ORCID ID
Graduation Date
Spring 5-7-2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Dr. Dong Wang
Second Advisor
Dr. Tatiana Bronich
Third Advisor
Dr. Kevin L. Garvin
Fourth Advisor
Dr. Hanjun Wang
MeSH Headings
macromolecular substances, pharmaceutical preparations, musculoskeletal diseases
Abstract
Water-soluble polymers are one of the most commonly used drug delivery vehicles for musculoskeletal diseases. During the past few decades, various biocompatible polymers have been employed in the development of thermoresponsive hydrogels as drug delivery systems for the treatment of local musculoskeletal pathologies. As part of our laboratory’s contribution to this field of study, I have successfully developed three thermoresponsive hydrogel-based formulations for the treatment of three different pathologies associated with the musculoskeletal system.
As my initial effort, I have developed a bone-targeting injectable hydrogel drug delivery system based on Pluronic 127 (Poloxamer 407), which is a Generally Recognized As Safe (GRAS) pharmaceutical excipient and one of the most widely-used thermoresponsive water-soluble polymers. To achieve bone affinity for the formulation, we chemically conjugated osteotropic pyrophosphate (PPi) to the chain termini of F127 (F127-PPi). This thermoresponsive bone-targeted hydrogel system (PF127) was considered as an excellent local delivery platform for simvastatin (SIM, an anti-inflammatory and bone anabolic agent) in the treatment of periodontitis because it could address the limitations of SIM’s poor water-solubility and lack of osteotropicity when administered into the periodontal pocket. During my study, SIM-loaded PF127 hydrogel was confirmed to exhibit strong binding to hydroxyapatite (HA) discs. When tested in vivo on an experimental periodontal rat model, the hydrogel was validated to be effective on periodontal bone preservation and inflammation resolution.
The second thermoresponsive hydrogel formulation was developed based on a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. It was found that after conjugating with a hydrophobic drug, such as Tanshinone IIA (Tan, a potent osteogenic and angiogenic agent), the aqueous solution of the amphiphilic polymeric prodrug (ProGel-Tan) would exhibit a unique thermoresponsive phase transition behavior when prepared at a high concentration. The polymer solution was a free-flowing liquid at 4 ºC but formed a hydrogel when the temperature was elevated to 30 ºC or greater. When evaluated in a glucocorticoid-induced delayed femoral fracture healing mouse model, the prodrug-based hydrogel system demonstrated superior efficacy in accelerating the formation and mineralization of fracture callus, and completely normalizing the biomechanical properties of the femur.
The third formulation that I worked with was similar to ProGel-Tan. It is a HPMA copolymer-dexamethasone (Dex) conjugate-based thermoresponsive hydrogel system (ProGel-Dex). When tested in osteoarthritis (OA) pain models in mice, it was found to provide potent and sustained pain relief for more than 1 month in a monoiodoacetate (MIA)-induced OA-like pain mouse model, and for more than 15 weeks in a destabilization of medial meniscus (DMM) surgery-induced post-traumatic OA (PTOA) mouse model.
Ultimately, we hope that these newly developed thermoresponsive hydrogel delivery systems may be adapted as powerful tools for better clinical management of different musculoskeletal pathologies.
Recommended Citation
Chen, Ningrong, "The Development of Thermoresponsive Hydrogel-Based Drug Delivery Systems for the Treatment of Musculoskeletal Diseases" (2022). Theses & Dissertations. 631.
https://digitalcommons.unmc.edu/etd/631