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Engineered Nanoparticle for Targeted and Controlled Drug Delivery

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2017, PhD, University of Cincinnati, Engineering and Applied Science: Chemical Engineering.
Cancer is still a major threat to public health worldwide. Thanks to the extensive studies in cancer biology and growing understanding in cancer, many novel and effective therapeutic agents and drug combinations have been discovered and designed. However, many of them are challenged in reaching their targeted site. Nano-scaled drug carriers that target and deliver therapeutic agents to the sites of diseases have shown great promises in cancer treatment. As a starting point, we designed a human epidermal growth factor receptor 2 (HER-2) targeting pH sensitive nanoparticle combining the advantages of polyhistidine (PHis) and Herceptin. This nanoparticle contains a pH sensitive hydrophobic core in which chemotherapeutic drug is loaded and hydrophilic layer which stabilizes the whole nanoparticle while providing active targeting to HER-2. This nanoparticle shows a pH triggered drug release (i.e. fast drug release at acidic condition and sustained release at physiological condition), a capability of endosomal escape which allows delivery of cargo to cytoplasm, and HER-2 targeting which enhances cellular uptake of the nanoparticle. This work is described in detail in chapter 2. In addition, there are growing needs in delivery of micro RNA inhibitor (miRi) for RNA interferences (RNAi). In chapter 3, a novel lipid coated calcium phosphate miRi complex was made to address poor encapsulation of hydrophilic RNA molecules in hydrophobic polymeric core for co-delivery of molecules with different physicochemical properties. This novel complex was co-encapsulated with paclitaxel in nanoparticle to achieve co-delivery. The co-delivery nanoparticle was found effective in regulating gene expression in vitro. The synergistic effects of co-delivery of miRi and paclitaxel were confirmed in culture cells. In the last part of the study, chapter 4-5 were focused on developing drug delivery systems address the unmet needs for systematic sequential delivery of combination therapeutic drug. The growing knowledge in cell signaling pathway points out importance of the order of drug presentation, optimal time course of drug administration could yield enhanced efficacy compared to conventional co-treatment. A nanoparticle was rationally design using the combined strategies of ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal growth factor receptor (EGFR) signaling applicable for the treatment of triple negative breast cancers. The nanoparticle system exhibited a desired sequential release of Gi and Dox, as verified through release and cellular uptake studies. The idea of using sequential delivery for enhanced cancer treatment was successfully validated using this nanoparticle design which demonstrated an approximate fourfold increase in anti-cancer efficacy compared to a control group of Dox-PLA-PEG conjugate. High tumor accumulation of the nanoparticles was also substantiated for potential in vivo applicability by non-invasive fluorescent imaging.
Joo Youp Lee, Ph.D. (Committee Chair)
Chia Chi Ho, Ph.D. (Committee Member)
Yoonjee Park, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
145 p.

Recommended Citations

Citations

  • Zhou, Z. (2017). Engineered Nanoparticle for Targeted and Controlled Drug Delivery [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505831582487098

    APA Style (7th edition)

  • Zhou, Zilan. Engineered Nanoparticle for Targeted and Controlled Drug Delivery. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505831582487098.

    MLA Style (8th edition)

  • Zhou, Zilan. "Engineered Nanoparticle for Targeted and Controlled Drug Delivery." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505831582487098

    Chicago Manual of Style (17th edition)