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Design and development of a polyhedral borane drug delivery system for the small-molecule antimetabolite 5-fluorouracil||Design and development of a polyhedral borane drug delivery system for the small-molecule antimetabolite 5-fluorouracil


Thesis
Houston and Zachary, H.
{journal}{booktitle}, 2014
Publication year: 2014
Polyhedral boranes represent a unique class of molecules that have been exploited for a variety of applications. Their unique bonding provides a novel scaffold for polyfunctionalized and dendrimer-like drug delivery vehicles. In particular, the closed-cage icosahedral closo-B12H122- has been the interest of extensive study and a multitude of applications. The 12-vertexes on the closo-B12H22- structure and its established chemistry for functionalization have allowed the development of more complex and higher molecular weight multimeric species. These 12-fold substituted polyhedral boranes, known as closomers, have been studied with respect to their chemistry and properties and are now being exploited for their use in medicinal applications. With the previously reported high-yielding synthesis of the perhydroxylated species [closo-B12(OH)12]2-, a plethora of complexes have been prepared through the exploitation of the similar reactivity of the B-OH and C-OH bond. Through the use of ester, ether, carbonate, carbamate, and Huisgen [3+2] dipolar cycloaddition reactions, a well-established library of closomers has been prepared and has established the chemistry needed for the development of medically applicable systems. The use of these established methods has been expanded upon herein to create vertex-differentiated and 12-fold homofunctionlaized closomer compounds. Furthermore, as a requisite to building higher-order closomers, an extensive library of heterofunctionalized poly(ethylene glycol) compounds have been prepared. In the work reported herein, the homo- and heterofunctionalization of closomers is discussed leading to the synthesis of a 12-fold 5-fluorouracil loaded and glucosamine targeted closomer drug delivery system.

Hydrolytic Stability of Carbamate and Carbonate Closomers for the Design of a Multifaceted Drug Delivery System

Thesis
Houston, Zachary H.
University of Missouri, 2010
Publication year: 2010

 

Twelve-fold substituted polyhedral boranes (closomers) are of therapeutic and diagnostic interest in the applications of targeted drug delivery. These compounds consist of a core molecule with 12 vertices and allow for a high degree of multifaceted substitution. Our group has previously reported on ester and ether based closomers1, but more recently have been working with the more synthetically useful carbonate and carbamate based closomers. The solution based properties of these structures their relative stability towards acid and base hydrolysis were investigated for the purpose of determining the best structural design for drug delivery applications. Some of the these molecules have limited solubility in aqueous media, and thus a system for analyzing these compounds with accurate pH monitoring using a glass electrode was established using IUPAC standards.2 The devised system is applicable to any organic-aqueous solvent mixture, and can be applied with any standard glass electrode that is primarily utilized for aqueous conditions. The system corrects for any solvent effects due to the presence of the organic component by the utilization of the Debye-Huckel Extended Law. Preliminary studies show that the carbonate and carbamate bond at the polyhedral borane cage are hydrolytically stable in the pH 2-12 range. The stability of these core structures allows for a potentially much more tunable release system in drug delivery applications, and solidifies the use of carbamate based systems for selective release of the pharmaceutical payload.