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

      Kolluru, Lakshmi Prasanna; College of Pharmacy
      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.
    • Formulation Develoment and Characaterization of Polycaprolacton/Pluronic F108 NanoParticles for Targeted Breast Cancer Therapy

      Chandran, Thripthy; College of Pharmacy
      Breast Cancer ranks first among cancer deaths for women after malignant lung cancer in the United States. Despite the major advancements in the treatment of breast cancer, it still poses a major challenge. While chemotherapeutic intervention remains the major treatment approach fr cancer, they suffer from several drawbacks including dose limiting toxicity, non-specific biodistribution, and emergence of resistance in solid tumors, thus posing a risk of relapse. Furthermore, the excipients used for the administration of the anticancer agents also cause several undesirable systemic effects such as nephrotoxicity, neurotoxicity, and hypersensitivity reactions when given intravenously. Biodegradable polymeric nanoparticles have emerged as promising targeted drug delivery systems for the delivery of anticancer drug owing to their size characteristics., their ability to passively accumulate by Enhanced Permeability and Retention (EPR) effect in the tumors, ability to protect the active ingredients from degradation, providing a controlled/sustained release of the active ingredients and b tunable for the attachment of active ligands according to a patient's tumor profile and thus provide a personalized therapy. In this study, we designed polymeric nanoparticles for the delivery of anticancer agent docetaxel using poly-e-caprolactone (PCL), which forms the core of the the nanopartilces. Pluronic polymer F108 is used as an emulsifying agent/stabilizer for the PCL nanoparticles, providing a hydrophilic PEG coating thus stealth properties to the nanoparticles. The passive targeting ability of the nanoparticles is evaluated using a near infrared carbocyanine dye (Dir). Trastuzmab is used as an active targeting ligand to target the HER-2 receptors present on the human breast cancer BT-474 cells. Thus, this project focuses on the formulation development, in vitro characterization of docetaxel loaded nanoparticles and finally the characterization of trastuzumab conjugated nanoparticles.