Date of Completion

7-24-2014

Embargo Period

7-24-2015

Keywords

calcium phosphate, nanoparticles, cancer, chemotherapy, targeted therapy

Major Advisor

Dr. Liisa Kuhn

Co-Major Advisor

Dr. A. Jon Goldberg

Associate Advisor

Dr. Diane Burgess

Associate Advisor

Dr. Aliassghar Tofighi

Field of Study

Materials Science and Engineering

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Overall cancer survival rates steadily decline each year following diagnosis and side effects of chemotherapy restrict its use. The chemotherapeutic cis-diamminedichloro-platinum (cisplatin, CDDP) is poorly soluble and has dose limiting side effects. Nanoparticle delivery systems can deliver a higher dose of drug directly to the tumor by both active and passive targeting, holding promise of fewer side effects and greater anti-tumor efficacy. To date, few nanoparticle systems have been FDA approved for the treatment of cancer due to complicated physicochemical characterization, drug inactivation by the delivery system, scale-up challenges, and lack of demonstrated in vivo safety and efficacy. Further research is needed in this area.

This dissertation examined a naturally biocompatible carrier for delivery of CDDP: calcium phosphate (CaP). Three molecules were tested to stabilize CaP nanoparticles (nCaP) and increase injectability: sodium polyacrylate (D), sodium citrate (CIT) and carboxymethyl hyaluronic acid (CMHA). nCaPDCDDP and nCaPCITCDDP were examined against a head & neck cancer (HNC) model, because HNC patients could greatly benefit from localized chemotherapy prior to surgical resection. Triple negative breast cancer (TNBC) with a CD44high/CD24-/low cell phenotype has emerged as an important new target for chemotherapeutics. CD44 is the major receptor for hyaluronic acid, targetable with CMHA. These studies showed all three molecules stabilized nCaP as measured by light scattering, zeta potential, x-ray diffraction and transmission electron microscopy, and released biologically active CDDP as measured by in vitro release studies and in vitro cytotoxicity testing. However, intratumoral (IT) delivery of nCaPDCDDP or nCaPCITCDDP was not as effective as CDDP IT in vivo against murine and human HNC tumor models, due stabilizer inhibition of CDDP. Surface plasmon resonance proved CMHA and nCaPCMHACDDP bind CD44. CMHA didn’t inactivate CDDP and nCaPCMHACDDP had comparable activity to free CDDP in vitro. Local delivery of nCaPCMHACDDP did not demonstrate a benefit over local delivery of CDDP in a human TBNC mouse model, due to lack of even distribution of nanoparticles throughout the tumor where CDDP alone could freely diffuse. These studies show that localized delivery of CDDP remains a promising strategy to increase drug effectiveness while decreasing drug side-effects that negatively impact cancer patients.

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