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Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics

LI, JILONG, LI
http://rave.ohiolink.edu/etdc/view?acc_num=osu1523617120897914

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
The objective of this dissertation thesis is to develop a novel lipid nanoparticle oligonucleotide delivery platform with pH responsive lipid combination and enhancement ligands to achieve therapeutic goals in cancer and wound management. Favored by numerus scientists and pharmaceutical industries, gene therapy has received a lot of compliments and has been extensively studied over many decades. A series of pre-clinical and clinical trials have revealed superior efficacy over conventional chemo-drugs on many genetic disorder diseases including cancer, inflammation, neural degenerative disease, hereditary disease. However, successful commercialization of gene therapy has been compromised due to several unfavorable properties. Naked oligonucleotides are considerably unstable due to chemical and enzymatic cleavage during manufacture and administration. Additionally, incapability of penetrating cell membranes due to high polarity and charge density has forbidden its bench-side application via conventional formulations. Moreover, highly-potent and long-last efficacy of gene therapeutics has compelled the demands for target-specific delivery to avoid off-target side effects or cytotoxicity. Hence, carefully engineered and delicate development of novel delivery system specifically designed for gene therapy has been called upon by research scientists and medical practionors. In Chapter 2, we have proposed a well-designed pH responsive lipid nanoparticle delivery platform (QTsome) with enhanced in vitro &in vivo gene trafficking efficacy to treat non-small cell lung cancer (NSCLC). The novelty of such pH responsive platform is substantially improved endosomal escape facilitated by the combination of quaternary and tertiary amine based cationic lipids. Three lead advantages can be acquired based on quaternary/tertiary cationic combination: firstly, near neutral or weak positive surface charges can be micro-adjusted to achieve optimal interactions between delivery system and targeting cells, while avoiding drawbacks including cytotoxicity and RES clearance associated with traditional cationic lipid nanoparticles; secondly, higher oligo encapsulation efficiency can be achieved by mixing the oligo cargos with lipid compositions at pH~4.0 to introduce stronger electrostatic interactions; thirdly, enhanced release of gene cargos into cytoplasm is introduced by presence of highly positive charges in late endosome stage. In our study, encapsulated anti-miR-21 has shown excellent stability and loading capacity within the QTsome, along with more than 50% of miR-21 suppression. Additionally, combinational therapy facilitated by incorporation of PTX (Paclitaxel) into QTsome/ anti-miR-21 has demonstrated greater capacity in cell proliferation inhibition and metastasis reduction. In Chapter 3, QTsome platform has been further adjusted to accommodate chronic wounds. To further improve in vivo transfection efficiency, ionophore reagent Gramicidin A was incorporated into the formulation. Gramicidin A has been proposed to enhanced cell penetration capacity as well as endosomal escape via promoting hexagonal II (HII) phases. QTsome surface properties have been carefully studied to in adaption to the presence of phagocytes and macrophages on the wound bed. Anti-miR-210 has been successfully inserted into keratinocytes to reverse ischemia memory of proliferation cease. Results have suggested restoration of basal keratinocyte cell hyper-proliferation and migration in mice ischemic wound models. In Chapter 4, a keratinocytes-specific targeting ligand has been conjugated onto the surface of QTsome to enhance cell-specific recognition. Studies have pointed out complications and side effects involved in non-specific targeting. Deep-burn wound bed environment has recruited a variety of cell types including bacteria, macrophage, phagocyte, fibroblast, keratinocyte. Random delivery of high potent oligo cargos has great potentials in causing unknown therapeutic outcomes and severe toxicities. Therefore, target delivery of miR cargos into specific cells without detection from surrounding tissues have become the major barrier to break. In this study, we have proposed a sophisticated designed targeting delivery system loaded with anti-miR-107 that is capable of keratinocytes recognition and accelerating wound closure and restoration of barrier function. In addition, lyophilization has been incorporated to accommodate a non-injection route of application with additional long-term storage capacity.
Robert Lee (Advisor)
195 p.
Pharmaceuticals

Recommended Citations

Citations

  • LI, LI, J. (2018). Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523617120897914

    APA Style (7th edition)

  • LI, LI, JILONG. Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics . 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1523617120897914.

    MLA Style (8th edition)

  • LI, LI, JILONG. "Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics ." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523617120897914

    Chicago Manual of Style (17th edition)

osu1523617120897914
722
© 2018, some rights reserved.Creative Commons License Development of a QTsome Lipid Nanoparticle Delivery Platform for Oligonucleotide Therapeutics by JILONG LI LI is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.