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Development and evaluation of polymeric hybrid a-Difluoromethylornithine (DFMO) & Etoposide loaded nanocarriers for the treatment of Neuroblastoma
|Title:||Development and evaluation of polymeric hybrid a-Difluoromethylornithine (DFMO) & Etoposide loaded nanocarriers for the treatment of Neuroblastoma|
|Authors:||Glasgow, Micah David Kealaka'i|
|Contributors:||Chougule, Mahavir B. (advisor)|
Pharmaceutical Sciences (department)
show 4 moreDrug Delivery
|Date Issued:||Aug 2016|
|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.
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