Graduation Year

2017

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Engineering

Major Professor

Piyush Koria, Ph.D.

Committee Member

Robert Frisina, Ph.D.

Committee Member

William Lee, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Nathan Gallant, Ph.D.

Committee Member

Joseph Walton, Ph.D.

Keywords

Fusion proteins, growth factors, transduction, drug delivery, virus

Abstract

Gene therapy is a technique used to inactivate, replace or insert a corrective copy of a defective gene in order to help diseased tissues to function properly. Gene therapy is a promising treatment for many diseases cancer, cystic fibrosis, and Parkinson’s. There are different methods to introduce a gene to the cell; one of them is the use of viruses. Among viruses, lentiviruses have been popular vectors for gene delivery due to their efficient mode of gene delivery. However, the non-specific delivery of genes associated with viruses may result in undesirable side effects. Here, we propose a heterogeneous nanoparticle delivery system for targeted delivery of lentiviral particles containing a therapeutic gene. The heterogeneous nanoparticles (NPs) consist of the low density lipoprotein receptor 3 (LDLR3) and the keratinocyte growth factor (KGF), each fused to elastin-like-polypeptides (ELPs), LDLR3-ELP and KGF-ELP, respectively. Our results show that while homogeneous nanoparticles comprising of LDLR3-ELP alone blocked viral transduction, heterogeneous nanoparticles comprising of KGF-ELP and LDLR3-ELP enhanced viral transduction in cells expressing high levels of the KGF receptors (KGFR) compared to cells expressing low levels of KGF receptors. Overall, this novel design may help with the targeting of specific cells that overexpressed growth factor such as KGFR.

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