DRUG DESIGN, DEVELOPMENT, AND DELIVERY
4D LABORATORY

The Drug Design, Development, and Delivery (4D) Lab’s mission is to alleviate pathological conditions and promote functional tissue regeneration through biomaterial-based synthesis, formulation, and delivery of therapeutic compounds. Our research focuses on the understanding of drug and gene delivery in biological systems and developing new therapeutics and biomaterials for the diagnosis and treatment of many diseases. We are currently working in the following areas:

Multi-functional Nanoparticle Delivery System

Polymeric micelle nanoparticle systems formed from amphiphilic block copolymers have been utilized as drug/gene delivery carriers due to their high loading capacity for drug/gene and their unique disposition characteristics in the body. In aqueous solution, amphiphilic co-polymers spontaneously aggregate to form micelles consisting of a hydrophobic core surrounded by a hydrophilic shell. Polymeric micelles are typically between 10 and 200 nm in diameter, which is a crucial factor for effective cellular uptake through endocytosis. Currently, we are developing tissue-specific polymeric micelle delivery system for the combinatorial therapy of drug and gene to improve drug therapeutic efficacy without undesired side effects .

1. Neural Regeneration

Due to the limited capacity for plasticity and regeneration in the adult central nervous system (CNS); spinal cord injury (SCI), traumatic brain injury (TBI), and neurodegenerative diseases such as multiple sclerosis, Parkinson’s, Alzheimer’s, Huntington’s diseases are devastating disorders. Currently, there is no effective clinical therapy to promote plasticity and axonal regeneration that will achieve functional recovery following these diseases. The goal of this project is to develop multi-functional polymeric micelle nanoparticles for combinatorial drug/nucleic acid delivery for the efficient treatment of CNS trauma and diseases. We synthesized amphiphilic block copolymers (PgP) as a delivery carrier for combinatorial therapy of nucleic acid and drug for the neural regeneration. We demonstrated that the PgP polymeric micelle is a promising carrier for both plasmid DNA and siRNA capable of transfecting primary chick forebrain neuron cells in vitro with low cytotoxicity. We also demonstrated that PgP is an efficient gene carrier in vivo after injecting PgP/pβ-Gal polyplexes in rat T9 spinal cord region. Currently, we are conjugating a neuron-specific antibody to deliver the nanotherapeutics to specifically neuron cells. We are also performing in vivo studies to evaluate axonal plasticity and functional recovery in response to delivery of drug-loaded PgP/ siRNA nanotherapeutics in a rat direct cortical impact model of TBI and rat dorsal compression model of spinal cord injury.

Collaborators:
Dr. Ken Webb (Bioengineering, Clemson University)
Dr. Mark Kindy (Dept. of Physiology and Neuroscience, MUSC)
Dr. Michael Lynn (Neurosurgeon, Greenville Health System)

Funding: SC COBRE Center of Biomaterials for Tissue Regeneration NIH grant # P20GM103444 from NIGMS (National Institutes of General Medical Sciences)

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2. Cancer Therapy

Brain and Spinal Cord Tumor
Spinal tumors are neoplasms of the central nervous system (CNS). Intramedually spinal cord tumors (IMSCT) are relatively rare neoplasms, accounting for five to 10 percent of all spinal tumors. However, these tumors exert non-mechanical back pain, especially middle or lower back pain. Pain may increase with activity and spread beyond the back to the hips, legs, feet or arms and may worsen over time. Treatment can vary depending on the type of tumor and chemotherapy, radiation therapy, and surgery are most common. However, there is no effective clinical treatment for IMCST. Therefore, in order to improve the quality of life for these patients, it is crucial to develop a novel treatment strategy. Our research team developed polymeric micelle delivery system for simultaneous delivery of the anticancer drug and nucleic acid therapeutics. We evaluated PgP as a efficient gene delivery carrier using pGFP in C6 glioma cells and B35 neuroblastoma cells in vitro. We also evaluated the feasibility of PgP as a gene delivery carrier using plasmid DNA encoding beta-galactosidase gene in an in vivo rat spinal cord tumor model. Currently, we are evaluating the synergistic effect of anticancer drug and therapeutic nucleic acid in tumor regression by delivering anticancer drug-loaded PgP/siRNA polyplexes in rat spinal cord tumor model.


Collaborators:
Dr. Mark Kindy (Dept. of Physiology and Neuroscience, MUSC)
Dr. Michael Lynn (Neurosurgeon, Greenville Health System)

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Breast cancer

Metastatic breast cancer is the leading cause of death for women and current therapies include radiation and surgical removal in combination with systemic chemotherapy. However, usage of anticancer drugs has been limited because of their side effects in normal organs and the eventual development of drug resistance by cancer cells1. We propose a novel polymeric micelle delivery system that combines targeted chemotherapeutic drug delivery with siRNA directed towards overcoming drug resistance for the treatment of drug resistant cancer. The objective of this research is to develop tumor-specific polymeric nanoparticles as simultaneous delivery carriers for combinatorial therapy of anticancer drug and siRNA for the efficient treatment of various types of drug resistant breast cancers. We conjugated folic acid (FA) to PgP and tested the feasibility of FA-PgP as a nucleic acid delivery carrier using pGFP and siGlo in human breast cancer cells, MCF-7 (FA+) and MDA-MB-468 (FA-) in 10 % serum condition. We have demonstrated that FA-PgP is an efficient nucleic acid carrier in both breast cancer cell types. We also demonstrated that FA-PgP can deliver this nanotherapeutic to tumor cells by ligand-specific active transport of drug delivery vehicle in the presence of free folic acid using MCF-7 (FA+) cells and MDA-AB 468 (FA-) cells.


Collaborator:
Dr. Wendy Cornett (Breast Surgeon, Greenville Health System)