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A Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Treatment of Choroidal Neovascularization
Title
A Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Treatment of Choroidal Neovascularization
Creator
Liu, Wenqiang
Date
2020
Description
Current standard of care for neovascular age-related macular degeneration (AMD) requires repeated intravitreal bolus injections of anti...
Show moreCurrent standard of care for neovascular age-related macular degeneration (AMD) requires repeated intravitreal bolus injections of anti-vascular endothelial growth factors (anti-VEGFs). This frequent repeated injection regimen present increased risks of potential complications including endophthalmitis, retinal detachment, intravitreal hemorrhage, and cataract. In addition, pharmacokinetic profiles of drugs are non-optimal, since the peak level of drug after bolus injections may cause potential toxic effect while the quick clearance later may render subtherapeutic concentration. Finally, the significant socioeconomic burden upon patients, family, and healthcare systems cannot be ignored. Therefore, a controlled delivery system for anti-VEGF drugs is in high demand to reduce injection frequencies, minimize potential risks, and improve efficacy.The overall goal of this study was to develop a biodegradable and injectable drug delivery system (DDS) capable of releasing therapeutic anti-VEGF (aflibercept) for six months. Based on our previous non-degradable DDS for anti-VEGFs, this work sought to introduce biodegradable polymeric crosslinker into the hydrogel matrix to make the DDS biodegradable. To accomplish this goal, three specific aims were pursued: (1) Development of a biodegradable and injectable microsphere-hydrogel DDS for controlled release of aflibercept for six months, important biomaterial parameters including thermoresponsive behavior, injectability, in vitro degradation and biocompatibility, release kinetics, and drug bioactivity were characterized to obtain the optimal DDS formulation; (2) Evaluation of long-term in vivo efficacy of aflibercept-loaded DDS in laser-induced CNV model; (3) Investigation of in vivo safety and biocompatibility of DDS injection and its degradation products.
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DEVELOPMENT OF FULLY BIOCOMPATIBLE HYDROGEL NANOPARTICLE FORMULATIONS FOR CONTROLLED-RELEASE DELIVERY OF A WIDE VARIETY OF BIOMOLECULES
Title
DEVELOPMENT OF FULLY BIOCOMPATIBLE HYDROGEL NANOPARTICLE FORMULATIONS FOR CONTROLLED-RELEASE DELIVERY OF A WIDE VARIETY OF BIOMOLECULES
Creator
Borges, Fernando Tancredo Pereira
Date
2020
Description
In recent years, our group has focused on the production of PEGDA-based hydrogel scaffolds and nanoparticles for drug delivery of small...
Show moreIn recent years, our group has focused on the production of PEGDA-based hydrogel scaffolds and nanoparticles for drug delivery of small molecules. However, with recent advances in modern therapeutic treatments, such as protein and genetic engineering, there is an increasing need for the development of drug delivery devices that would be able encapsulate larger molecules. Therefore, the goal of this thesis work was to develop a systematic way to produce fully biocompatible PEGDA-based hydrogel nanoparticle formulations that would be able to encapsulate any size molecule, ranging from small ionic molecules, to peptides and proteins, all the way to large nucleic acids, and deliver it in a controlled manner.The first of part of this work consisted of developing a stable and reproducible process for the production of hydrogel PPi-NPs. Initial studies were done in order to assess the influence of phosphate salts in the polymerization system and it was found that both monophosphate and polyphosphate salts significantly damper the NVP homo-polymerization kinetics, but do not affect the co-polymerization of NVP and PEGDA. Then, emulsion stability studies were done to determine whether phosphate salts affected the stability of the minimeulsion system used in the production of the nanoparticles. Cloud point measurements and droplet size screening measurements showed that by transitioning from a Pi-loaded emulsion system to a PPi-loaded emulsion system, the required HLB of the emulsion shifts by 1.5 points. Upon correction for that shift, a reproducible process for production of PPi-loaded nanoparticles was obtained. A parametric study was then performed to see how the different process parameters affected the different properties of the produced particles. The second part of the work consisted in developing a platform for encapsulation of large to very-large molecules within these hydrogel systems. A new set of equations was developed for better estimation of the interstitial space, available for encapsulation of molecules, of crosslinked polymers that used very high molecular weight crosslinkers and/or high amounts of crosslinker. Upon development of this new set of equations, hydrogel discs were made via photopolymerization in order to validate the equations. By introducing a third monomer, EGA, and varying the molecular weight and concentration of the crosslinker, hydrogels with a wide range of mesh dimensions from 25 to 700 were achieved. These gels were then used to encapsulate 4 different sample molecules of varying molecular weights and size. A new heuristic was developed for encapsulation of non-spherical molecules, where the aspect ratios of the molecule and of the polymer network are considered. By varying the size of the ratios of the dimensions of the hydrogel network to the dimensions of the molecule, significantly different release profiles of small molecules, peptides and oligonucleotides were obtained. Finally, in order to explore different administration routes, the process was transitioning into being fully biocompatible. The organic solvent previously used in the emulsion system was replaced by soybean oil and the surfactants were replaced by a food-grade surfactant, PGPR, to form Bio-Compatible Nanoparticle Emulsions (BCNEs). Qualitative release from the BCNEs was shown. A new method for quantitative measuring of release from BCNE was developed. Release from QK-BCNE was observed up to 46 days, which is unprecedented for sustained-release and revolutionary for the field. A BCNE spreadable ointment formulation was also developed.
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