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NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY

Yung, Bryant Chinung
http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Pharmacy.
The design of lipid nanoparticles (LNs) for the delivery of oligonucleotides (ONs) remains a critical challenge in the clinical translation of RNA interference (RNAi) based therapeutics for cancer. Despite facilitating a protective function and passive targeting to ONs, optimization of lipid composition is necessary to promote intracellular delivery. The objective of this dissertation is to provide models for the design, manufacture, and characterization of LN drug delivery systems. Key innovative approaches include the application of lipid coated albumin nanoparticle (LCAN), quaternary-tertiary lipoamine liposome (QTsome), and small peptide lipid nanoparticle (SPLN) for ON delivery. LCAN is formed by the conjugation of cationic polymers to albumin to form a dense cationic core for electrostatic interaction with ON. This electrostatically stabilized complex is then surrounded by a lipid coat to protect the ON from opsonization. LCAN are utilized for the delivery of LOR-2501, an ON against ribonuclease reductase subunit 1 (RNR1). QTsome include a combination of permanently ionized quaternary and conditionally ionizable tertiary amine. Upon acidification within the endosome compartment following uptake, QTsome become highly cationized, facilitating interaction with negatively charged lipids of the endosome, thus promoting intracellular delivery. QTsome are applied towards the delivery of anti-miR-21 (AM-21) combination therapy with paclitaxel (PTX) in a non-small cell lung carcinoma (NSCLC) model. SPLN are composed of a combination of lipids and antibiotic peptide, gramicidin. SPLN employs the fusogenic nature of gramicidin to destabilize lipids in the endosome to promote delivery of ON. A microfluidic hydrodynamic focusing (MHF) system based on ethanol dilution method is outlined to demonstrate the advantages of microfluidic based manufacture of LNs. SPLN are combined with AM-221 and AM-21 in a triple negative breast cancer (TNBC) model to examine the potential of combination therapy with tamoxifen (TMX) to induce sensitivity in resistant cells.
Robert Lee (Advisor)
Thomas Schmittgen (Committee Member)
L. James Lee (Committee Member)
Mitch Phelps (Committee Member)
180 p.
Biology; Biomedical Research; Pharmaceuticals; Pharmacy Sciences
nanoparticle; cancer therapy; oligonucleotide; microRNA; liposome; microfluidics; anti-miR

Recommended Citations

Citations

  • Yung, B. C. (2014). NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665

    APA Style (7th edition)

  • Yung, Bryant. NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY . 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665.

    MLA Style (8th edition)

  • Yung, Bryant. "NANOPARTICLE DRUG DELIVERY SYSTEMS FOR CANCER THERAPY ." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417614665

    Chicago Manual of Style (17th edition)

osu1417614665
196
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This open access ETD is published by The Ohio State University and OhioLINK.