Degradable Acetalated Dextran Microparticles for Tunable Release of an Engineered Hepatocyte Growth Factor Fragment

Abstract

Injectable biomaterials are promising as new therapies to treat myocardial infarction (MI). One useful property of biomaterials is the ability to protect and sustain release of therapeutic payloads. In order to create a platform for optimizing the release rate of cardioprotective molecules we utilized the tunable degradation of acetalated dextran (AcDex). We created microparticles with three distinct degradation profiles and showed that the consequent protein release profiles could be modulated within the infarcted heart. This enabled us to determine how delivery rate impacted the efficacy of a model therapeutic, an engineered hepatocyte growth factor fragment (HGF-f). Our results showed that the cardioprotective efficacy of HGF-f was optimal when delivered over three days post-intramyocardial injection, yielding the largest arterioles, fewest apoptotic cardiomyocytes bordering the infarct and the smallest infarcts compared to empty particle treatment four weeks after injection. This work demonstrates the potential of using AcDex particles as a delivery platform to optimize the time frame for delivering therapeutic proteins to the heart.

Biodegradable Spheres Protect Traumatically Injured Spinal Cord by Alleviating the Glutamate‐Induced Excitotoxicity

“…Recently, a biodegradable water‐insoluble polymer “acetalated‐dextran” (AcDX) was synthesized by modifying hydroxyl groups of water‐soluble dextran with 2‐methoxypropene . Because of its high solubility in organic solvents, AcDX and its derivatives have been formulated into micro‐ and nanoparticles for biomedical applications, such as immunotherapy and myocardial infarction treatment . The immunogenicity of subunit vaccines could be enhanced by encapsulating a protein antigen and/or adjuvant within AcDX microspheres .…”

“…The immunogenicity of subunit vaccines could be enhanced by encapsulating a protein antigen and/or adjuvant within AcDX microspheres . AcDX microspheres loaded with an engineered hepatocyte growth factor fragment have been employed for the treatment of myocardial infarction . The cardioprotective efficacy of payload is optimal when delivered over 3 d post‐intramyocardial injection, yielding the largest arterioles and the fewest apoptotic cardiomyocytes bordering the infarct.…”

Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing

“…Older studies have measured high hydrogen ion concentrations in inflamed tissue (down to pH 5.4), fracture related hematomas (down to pH 4.7), and in caridac ischemia (down to pH 5.7) . Indeed, our group has previously used AcDex for treating models of cardiac ischemia . Due to the airpouch model cell and tissue recovery process where a buffer is injected to collect the cells, the measured pH ranging from pH 7.2–7.4 was most likely not representative value of the pH at the time of inflammation and drug release, and satisfactory conclusions could not be drawn.…”

“…Measuring pH‐fluctuations noninvasively would certainly aid in the design of disease‐triggered drug release, and highly sensitive probes are being developed . Expanding the versatility of the particles and tailor them to the desired disease could include tuning the degree of acetalation and particle size to better suit the desired pH‐range, where the tuned release kinetics and stability could extend the prophylactic capacity of the particles …”

“…Nonmodified dextran has clinically been used as a plasma expander for decades due to its water solubility . Acetalated dextran (AcDex) has been studied as a bioresponsive polymer for many medical applications, exhibiting high versatility in delivery functions and very low toxicity . AcDex is readily synthesized, easily tunable, and its degradation products are pH neutral and water‐soluble .…”