The Nanoparticulate Drug Delivery System of Anticancer Agents: The Preparation, Characterization and Optimization of Nanoparticles of Antisense Oligonucleotide HDMAS5

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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.