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Title page for ETD etd-11242014-221103


Type of Document Dissertation
Author Hariri, Ghazal
URN etd-11242014-221103
Title Development, Optimization and Evaluation of Tumor-Specific Nanosponge Drug Delivery Systems as Chemotherapeutics
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
H. Charles Manning Committee Chair
Andries Zijlstra Committee Member
David Hachey Committee Member
Eva M. Harth Committee Member
Lawrence J. Marnett Committee Member
Keywords
  • cancer
  • chemotherapy
  • drug delivery
  • nanoparticles
Date of Defense 2014-03-12
Availability unrestricted
Abstract
Current chemotherapeutic treatments for cancer utilize systemic administration of cytotoxic drugs and produce many side effects in healthy tissues, making optimal treatment of cancer hard to achieve. Tumor targeted chemotherapy treatment enables these drugs to selectively treat cancer cells with minimal effect on healthy tissues. By using targeting agents that specifically recognize receptors present only on cancer cells and neovasculature, tumor-specific chemotherapy can be achieved. These targeting agents can be used to direct nanoparticle drug delivery carriers in order to deliver greater drug doses to tumor tissue, enhance bioavailability, pharmacokinetics and pharmacodynamics of many chemotherapy drugs, as well as reduce toxicity and undesirable side effects in vivo.

The development, optimization and evaluation of tumor-specific drug delivery systems composed of second generation ‘nanosponges’ has been investigated as a potential therapeutic for the treatment of lung cancer. This drug delivery system is hypothesized to optimize bioavailability and therapeutic efficacy of chemotherapy drugs in tumors, reduce side effects in normal tissues, and result in improved cancer treatment. These nanosponges have been developed from optimized linear polyester copolymers using tin (II) triflate catalyzed ring-opening polymerization methods. They contain functional groups for modification with targeting and imaging agents in order to both target malignant tumor cells as well as visualize them in vitro and in vivo. Tumor targeting peptides such as cyclo-RGD that target the αvβ3 integrin receptor, and the HVGGSSV peptide that target radiation-inducible tax-interacting protein 1 receptor allow for tumor-specific targeting of nanosponges. These nanosponges enable controlled linear drug release of small molecule chemotherapeutics that can optimize combination chemotherapy strategies for the treatment of lung cancer.

Due to their biodegradability, high encapsulation efficiency, and sustained linear drug release profiles, these optimized nanosponges are ideal for the encapsulation and controlled release of chemotherapy drugs. The applicability of a HVGGSSV peptide targeted nanosponge drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer mouse model. Combination therapy with these two drugs will allow for multiple mechanisms of action for inhibiting cancer growth, resulting in enhanced cytotoxicity when delivered in varying sequences.

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