Fifth
Annual Grant Winners 2004-2005
Adam Yuan, Ph.D., HPD – College of Pharmacy
Appu Rathinavelu, Ph.D., HPD – College
of Pharmacy
Jennie Lou, M.D., HPD – College of
Osteopathic Medicine
Dean William Hardigan, HPD – College of Pharmacy
Dean Anthony Silvagni, HPD – College
of Osteopathic Medicine
Title: The
Nanoparticulate Drug Delivery System of Anticancer
Agents: The Preparation, Characterization and
Optimization of Nanoparticles of Antisense Oligonucleotide
HDMAS5
Abstract:
Biodegradable polymeric micro/nanoparticulates
can enhance the therapeutic efficacy of anticancer drugs
while reduce their systemic side effects. In particular,
nanoparticulates enable intravenous, intramuscular injection
and subcutaneous administration by minimizing possible
irritant reactions. The goal of this project is to fabricate,
optimize and characterize the nanoparticulate delivery
system using a model anticancer agent, which is a murine
double minute (mdm2) specific antisense phosphorothioate
oligodeoxynucleotide (HDMAS5). The mutant oligonucleotide
(M4) containing 4 base mismatches will be used as the reference.
In fact, the antisense anticancer oligonucleotide drug
delivery is a new, exciting and yet very challenging area
of research in Pharmaceutics. The long-term objective is
to achieve enhanced and targeted delivery of anticancer
agents to tumor cells by using this proposed nanoparticulate
drug delivery system. The proposed studies center around
a biocompatible and biodegradable delivery device, the
nanoparticulates, as a means to provide sustained, targeted
drug delivery to the sites of tumors. The key elements
of the nanoparticulate delivery system are low toxicity
and compositional flexibility, based on interactions of
charged polymer pairs. The techniques of emulsion-droplet
coalescence, high-speed homogenization, sonification, freeze-dry
solvent evaporation will be used to prepare and optimize
the nanoparticulate delivery system of oligonucleotide.
Characterization of particle size, size distribution, stability,
surface morphology, porosity of nanoparticles will be done
using particle sizer, differential scanning calorimetry
(DSC), scanning electron microscopy (SEM). The drug loading
efficiency, drug stability, in vitro evaluation
of the nanoparticulate delivery system will be studied
using liquid-liquid extraction (LLE), solid-phase extraction
(SPE), UV, HPLC and dissolution testing. In future research, in
vivo studies of nanoparticulate drug delivery system
will be done using cell culture of targeted tumor cells,
RT-PCR and immunoblotting techniques, in collaboration
with Dr. Appu Rathinavelu’s pharmacology research
lab. To provide better retention of the antisense oligonucleotide,
the model drugs can also be investigated for the possibility
to be prepared as polyethylene glycol conjugates and
lyposomal formulations, which retain biological activity
with reduced toxicity as well.
