characteristic peaks of the G3 dendron were observed in the spectrum, however the proton signals associated with the triazole ring formation were not observed most likely due to interference between residual solvent signals. Follow-up studies to further confirm the structure will follow. Characterization of the PEGylated dendron coil is underway and thus not included. Here we present the synthesis and characterization of a novel PEGylated dendron coil which is comprised of a hydrophobic polylactide block which is PEGylated through the mediation of a generation 3 polyester dendron. The resulting structure is highly hydrophilic which upon self- assembly, may form micelles with a dense PEG surface which is ideal for a drug delivery carrier. Further studies will involve testing the critical micelle concentration (CMC) and hydrophobic drug encapsulation and release potential. An integral portion of the synthesis of any chemical compound is the confirmation that the desired product was successfully synthesized. As a chemistry teacher who does teach a little bit of organic chemistry, it would be a wonderful opportunity for students to be exposed to proton NMR spectroscopy. It is proposed that students would create small tutorial videos for interpreting proton NMR spectra for the purpose of proper characterization of small molecular weight organic compounds of various functional groups.