Micellar strategies for targeting bone diseases

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Publication Type dissertation
School or College College of Engineering
Department Bioengineering
Author Low, Stewart Andrew
Title Micellar strategies for targeting bone diseases
Date 2015
Description Bone diseases range from degenerative osteoporosis to bone cancers and metastasized malignancies. They can be congenital or developed late in life and represent a major cause of decreased quality of life and increased mortality. Large molecule drug delivery systems have been in development and are aimed at delivering targeted drugs to bone. They do this by increasing accumulation with targeting ligands to attach to bone, with large size increasing accumulation in inflamed and malignant tissue and extending circulation half-life due to their reduced clearance by the kidneys. Unfortunately, they often have large dispersities, making consistency among batches more complicated. Small molecules, on the other hand, can be replicated predictably for each batch but lack in extended circulation time and good accumulation due to their size. Micelles have the capability of bridging this gap. By conjugating a high-affinity bone- targeting ligand, aspartic acid octapeptide, to a hydrophobic drug by a degradable linker, a monodisperse unimer is formed that can self-assemble into a large molecule micelle. This dissertation describes the development of a bone-targeted micelle and the incorporation of two different drugs, doxorubicin and 6-bromoindirubin-3’-oxime (6BIO), for the application of treating osteosarcoma and bone fractures, respectively. Four doxorubicin-containing micelles were designed and synthesized. These micelles demonstrated micellar aggregation at low concentrations, increasing the overall size of the delivery system. The micelles also were able to retain their binding to hydroxyapatite and release unmodified drug for treatment of osteosarcoma. From osteosarcoma, efforts were made to examine the versatility of the micellar drug delivery system by applying it to bone fractures. We adapted the delivery system by conjugating it to the GSK3β inhibitor, 6BIO. The modified micelle retained its micelle-assembling capabilities and was able to release drug over several days. Animal studies demonstrated the micelles’ high affinity to bone fractures and ability to increase the bone density of fractured femurs. We have developed a drug delivery system that can be adapted for multiple applications. The micelle has demonstrated its capabilities both in vitro and in vivo.
Type Text
Publisher University of Utah
Subject Bone Fracture; Drug Delivery; Micelle; Osteosarcoma; Polymer Therapeutics; Targeting
Dissertation Name Doctor of Philosophy
Language eng
Rights Management ©Stewart Andrew Low
Format Medium application/pdf
ARK ark:/87278/s6b60qqs
Setname ir_etd
Date Created 2018-07-30
Date Modified 2021-05-06
ID 1355503
Reference URL https://collections.lib.utah.edu/ark:/87278/s6b60qqs
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