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TOWARDS THE RATIONAL DESIGN AND APPLICATION OF POLYMERS FOR GENE THERAPY: INTERNALIZATION AND INTRACELLULAR FATE
Published 2019 · Chemistry
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OF DISSERTATION TOWARDS THE RATIONAL DESIGN AND APPLICATION OF POLYMERS FOR GENE THERAPY: INTERNALIZATION AND INTRACELLULAR FATE Gene therapy is an approach for the treatment of acquired cancers, infectious disease, degenerative disease, and inherited genetic indications. Developments in the fields of immunotherapies and CRISPR/Cas9 genome editing are revitalizing the efforts to move gene therapy to the forefront of modern medicine. However, slow progress and poor clinical outcomes have plagued the field due to regulatory and safety concerns associated with the flagship delivery vector, the recombinant virus. Immunogenicity and poor transduction in certain cell types severely limits the utility of viruses as a delivery agent of nucleic acids. As a result, significant efforts are being made to develop non-viral delivery systems that perform mechanistically similarly to viral delivery but lack immunogenic factors. Though safer, existing agents lack the efficacy inherent in the natural design of viral vectors. Clinical relevance of non-viral vectors will therefore depend on the ability to engineer optimized systems for cellular delivery in physiological environments. Progress in non-viral vector design for gene delivery requires a deep understanding of the various barriers associated with nucleic acid delivery, including cell surface interaction, internalization, endosomal escape, cytosolic transport, nuclear localization, unpackaging, etc. Further, it requires a knowledge of vector design properties (surface chemistry, charge, size, shape, etc.) and how these physical parameters affect interactions with the cellular environment. Of these interactions, charge is shown to govern how particles are internalized and subsequently processed, thereby affecting the intracellular fate and efficacy of delivery. Charge also affects the in-serum stability where negative zeta potential improves stability and circulation time. Therefore, it is important to understand the effects of polyplex charge and other parameters on the internalization and intracellular fate of polyplexes for gene therapy. In chapter 2, studies are performed to delineate the effects of polyplex charge on the cellular internalization and intracellular processing of polymer-mediated gene delivery. Charge is shown to affect the endocytic pathway involved in internalization, and the caveolin-dependent and macropinocytosis pathways lead to higher gene delivery efficacy, likely due to avoidance of acidified compartments such as late endosomes and lysosomes. In chapters 3-4, novel nanoparticles carrying DNA, RNA, and antioxidants are assessed for therapeutic effect with an emphasis on studying the internalization mechanisms and resulting effect on efficacy. Novel RNA delivery agents are shown to benefit from EGFRtargeting aptamer and nanoceria/PEI hybrids are demonstrated to provide simultaneous antioxidant and gene therapy. Finally, chapter 5 demonstrates the use of silencing RNA and CRISPR/Cas9 genome editing to study the prevalence of gene targets in vivo. The overall goal of this work is to contribute to the design and application of novel nanoparticles for gene delivery and offer insight into the engineering of novel polyplexes. It remains clear that route of internalization is key to successful gene delivery, and designing polyplexes to enter through non-acidified endocytic pathways is highly beneficial to transgene expression. This can be achieved through incorporation of surface chemistries that trigger internalization through targeted pathways and is the source of further work in the lab.
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Mitigated cytotoxicity and tremendously enhanced gene transfection efficiency of PEI through facile one-step carbamate modification.
C. Yang (2013)
Getting across the nuclear pore complex.
B. Talcott (1999)
Poly(α-glutamic acid) combined with polycation as serum-resistant carriers for gene delivery.
C. Wang (2010)
Nrf2 Gene Transfer Induces Antioxidant Enzymes and Suppresses Smooth Muscle Cell Growth In Vitro and Reduces Oxidative Stress in Rabbit Aorta In Vivo
Dimerization drives EGFR endocytosis through two sets of compatible endocytic codes
Q. Wang (2015)
Intracellular dynamics of the gene delivery vehicle polyethylenimine during transfection: investigation by two-photon fluorescence correlation spectroscopy.
Jean-Pierre Clamme (2003)
Properties of cell penetrating peptides (CPPs)
A. Kerkis (2006)
Cellular Uptake of Cationic Polymer-DNA Complexes Via Caveolae Plays a Pivotal Role in Gene Transfection in COS-7 Cells
M. van der Aa (2007)
Evidence for targeted gene transfer by receptor-mediated endocytosis. Stable expression following insulin-directed entry of NEO into HepG2 cells.
B. Huckett (1990)
Intracellular Distribution and Mechanism of Delivery of Oligonucleotides Mediated by Cationic Lipids
O. Zelphati (2004)
Strategies for the intracellular delivery of nanoparticles.
L. Chou (2011)
DNA vaccines: a review
M. Liu (2003)
Genetic Evidence Supporting Caveolae Microdomain Regulation of Calcium Entry in Endothelial Cells*
T. Murata (2007)
Targeted cancer gene therapy: the flexibility of adenoviral gene therapy vectors.
M. Rots (2003)
M. Aleku (2008)
The headgroup evolution of cationic lipids for gene delivery.
Defu Zhi (2013)
Transcriptional Regulation by Nrf2
Claudia Tonelli (2018)
Virus entry by macropinocytosis
Jason Mercer (2009)
M. Sankar (1824)
A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy.
S. Moghimi (2005)
Amantadine and dansylcadaverine inhibit vesicular stomatitis virus uptake and receptor-mediated endocytosis of alpha 2-macroglobulin.
R. Schlegel (1982)
DNA: Reaction with Chloroquine
J. L. Allison (1965)
Low molecular weight PEI-appended polyesters as non-viral gene delivery vectors.
Miao-Miao Xun (2014)
Receptor-mediated endocytosis of transferrin-polycation conjugates: an efficient way to introduce DNA into hematopoietic cells.
M. Zenke (1990)
Targeted integration of adeno‐associated virus (AAV) into human chromosome 19.
R. Samulski (1991)
CpG motifs in bacterial DNA and their immune effects.
A. Krieg (2002)
Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER.
D. Chinnapen (2007)
EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases
Sarah Urnauer (2017)
Gene Therapy Targeting Nuclear Factor-κB: Towards Clinical Application in Inflammatory Diseases and Cancer
S. Tas (2009)
Targeted nonviral gene therapy in prostate cancer
Najla A. Altwaijry (2018)
FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer.
P. Ray (2010)
A Novel Non-Viral Vector for DNA Delivery Based on Low Molecular Weight, Branched Polyethylenimine: Effect of Molecular Weight on Transfection Efficiency and Cytotoxicity
D. Fischer (2004)
Challenges and strategies: The immune responses in gene therapy
H. Zhou (2004)
Polyethylenimine but Not Cationic Lipids Promotes Transgene Delivery to the Nucleus in Mammalian Cells*
H. Pollard (1998)
R. Wattiaux (2000)