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The Center for Targeted Drug Delivery (CTDD) at Chapman University serves to unite scientific and technical knowledge in biomedical, pharmaceutical, and material science research to create an interdisciplinary targeted drug delivery program. CTDD members bring together expertise in drug delivery, gene therapy, cancer biology, polymer science, and nanotechnology at CUSP and other colleges at Chapman University.
The mission of the Center is to design, develop, and evaluate novel approaches for targeted delivery of therapeutic agents. Innovative drug delivery systems or approaches for delivery of drugs and therapeutic proteins will lead to breakthrough advances in health care.
The Center is located at the Chapman University School of Pharmacy, Irvine, CA, providing a comprehensive facility for targeted drug delivery projects. The facility will advance new technologies for drug targeting from conception to synthesis, including in vitro testing followed by in vivo evaluation.
Director, Center for Targeted Drug Delivery
Targeted delivery of doxorubicin for breast cancer treatment
Peptide-drug conjugates are being developed for targeted delivery of anticancer drugs, doxorubicin and cyclophosphamide, to breast cancer cells. The drugs are conjugated to small peptides (10-residue long) via a linker. The peptides are designed to target breast cancer cell surface receptor(s) specifically. The conjugates are synthesized using solid-phase and solution phase chemistry followed by purification and characterization using different analytical techniques. The conjugates will be evaluated using breast cell lines and breast cancer xenografts before embarking preclinical studies.
Controlled release of anti-cytokine biologics for intra-articular applications in arthritis
Osteoarthritis (OA) is a chronic degenerative joint disease affecting articular cartilage, synovium and bone. Owing to the limited number of joints involved in OA coupled with the avascular nature of cartilage, intra-articular (IA) drug delivery is well-positioned as a principal strategy to achieve therapeutic drug levels in the joint tissues and if desired, to minimize systemic toxicity. The efficacy of IA treatments is severely limited by the rapid joint clearance of small molecules and large polymers alike. We have recently shown in a proof-of-concept that encapsulating interleukin-1 receptor antagonist (IL-1 ra) in biodegradable poly (lactic-co-glycolic acid) (PLGA) exerts a disease modifying effect in a pre-clinical posttraumtic OA model (Elsaid KA, et al, Journal of Experimental Orthopaedics (2016) 3:18).
Currently, we are developing novel platforms to optimize IL-1 ra joint residence. This includes combining PLGA encapsulation of IL-1 ra and hyaluronic acid-based hydrogel scaffolding to evaluate the effect of PLGA composition and HA crosslinking on release of IL-1 ra as defined by 100% and steady-state release as well as extracellular availability of IL-1 ra using a co-culture models of macrophages and synovial fibroblasts. Ultimately, the efficacy of a single-dose treatment of the optimized delivery system will be studied in-vivo.
Multistage delivery system for cancer treatment
Here, the multistage nanoparticle delivery system utilizes polymeric materials to achieve a temporal drug release. Tumor stroma is associated with limited penetration and poor spatial distribution of drugs throughout solid tumors and represents significant barrier to drugs’ anticancer efficacy. To overcome this stromal barrier, the multistage delivery system first releases a drug which targets the stromal barrier. In the second step, the release of chemotherapy agents will deplete the cancer cells. It is hypothesized that the stroma inhibition resulted from the first wave of drug release will enhance the penetration of chemotherapy agents into the tumor and therefore potentiate its therapeutic effect.
Stable nucleic acid-lipid particles for delivery of therapeutics
Here we are developing Stable Nucleic Acid-Lipid Particles (SNALPs), which are nanoparticles that form a liposome-like structure, for delivery of nucleic acids such as small RNAs and plasmid DNA for RNA interference and gene therapy, respectively. We have synthesized a library of linear and cyclic peptides that are positively charged and therefore, spontaneously interact with nucleic acids. The peptides will be used for nucleic acid delivery, and are designed for incorporation into a multi-component delivery system or SNALP. The SNALP delivery system allows improved in vivo performance and active targeting of nucleic acids to the site of action.
Carrier-mediated selective delivery of anticancer and antiviral drugs
Peptide nano-materials and peptide-capped metal nanoparticles are evaluated as cell-penetrating nuclear targeting agents, molecular transporters of bioactive cell-impermeable compounds, or self-assembled scaffolds for drug delivery applications. Amphiphilic cyclic peptides are used for enhanced cellular delivery of anticancer drugs, antiviral drugs, siRNA, and phosphopeptides. It is envisioned that cellular delivery by functionalized cyclic peptides will improve the stability, cellular uptake, biological activities, and active targeting of cell-impermeable compounds, such as anticancer and antiviral drugs and siRNA, with limited solubility, permeability, or stability.
Prostate cancer targeted drug delivery systems
Here prostate cancer targeted drug delivery systems are developed using prostate specific peptide and FDA-approved anticancer drugs. The anticancer drug conjugates are designed where the fibronectin-specific receptor peptide is conjugated to the drug via enzyme-specific linker, and the drug is specifically released at the prostate cancer site avoiding potential toxic effect of cytotoxic drugs like doxorubicin and paclitaxel. The peptide is synthesized by Fmoc/tBu solid phase chemistry followed by purification and characterization. Synthesized conjugates will be tested in prostate cancer cell lines before evaluation using in vivo animal models.
Tunable release devices for the treatment of infectious and oncological diseases
Tunable release devices are designed to allow for in situ adjustment of the drug release kinetics to the rates of new tissue growth, body fluids flux and tissue remodeling. To that end, predominantly inorganic nanoparticles, e.g., bone mineral, iron oxide, silica and various carbons, are used as carriers. Drug delivery devices emerging from this work are to fulfill a dual purpose: tissue regeneration and obliteration of the disease cause. Magnetically guided, hyperthermia-effective particles are being designed for the treatment of oncological pathologies, while injectable, self-setting bone cements are being designed for the treatment of chronic bone infection. The development of advanced non-viral gene delivery devices and vehicles for the oral delivery of peptides and antibodies are additional projects pursued in Dr. Uskokovic’s lab.
Novel APE/Ref-1 inhibitors for human melanoma therapy
In this project, novel APE/Ref-1 inhibitors are being developed for human melanoma therapy. These compounds will be further optimized before translational studies and clinical trials leading to novel therapeutic candidates in the areas of chemoprevention and cancer therapy.
Dr. Kamaljit Kaur
Chapman University School of Pharmacy