Formulation Design and Development of Theranostic Nanoparticles for Tumor Targeted Drug Delivery

Abstract

Cancer is among the leading cause of death in the world, accounting for one in every four deaths in United States. Researchers from academia and industry are working on discovering new drug targets, developing better drug products and enhancing efficacy of drug delivery systems. In spite of the advancements, drug delivery still remains a challenge in the management of cancer. Currently, Chemotherapy (mostly in combination with radiation) is a major therapeutic approach for the treatment of cancer. However several chemotherapeutic drugs lack the ability to differentiate between normal and tumor tissues and suffer from drawbacks such as dose limiting toxicity, low specificity and emergence of multidrug resistance. Major concerns associated with current anti-cancer agents which are gaining wide importance include rapid elimination from kidney and non-specific biodistribution. In addition, the rapid clearance of the drug from the body might require administration of larger doses which can cause toxic effects. One approach to reduce the systemic toxicity and enhance the efficacy of the drugs us to administer through selective drug delivery carriers. Polymeric nanoparticles offer promise for targeted drug delivery as they have the potential for passive targeting of drugs by Enhanced Permeable and Retention (EPR) effect, controlled/sustained release of drug, reduced clearance and ability for surface fuctionalization with tumor targeting ligands.

In this studym we have successfully fabricated polymeric nanoparticles for the delivery of diagnostic and therapeutic agents using Bovine Serum Albumin (BSA) polymeric nanoparticles. Near Infrared dye, Indocyanine green and anti-cancer drug, Doxorubicin are used as model diagnostic and therapeutic agents respectively. Folic acid and cyclic RGD are used as tumor targeting ligands to target tumor microenvironment and tumor cells. This project focuses on the preformulation, formulation development, in vitro characterization and in vivo evaluation of the drug-dye loaded nanoparticles and evaluation of the active targeting potential is proposed. Spray drying and Nanoprecipitation techniques are evaluated and nanoprecipotation technique is used in final preparation. Nanoparticle suspension was then subjected to lyophilization. The formulation is further extensively characterized in vitro by Dynamic light scattering (DLS), Release Studies, Differential SCanning Calorimetry (DSC) and MTS Cytotoxicity Assey. In addition, the formulation is also evaluated in vivo for its tumor targeting potential by monitoring the biodistribution of entrapped near infrared dye using whole body non-invasive imaging technique.

Results of our work demonstrated that diagnostic and therapeutic agents can be effectively delivered in a single delivery system. Our work further emphasizes that nanoparticle based system can enhance localization of diagnostic (or therapeutic agents) into the tumor, thereby contributing to reduces side effects and enhanced efficacy.