Development and evaluation of polymeric hybrid a-Difluoromethylornithine (DFMO) & Etoposide loaded nanocarriers for the treatment of Neuroblastoma

Simple item page
dc.contributor.advisor Chougule, Mahavir B.
dc.contributor.author Glasgow, Micah David Kealaka'i
dc.contributor.department Pharmaceutical Sciences
dc.date.accessioned 2017-02-02T00:17:34Z
dc.date.issued 2016-08
dc.description.abstract Neuroblastoma (NB) is the most common extra-cranial solid cancer in childhood and infancy with patients having an average age of 17 months. Most are diagnosed with advanced stage NB when tumor progression is aggressive, making treatment of NB even more difficult. Up to 45% of patients are in the high-risk category with MYCN gene amplification being observed. The FDA-approved drug difluoromethylornithine (DFMO) exhibits anticancer activity against MYCN-amplified NB cells. DFMO is a suicide inhibitor of ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines. ODC gene expression is directly activated by MYCN suggesting that MYCN amplification is connected to high ODC expression. ODC expression produces high polyamine levels that contribute to the malignant phenotype and maintenance of NB tumorgenesis. This MYCN-ODC connection suggests that ODC may be a suitable new target for the treatment of NB with the administration DFMO. Etoposide, a topoisomerase inhibitor is often used in front-line therapy in the treatment of NB. The use of DFMO/Etoposide in vivo is currently limited due to the short half-lives (fast elimination/clearance) of both drugs which may explain why antitumor in vivo were not synergistic as observed in vitro. iRGD peptide-conjugated PEGylated polymeric hybrid nanocarriers loaded with synergistically acting DFMO and Etoposide drugs (iRGD-PEG-HNC-D-E) were characterized at 81ﾱ7nm in size, +12ﾱ2.5mV in zeta potential with a mean polydispersity index 0f 0.354ﾱ0.03. The developed nanocarriers had a 10 and 6-fold decrease in initial drug concentrations, DFMO and Etoposide respectively, with similar efficacy as compared to free drugs alone against various NB cell-lines over a 72h period. The current formulation shows stability suspended in phosphate buffer saline (PBS) 7.4 over 6 days. iRGD-PEG-HNC-D-E formulations can be modified (polymer: polymer ratio) to alter drug release profiles with the developed formula having a 90% release of both drugs after 72h.
dc.description.degree Ph.D.
dc.description.institution University of Hawaii at Hilo
dc.embargo.liftdate 2019-02-01
dc.format.extent 407 pages
dc.identifier.uri http://hdl.handle.net/10790/2951
dc.language.iso en
dc.subject Pharmaceutical sciences
dc.subject Nanotechnology
dc.subject Nanoscience
dc.subject Combination Chemotherapy
dc.subject DFMO
dc.subject Drug Delivery
dc.subject Etoposide
dc.subject Multifunctional Nanocarrier
dc.subject Neuroblastoma
dc.title Development and evaluation of polymeric hybrid a-Difluoromethylornithine (DFMO) & Etoposide loaded nanocarriers for the treatment of Neuroblastoma
dcterms.rights All UHH dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
local.identifier.alturi http://dissertations.umi.com/hilo.hawaii:10118
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Glasgow_hilo.hawaii_1418E_10118.pdf
Size:
13.66 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Pharmaceutical Science