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DEVELOPMENT OF A HYDROGEL NANOPARTICLE SYSTEM FOR SUSTAINED DELIVERY OF ANIGOGENIC FACTORS FOR THERAPEUTIC NEOVASCULARIZATION
Title
DEVELOPMENT OF A HYDROGEL NANOPARTICLE SYSTEM FOR SUSTAINED DELIVERY OF ANIGOGENIC FACTORS FOR THERAPEUTIC NEOVASCULARIZATION
Creator
Young, Daniel A
Date
2018, 2018-05
Description
Neovascularization requires controlled and sustained delivery of proangiogenic factors to stimulate reperfusion of ischemic tissues. Tissue...
Show moreNeovascularization requires controlled and sustained delivery of proangiogenic factors to stimulate reperfusion of ischemic tissues. Tissue engineering strategies for therapeutic neovascularization have used proangiogenic, recombinant growth factors to direct vessel development. Recently, peptides that mimic the bioactivity of growth factors have emerged as therapeutics for a variety of drug delivery applications, including therapeutic neovascularization. We designed hydrogel nanoparticles to provide sustained and tunable di usion-based release of a proangiogenic peptide, QK, and a vessel stabilizing peptide, Vasculotide (VT). These nanoparticles were combined with a tissue engineering sca old to promote tissue neovascularization. We used this nanocomposite system, utilizing peptide loaded hydrogel nanoparticles embedded in an implantable sca old, to investigate the e cacy of a dual peptide delivery strategy for therapeutic neovascularization. Inverse phase mini-emulsion polymerization (IPMP) was used to generate crosslinked poly(ethylene) glycol (PEG) hydrogel nanoparticles. We characterized the nanoparticles in terms of their swelling ratio, mesh size, surface charge ( -potential), and particle size distributions. We developed several nanoparticle formulations using various sizes and molar concentrations of PEG chains to study the e ects of crosslink density on peptide release kinetics. This resulted in the formation of nanoparticles with low and high crosslink density as well as time-dependent variations in network density due to hydrolysis. We utilized two di erent loading techniques, peptide entrapment during IPMP and peptide post-loading into the nanoparticles, and found both to be e ective via peptide loading measurements and release kinetic studies. In the case of entrapment loading, peptides were included in the aqueous precursor during nanoparticle IPMP. Peptide release kinetics were tuned through adjustments in nanoparticle crosslink density. The resulting nanoparticle crosslink density impacted both peptide loading and fractional release, as studies showed higher crosslink density nanoparticles resulted in slower peptide release. The IPMP process preserved QK secondary structure and bioactivity, as con rmed with released peptide using circular dichroism spectroscopy and a Matrigel tubulogenesis assay, respectively. In the case of the post-loading method, pristine nanoparticles were soaked in various concentrations of either QK or VT. Unlike with the entrapment loading method, crosslink density of the nanoparticles had little e ect on release kinetics. However, much higher mass amounts of peptide could be loaded using this method and thus this method was chosen for the in vivo studies. Next, we developed a hydrogel nanocomposite sca old system to sequester nanoparticles for implantation. We characterized the nanocomposite sca old system experimentally and theoretically using one-dimensional transport models of molecular di usion. We estimated peptide di usion coe cients from nanoparticles and the nanocomposites under perfect sink conditions. Importantly, we found this system capable of providing previously reported therapeutic thresholds of QK and VT. Finally, the in uence of sustained release of QK and VT on neovascularization was evaluated using a subcutaneous rat implant model. Results demonstrated statistically higher increases in perfused vessel density from peptide loaded nanocomposite sca olds as compared to sca olds where peptide was simply entrapped. These results suggest that controlled release of proangiogenic peptides from the developed nanoparticle system holds great potential for ischemic tissue repair.
Ph.D. in Biomedical Engineering, May 2018
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SIMULTANEOUS RELEASE OF BIOACTIVE AFLIBERCEPT AND DEXAMETHASONE FROM A MICROSPHERE- AND NANOPARTICLE-HYDROGEL OCULAR DRUG DELIVERY SYSTEM FOR THE ENHANCED TREATMENT OF NON-RESPONSIVE PATIENTS WITH CHOROIDAL NEOVASCULARIZATION
Title
SIMULTANEOUS RELEASE OF BIOACTIVE AFLIBERCEPT AND DEXAMETHASONE FROM A MICROSPHERE- AND NANOPARTICLE-HYDROGEL OCULAR DRUG DELIVERY SYSTEM FOR THE ENHANCED TREATMENT OF NON-RESPONSIVE PATIENTS WITH CHOROIDAL NEOVASCULARIZATION
Creator
Rudeen, Kayla M
Date
2022
Description
There is a growing subset of wet age-related macular degeneration (AMD) patients who do not fully respond to standard of care treatment, which...
Show moreThere is a growing subset of wet age-related macular degeneration (AMD) patients who do not fully respond to standard of care treatment, which consists of bimonthly/monthly bolus intravitreal injections of anti-vascular endothelial growth factors (anti-VEGFs). Some of these patients may respond to a combination therapy of anti-VEGF and corticosteroids. One treatment option uses a dexamethasone implant that releases for six months. This regimen, however, requires both the bimonthly/monthly intravitreal injections of anti-VEGF and semiannual intravitreal injections of the dexamethasone implant. Combining the two treatments into a single drug delivery system (DDS) would reduce the total number of injections, reducing the risk of potential complications (endophthalmitis, retinal detachment, intravitreal hemorrhage, increased intraocular pressure, and cataract) as well as the socioeconomic burden of treatment.The overarching goal of this study was to develop a single DDS that simultaneously releases anti-VEGF (aflibercept) and corticosteroid (dexamethasone) for the treatment of non-responsive wet AMD patients. Our laboratory previously developed a thermoresponsive, biodegradable microparticle-hydrogel DDS that releases anti-VEGF over a period of six months. The aims of the study were to (1) modify this system to include dexamethasone-loaded nanoparticles, optimize release kinetics for both drugs, and characterize the DDS; (2) evaluate the in vivo treatment efficacy in a laser-induced choroidal neovascularization (CNV) model; and (3) investigate the impacts of temperature and storage on the DDS integrity.
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