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Polymeric Microparticles and Stimuli-Responsive Hydrogels Targeting Macrophages /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Polymeric Microparticles and Stimuli-Responsive Hydrogels Targeting Macrophages /Emerson L Grey.
Author:	Grey, Emerson L.,
Description:	1 electronic resource (304 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-06, Section: B.
Notes:	Advisors: Bryant, Stephanie J. Committee members: Alper, Scott; Bowman, Christopher; Goodwin, Andrew; Shields, Wyatt.
Contained By:	Dissertations Abstracts International86-06B.
Subject:	Chemical engineering.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31639632
ISBN:	9798346876847

Polymeric Microparticles and Stimuli-Responsive Hydrogels Targeting Macrophages /
Grey, Emerson L.,

Polymeric Microparticles and Stimuli-Responsive Hydrogels Targeting Macrophages /Emerson L Grey. - 1 electronic resource (304 pages)

Source: Dissertations Abstracts International, Volume: 86-06, Section: B.

Chronic inflammation in the lungs can set off a cascade of harmful changes, ultimately leading to diseases like pulmonary fibrosis that permanently damage lung architecture and impair function. At the forefront of this defense and repair process are the cells of the innate immune system, particularly macrophages. These cells play a crucial role in managing the body's inflammatory response and, because of their central role in both immunity and repair, they've become a key target for drug delivery approaches aimed at reducing inflammation in the lungs. This thesis explored two distinct delivery systems targeting macrophages: one using thiol-Michael polymeric microparticles taken up by macrophages, and another using stimuli-responsive hydrogels designed to release anti-inflammatory drugs directly within inflamed tissues. In the first part of the research, polymeric microparticles were developed with precise control over their physical and chemical properties. Through adjusting monomer concentration, particle stability across pH ranges, and chemistry via off-stoichiometry techniques, the particles were fine-tuned for optimal interaction with macrophages. The uptake of these particles by various macrophage models-including RAW 264.7 cells, human alveolar macrophages, and in vivo murine macrophages-was carefully tested across different particle sizes, chemistries, and exposure times. Notably, amine-terminated particles showed no inflammatory response upon interaction with the cells and were successfully taken up under a variety of conditions.The second part of the research centered around delivering a specific anti-inflammatory agent, T6167923, a MyD88 inhibitor known to reduce inflammation. For this, the therapeutic was integrated into a hydrogel delivery system using a cleavable peptide linker responsive to the MMP-12 enzyme, which is active in inflamed tissues. The hydrogel served as a scaffold, releasing the therapeutic only when exposed to MMP-12, as demonstrated by monitoring the breakdown of an enzyme-cleavable peptide linkage. Tests confirmed the enzyme's ability to diffuse through the hydrogel, setting the stage for the delivery of T6167923 in tissue environments. This was successfully demonstrated using a subcutaneous implantation model in mice.In sum, this research has established two promising pathways for targeting alveolar and tissue macrophages. Microparticles emerged as a versatile platform for macrophage-specific delivery in the lungs, while the MyD88 inhibitor T6167923 delivered via enzyme-responsive hydrogels offers a targeted approach for reducing inflammation in tissue. These innovations present new avenues for localized, macrophage-focused therapies to address inflammatory conditions in the lungs and beyond.

English

ISBN: 9798346876847Subjects--Topical Terms:

206267
Chemical engineering.
Subjects--Index Terms:

Chronic inflammation

Polymeric Microparticles and Stimuli-Responsive Hydrogels Targeting Macrophages /
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520 $a Chronic inflammation in the lungs can set off a cascade of harmful changes, ultimately leading to diseases like pulmonary fibrosis that permanently damage lung architecture and impair function. At the forefront of this defense and repair process are the cells of the innate immune system, particularly macrophages. These cells play a crucial role in managing the body's inflammatory response and, because of their central role in both immunity and repair, they've become a key target for drug delivery approaches aimed at reducing inflammation in the lungs. This thesis explored two distinct delivery systems targeting macrophages: one using thiol-Michael polymeric microparticles taken up by macrophages, and another using stimuli-responsive hydrogels designed to release anti-inflammatory drugs directly within inflamed tissues. In the first part of the research, polymeric microparticles were developed with precise control over their physical and chemical properties. Through adjusting monomer concentration, particle stability across pH ranges, and chemistry via off-stoichiometry techniques, the particles were fine-tuned for optimal interaction with macrophages. The uptake of these particles by various macrophage models-including RAW 264.7 cells, human alveolar macrophages, and in vivo murine macrophages-was carefully tested across different particle sizes, chemistries, and exposure times. Notably, amine-terminated particles showed no inflammatory response upon interaction with the cells and were successfully taken up under a variety of conditions.The second part of the research centered around delivering a specific anti-inflammatory agent, T6167923, a MyD88 inhibitor known to reduce inflammation. For this, the therapeutic was integrated into a hydrogel delivery system using a cleavable peptide linker responsive to the MMP-12 enzyme, which is active in inflamed tissues. The hydrogel served as a scaffold, releasing the therapeutic only when exposed to MMP-12, as demonstrated by monitoring the breakdown of an enzyme-cleavable peptide linkage. Tests confirmed the enzyme's ability to diffuse through the hydrogel, setting the stage for the delivery of T6167923 in tissue environments. This was successfully demonstrated using a subcutaneous implantation model in mice.In sum, this research has established two promising pathways for targeting alveolar and tissue macrophages. Microparticles emerged as a versatile platform for macrophage-specific delivery in the lungs, while the MyD88 inhibitor T6167923 delivered via enzyme-responsive hydrogels offers a targeted approach for reducing inflammation in tissue. These innovations present new avenues for localized, macrophage-focused therapies to address inflammatory conditions in the lungs and beyond.
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