Transcript Bentley Poster 2011

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
Abstract
Introduction
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 materials1.
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.
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 2011.2 Cancer is the second most common cause
Hypothesis
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 50-200 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.
Results
Materials and Methods
Scheme 1: Ring opening polymerization of D,L Lactide. Stannous Octoate (Sn(oct)2); 2-ethyl-1butanol (EB); Polylactide (PLA).
Scheme 2: Synthesis of azido-functionalized PLA8.5K. PLA8.5K was first brominated using 2bromoethyl isocyanate (BEI) followed by reaction with sodium azide (NaN3) to yield PLA8.5K-N3.
Dibutyltindilaurate (DBTDL).
Figure 1: 1H-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-N3.
Characteristic proton signals are labeled.
Scheme 3: Synthesis of PLA8.5K-G3 Dendron via ‘Click’ Chemistry. Copper Bromide (CuBr);
N, N, N’, N”,N”-Pentamethyldiethylenetriamine (PMDETA).
Figure 2: 1H-NMR characterization of ‘click’ chemistry between PLA-N3 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.
Scheme 4: PEGylation of G3 dendron. p-nitrophenyl chloroformation (p-NPC); triethylamine (TEA).
Conclusion
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 selfassembly, 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.
1. Duncan, R. The Dawning Era of Polymer Therapeutics. Nature Reviews Drug Discovery. 2003, 2, 347-360.
2. American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011.
3. Peer et al., Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech. 2007, 2, 751-60.
Teaching Module Plan
Acknowledgements
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.
This study was supported by NSF Grant # EEC-0743068 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.