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Optimization, Characterization, Modeling, and Efficacy Analysis of Modified PLGA Microspheres for Intra-Articular Corticosteroid Therapies.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Optimization, Characterization, Modeling, and Efficacy Analysis of Modified PLGA Microspheres for Intra-Articular Corticosteroid Therapies./
作者:	Myers, Nathaniel McKinley.
面頁冊數:	1 online resource (101 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
Contained By:	Dissertations Abstracts International84-12B.
標題:	Biomedical engineering. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30485746click for full text (PQDT)
ISBN:	9798379592738

Optimization, Characterization, Modeling, and Efficacy Analysis of Modified PLGA Microspheres for Intra-Articular Corticosteroid Therapies.
Myers, Nathaniel McKinley.

Optimization, Characterization, Modeling, and Efficacy Analysis of Modified PLGA Microspheres for Intra-Articular Corticosteroid Therapies. - 1 online resource (101 pages)

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

Thesis (Ph.D.)--Villanova University, 2023.

Includes bibliographical references

In recent years, unmodified poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) have become an extended-release cornerstone in anti-rheumatic medication formulations. The first approved extended-release formulation for intra-articular injections called Zilretta®2, delivers an anti-rheumatic therapy using these PLGA MSs. This treatment has shown increased duration of therapeutic drug delivery mitigating the most limiting aspect of current anti-rheumatic intraarticular injections; dosing frequency. Even still, current treatments can only be administered 3-4 times a year due to local and systemic toxicity of the drug2-5, while patients report the disappearance of therapeutic effects after just a few weeks, resulting in uncontrolled discomfort and stiffness. While Zilretta ® has been shown to alleviate these issues partially, we believe additional optimization and surface modifications can further increase this treatment's efficacy. We propose by functionalizing PLGA microspheres to increase bioavailability and therapeutic duration of hydrocortisone-17-butyrate (HCB), a more efficacious intra-articular corticosteroid injection can be achieved. To increase bioavailability in healthy concentrations, we will minimize burst release and extend controlled release of HCB from the microcarrier. A single-stage Oil/Water emulsion can be used to synthesize both surface-modified and unmodified corticosteroid-loaded extended-release PLGA microspheres (MSs) via an avidin/biotin system. These MSs were characterized via microscopy, DLS, and release tested for drug that was computationally modeled. Optimized MSs were 1.22 +/- 0.0132µm with a zeta potential of - 23.17 +/- 0.97 mV, entrapment efficiency of 72.0%, and a feed-to-product conversion rate of 69.8%. Effects of surface modification including PEGylation was found to significantly alter the biphasic release by over a 2-fold reduction in burst release, and is computationally modeled with all model fits being significant. (R2 > 0.95).Fluorescent homologs are also investigated and over 99% of fluorescently surface conjugated (biotinylated) homologs were found to be fluorescently distinguishable from their control counterparts after 72 hours. Through confocal microscopy, these homologs were found to begin diffusing into the cartilage within a few minutes with significant penetration into the deep zone within 6 hours. Similarly, PLGA-FITC (fluorescent PLGA) MSs were found to remain in healthy bovine femoral cartilage for over 12 days, defying previously accepted articular cartilage pore size assumptions. Investigations into PEGylated, HCB-loaded MS's therapeutic efficacy were conducted using an IL-1β induced inflammation response in explanted bovine femoral cartilage plugs. Both high and low dose therapies were found to preserve more glycosaminoglycan (GAG) content throughout the cartilage over a 16-day period when compared to IL-1β controls and unloaded MS treatments. Additionally, qPCR results confirm these engineered MSs enact more effective suppression of the inflammation pathway, and greater expression of collagen 2 and aggrecan; suggesting healthier cartilage than free drug treatments.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379592738Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

AutoimmuneIndex Terms--Genre/Form:

542853
Electronic books.

Optimization, Characterization, Modeling, and Efficacy Analysis of Modified PLGA Microspheres for Intra-Articular Corticosteroid Therapies.
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520 $a In recent years, unmodified poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) have become an extended-release cornerstone in anti-rheumatic medication formulations. The first approved extended-release formulation for intra-articular injections called Zilretta®2, delivers an anti-rheumatic therapy using these PLGA MSs. This treatment has shown increased duration of therapeutic drug delivery mitigating the most limiting aspect of current anti-rheumatic intraarticular injections; dosing frequency. Even still, current treatments can only be administered 3-4 times a year due to local and systemic toxicity of the drug2-5, while patients report the disappearance of therapeutic effects after just a few weeks, resulting in uncontrolled discomfort and stiffness. While Zilretta ® has been shown to alleviate these issues partially, we believe additional optimization and surface modifications can further increase this treatment's efficacy. We propose by functionalizing PLGA microspheres to increase bioavailability and therapeutic duration of hydrocortisone-17-butyrate (HCB), a more efficacious intra-articular corticosteroid injection can be achieved. To increase bioavailability in healthy concentrations, we will minimize burst release and extend controlled release of HCB from the microcarrier. A single-stage Oil/Water emulsion can be used to synthesize both surface-modified and unmodified corticosteroid-loaded extended-release PLGA microspheres (MSs) via an avidin/biotin system. These MSs were characterized via microscopy, DLS, and release tested for drug that was computationally modeled. Optimized MSs were 1.22 +/- 0.0132µm with a zeta potential of - 23.17 +/- 0.97 mV, entrapment efficiency of 72.0%, and a feed-to-product conversion rate of 69.8%. Effects of surface modification including PEGylation was found to significantly alter the biphasic release by over a 2-fold reduction in burst release, and is computationally modeled with all model fits being significant. (R2 > 0.95).Fluorescent homologs are also investigated and over 99% of fluorescently surface conjugated (biotinylated) homologs were found to be fluorescently distinguishable from their control counterparts after 72 hours. Through confocal microscopy, these homologs were found to begin diffusing into the cartilage within a few minutes with significant penetration into the deep zone within 6 hours. Similarly, PLGA-FITC (fluorescent PLGA) MSs were found to remain in healthy bovine femoral cartilage for over 12 days, defying previously accepted articular cartilage pore size assumptions. Investigations into PEGylated, HCB-loaded MS's therapeutic efficacy were conducted using an IL-1β induced inflammation response in explanted bovine femoral cartilage plugs. Both high and low dose therapies were found to preserve more glycosaminoglycan (GAG) content throughout the cartilage over a 16-day period when compared to IL-1β controls and unloaded MS treatments. Additionally, qPCR results confirm these engineered MSs enact more effective suppression of the inflammation pathway, and greater expression of collagen 2 and aggrecan; suggesting healthier cartilage than free drug treatments.
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