Title

Development and Characterization of Methylene Blue Oleate Salt-Loaded Polymeric Nanoparticles as a Treatment for Glioblastoma

Date of Award

12-1-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Jamboor K. Vishwanatha

Second Advisor

Amalendu P. Ranjan

Third Advisor

Shaohua Yang

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in older adults, resulting in an average survival of 15 months post-diagnosis and treatment. While recent research has provided essential information, GBM relapse following traditional combinatorial regimens (surgery, radiation, and chemotherapy) is common, necessitating the development of more effective, less toxic therapies. Methylene blue (MB), a dye with noted medicinal applications, has received recent consideration as a potential neurotherapeutic due to its ability to infiltrate the blood-brain barrier (BBB), improve processes within distinct brain cell compartments and types, and preferential accumulation in the brain. While MB displays these advantages, one drawback is increased administration to produce therapeutic effects, leading to excessive brain deposition and potential neurotoxicity. A common method to enhance drug delivery is via encapsulation in submicron-sized nanoparticles (NPs) composed of the biodegradable/biocompatible co-polymer, poly(lactic-co-glycolic) acid (PLGA). We have previously shown their application as potential cancer therapies, as well as preferential brain accumulation. Thus, our goal was to develop MB-loaded NPs capable of permeating the BBB in order to treat GBM, based on our hypothesis that encapsulation of MB into PLGA NPs would enhance accumulation in cancerous regions, resulting in reduced tumor size and prolonged survival.

In this study, we prepared a methylene blue-oleate salt conjugate (MBOS) to enhance its stability, then formulated and characterized methylene blue oleate salt-loaded polymeric nanoparticles (MBOSNPs) via size, surface charge, drug loading (DL), and encapsulation efficiency (EE). We also analyzed their in vitro effects to establish biological, and potentially therapeutic, activity.

As a result, we obtained preparations physio-chemically comparable to other at 162.4nm, with a surface charge of -31.7 and DL and EE values of 2.2% and 29.2%, respectively. Next, MB(OS)NPs were determined to produce a peak drug release at 24hrs, and induce cytotoxicity comparable to, if not better than, free drug, in two GBM cell lines. Additionally, MB(OS)NPs enhanced cellular metabolism, a capability noted in free MB. Lastly, animal studies confirmed enhanced BBB permeation by MBOSNPs compared to free MBOS, demonstrating their therapeutic potential.

Comments

Castañeda-Gill, Jessica M., Development and Characterization of Methylene Blue Oleate Salt-Loaded Polymeric Nanoparticles as a Treatment for Glioblastoma. Doctor of Philosophy (Biomedical Sciences, Cancer Biology), November, 2016, 127 pp., 2 tables, 12 illustrations, 413 titles. Available December 2018.

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