Dissertation/Thesis Abstract

Preparation, Drug Release, and Cell Growth Inhibition of a Gelatin-Doxorubicin Conjugate
by Wu, Darren C., Ph.D., University of the Sciences in Philadelphia, 2018, 73; 13850242
Abstract (Summary)

Doxorubicin (DOX) adsorption in polypropylene containers as a function of pH and drug concentration was investigated based on anecdotal evidence of such adsorption to lay the groundwork for subsequent DOX delivery studies. DOX loss was first examined in high-performance liquid chromatography (HPLC) glass inserts by ultraviolet (UV) absorbance to determine appropriate pH and time durations for subsequent analysis. DOX loss was then examined in polypropylene microcentrifuge tubes at different pH values and starting drug concentrations at 37°C over 48 h using HPLC with fluorescent detection. DOX concentrations were essentially constant in HPLC glass inserts at pH 4.8 up to 12 h but declined 5% at pH 7.4 in 3 h. The percent DOX adsorption was calculated in polypropylene microcentrifuge tubes from initial concentration by extrapolations to zero time. Adsorption was the least at pH 4.8, but increased with pH values of 6.5 and 7.4, and reached a maximum extent of adsorption of 45% at lower concentration of 2.0 μg/mL at pH 7.4 and 37°C. First-order degradation rate constants, ranging from 0.0021 to 0.019 h–1, also increased with pH in these studies. Determinations of low amounts of DOX in polypropylene containers at pH 7.4 may be underestimated if adsorption and degradation issues are not taken into account.

The feasibility of a novel macromolecular delivery system for DOX which combines pH- dependent DOX release with a high molecular weight and biodegradable gelatin carrier was investigated. DOX was conjugated to gelatin using an acid-labile hydrazone bond and a glycylglycine linker. The gelatin-doxorubicin conjugate (G-DOX) was evaluated for DOX content, in vitro DOX release at various pH, and cell growth inhibition using EL4 mouse lymphoma cells. A macromolecular DOX conjugate containing 3.4-5.0% w/w DOX was prepared. The maximal DOX release was 48% in pH 4.8 phosphate buffer, 23% at pH 6.5, and 9% at pH 7.4. The G-DOX IC50 values in EL4 was 0.26 μM, which was 9 times greater than that of free DOX. The pH-dependent drug release in combination with a biodegradable gelatin carrier offer potential therapeutic advantages of enhanced tumor cell localization and reduced systemic toxicities of the drug.

In order to further understand the drug release mechanism, a mathematical model describing drug release from G-DOX was derived and proved to be suitable. Finally, drug release profiles under an ideal condition without degradation were constructed to demonstrate intrinsic profiles. DOX release profiles based on the proposed model showed additional drug release ranged from 4 to 10% at 48 h.

Indexing (document details)
Advisor:
Commitee:
School: University of the Sciences in Philadelphia
Department: Pharmaceutical Sciences
School Location: United States -- Pennsylvania
Source: DAI-B 80/07(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmaceutical sciences
Keywords: Cancer, Conjugate, Doxorubicin, Drug delivery, Drug release, Ph
Publication Number: 13850242
ISBN: 9780438973596
Copyright © 2019 ProQuest LLC. All rights reserved. Terms and Conditions Privacy Policy Cookie Policy
ProQuest