Document Type

Dissertation - Open Access

Award Date

2019

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Keywords

Drug Delivery, Nanotechnology, Pharmaceutics, Pharmacokinetics and Circulation Time, Transporters, Tumor Targeting

Abstract

Recent advancements in nanotechnology have unfolded novel opportunities in medicine, especially in targeted therapeutics and imaging for cancer. However, the majority of the existing nanotechnologies for cancer suffer from shortcomings such as (i) rapid elimination from the systemic circulation before reaching the cancer tissue. (ii) poor tumor accumulation, targeting, and penetration due to inadequate vasculature and extensive extracellular matrix in the tumor. Thus, overcoming these two limitations of nanotechnology is of considerable interests for cancer researchers. In this dissertation, we demonstrate the feasibility of glucose-modified nanoparticles (GLU-NPs) as an efficient cancer targeted-delivery system for enhancing the systemic circulation time and tumor accumulation. In chapter II, using a natural physiological interaction between glucose on the GLU-NPs and the surface glucose transporter GLUT1 on the RBCs, we have demonstrated the enhancement of systemic circulation time and thereby, improved tumor accumulation. GLU-NPs interaction with GLUT1 is non-covalent, reversible and importantly, established in-vivo. GLU-NPs enhanced the circulation time by hitchhiking on RBCs and reducing opsonization. In chapter III, we have demonstrated the ability of GLU-NPs to differentiate breast cancer versus noncancer cells based on the expression levels of GLUT1. GLUT1 is overexpressed in multiple cancer types, and the level of expression is correlated with the invasiveness of cancer. GLU-NPs were able to deliver significantly large amounts of encapsulated cargo to breast cancer cells potentially through caveolae-mediated endocytosis. The in-vivo tumor imaging results depict that the GLU-NPs highly accumulated into tumors compared to state-of-art technology PEGylation. In summary, we have demonstrated the ability of GLU-NPs as a smart drug delivery system for in-vivo enhancement of systemic circulation time and tumor accumulation, which will have applications beyond cancer therapy and imaging, such as sustained drug delivery and targeting to other organs.

Library of Congress Subject Headings

Drug delivery systems.
Cancer -- Treatment.
Nanotechnology -- Health aspects.
Nanomedicine.
Glucose -- Physiological transport.

Format

application/pdf

Number of Pages

187

Publisher

South Dakota State University

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Rights Statement

In Copyright