Donghyuck Yoo

Antioxidant polymeric nanoparticles as novel therapeutics for airway inflammatory diseases.

Successful pulmonary drug delivery requires polymeric drug delivery systems which have excellent biocompatibility and fast degradation rates, when frequent administration is necessary. Here, we report a new family of fully biodegradable hydroxybenzyl alcohol (HBA)-incorporated polyoxalate (HPOX) as a novel therapeutics of airway inflammatory diseases. HPOX was designed to incorporate antioxidant and anti-inflammatory HBA and peroxalate ester linkages capable of reacting with hydrogen peroxide (H2O2) in its backbone. HPOX nanoparticles exhibited highly potent antioxidant and anti-inflammatory effects by scavenging H2O2, reducing the generation of intracellular oxidative stress and suppressing the expression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin (IL)-1β in stimulated macrophages. The potential of HPOX nanoparticles as an anti-asthmatic agent was evaluated using a murine model of asthma. Intratracheal administration of HPOX nanoparticles remarkably reduced the recruitment of inflammatory cells and expression of pro-inflammatory mediators such as IL-4 and iNOS. Based on their excellent antioxidant, anti-inflammatory and anti-asthmatic activities, we believe that HPOX nanoparticles have great potential as therapeutics and drug carriers for the treatment of airway inflammatory diseases such as asthma.

Porous antioxidant polymer microparticles as therapeutic systems for the airway inflammatory diseases.

Inhaling steroidal anti-inflammatory drugs is the most common treatment for airway inflammatory diseases such as asthma. However, frequent steroid administration causes adverse side effects. Therefore, the successful clinical translation of numerous steroidal drugs greatly needs pulmonary drug delivery systems which are formulated from biocompatible and non-immunogenic polymers. We have recently developed a new family of biodegradable polymer, vanillyl alcohol-containing copolyoxalate (PVAX) which is able to scavenge hydrogen peroxide and exert potent antioxidant and anti-inflammatory activity. In this work, we report the therapeutic potential of porous PVAX microparticles which encapsulate dexamethasone (DEX) as a therapeutic system for airway inflammatory diseases. PVAX microparticles themselves reduced oxidative stress and suppressed the expression of pro-inflammatory tumor necrosis factor-alpha and inducible nitric oxide synthase in the lung of ovalbumin-challenged asthmatic mice. However, DEX-loaded porous PVAX microparticles showed significantly enhanced therapeutic effects than PVAX microparticles, suggesting the synergistic effects of PVAX with DEX. In addition, PVAX microparticles showed no inflammatory responses to lung tissues. Given their excellent biocompatibility and intrinsic antioxidant and anti-inflammatory activity, PVAX microparticles hold tremendous potential as therapeutic systems for the treatment of airway inflammatory diseases such as asthma.

H2O2-responsive antioxidant polymeric nanoparticles as therapeutic agents for peripheral arterial disease.

Peripheral artery disease (PAD) is a common circulatory disorder in which narrowed arteries limit blood flow to the lower extremity and affect millions of people worldwide. Therapeutic angiogenesis has emerged as a promising strategy to treat PAD patients because surgical intervention has been showing limited success. Leg muscles of PAD patients have significantly high level of ROS (reactive oxygen species) and the increased production of ROS is a key mechanism of initiation and progression of PAD. We have recently developed H2O2-responsive polymer PVAX, which is designed to rapidly scavenge H2O2 and release vanillyl alcohol with antioxidant and anti-inflammatory activity. In this study, we investigated the therapeutic efficacy of PVAX nanoparticles for PAD using a cell culture model and a mouse model of hindlimb ischemia. PVAX nanoparticles significantly enhanced the expression of angiogenic inducers such as vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (PECAM)-1 in human umbilical vein endothelial cells (HUVEC). PVAX nanoparticles promoted revascularization and restoration of blood perfusion into ischemic tissues by upregulating angiogenic VEGF and PECAM-1. This work demonstrates that H2O2-responsive PVAX nanoparticles facilitate therapeutic angiogenesis and hold tremendous translational potential as therapeutic systems for ischemic diseases such as PAD.

Fully biodegradable and cationic poly(amino oxalate) particles for the treatment of acetaminophen-induced acute liver failure

Acute inflammatory diseases are one of major causes of death in the world and there is great need for developing drug delivery systems that can target drugs to macrophages and enhance their therapeutic efficacy. Poly(amino oxalate) (PAOX) is a new family of fully biodegradable polymer that possesses tertiary amine groups in its backbone and has rapid hydrolytic degradation. In this study, we developed PAOX particles as drug delivery systems for treating acute liver failure (ALF) by taking the advantages of the natural propensity of particulate drug delivery systems to localize to the mononuclear phagocyte system, particularly to liver macrophages. PAOX particles showed a fast drug release kinetics and excellent biocompatibility in vitro and in vivo. A majority of PAOX particles were accumulated in liver, providing a rational strategy for effective treatment of ALF. A mouse model of acetaminophen (APAP)-induced ALF was used to evaluate the potential of PAOX particles using pentoxifylline (PTX) as a model drug. Treatment of PTX-loaded PAOX particles significantly reduced the activity of alanine transaminase (ALT) and inhibited hepatic cell damages in APAP-intoxicated mice. The high therapeutic efficacy of PTX-loaded PAOX particles for ALF treatment may be attributed to the unique properties of PAOX particles, which can target passively liver, stimulate cellular uptake and trigger a colloid osmotic disruption of the phagosome to release encapsulated PTX into the cytosol. Taken together, we believe that PAOX particles are a promising drug delivery candidate for the treatment of acute inflammatory diseases.

Dual Stimuli-Activatable Oxidative Stress Amplifying Agent as a Hybrid Anticancer Prodrug

Compared to normal cells, cancer cells have a higher level of reactive oxygen species (ROS) due to aberrant metabolism and disruption of redox homeostasis which drive their proliferation and promote progression and metastasis of cancers. The altered redox balance and biological difference between normal cells and cancer cells provide a basis for the development of anticancer agents which are able to generate pharmacological ROS insults to kill cancer cells preferentially. In this study, we report a new hybrid anticancer drug, termed OSamp, which undergoes esterase- and acid-catalyzed hydrolysis to deplete antioxidant glutathione (GSH) and generate ROS, simultaneously. OSamp significantly elevated oxidative stress in cancer cells, leading to enhanced apoptotic cancer cell death through mitochondrial membrane disruption, cytochrome c release, activation of pro-caspase 3, and deactivation of STAT3 (signal transducer and activator of transcription-3). OSamp, administered intravenously, significantly suppressed the tumor growth in a mouse model of tumor xenografts without notable side effects. Oxidative stress amplifying OSamp holds tremendous potential as a new anticancer therapeutic and provides a new therapeutic paradigm which can be extended to development of hybrid anticancer drugs.

Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy

Abstract Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide‐based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde‐conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid‐cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid‐triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT‐loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Graphical abstract Figure. No Caption available.

Molecularly Engineered Theranostic Nanoparticles for Thrombosed Vessels: H2O2-Activatable Contrast-Enhanced Photoacoustic Imaging and Antithrombotic Therapy

A thrombus (blood clot), composed mainly of activated platelets and fibrin, obstructs arteries or veins, leading to various life-threatening diseases. Inspired by the distinctive physicochemical characteristics of thrombi such as abundant fibrin and an elevated level of hydrogen peroxide (H2O2), we developed thrombus-specific theranostic (T-FBM) nanoparticles that could provide H2O2-triggered photoacoustic signal amplification and serve as an antithrombotic nanomedicine. T-FBM nanoparticles were designed to target fibrin-rich thrombi and be activated by H2O2 to generate CO2 bubbles to amplify the photoacoustic signal. In the phantom studies, T-FBM nanoparticles showed significant amplification of ultrasound/photoacoustic signals in a H2O2-triggered manner. T-FBM nanoparticles also exerted H2O2-activatable antioxidant, anti-inflammatory, and antiplatelet activities on endothelial cells. In mouse models of carotid arterial injury, T-FBM nanoparticles significantly enhanced the photoacoustic contrast specifically in thrombosed vessels and significantly suppressed thrombus formation. We anticipate that T-FBM nanoparticles hold great translational potential as nanotheranostics for H2O2-associated cardiovascular diseases.

Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H 2 O 2 -Activated bubble generating anti-inflammatory polymer particles

Muscles of peripheral artery disease (PAD) patients are under oxidative stress associated with a significantly elevated level of reactive oxygen species (ROS) including hydrogen peroxide (H2O2). Curcumin is a major active constituent of turmeric and is well known for its highly potent antioxidant, anti-inflammatory and angiogenic effects. We previously reported antioxidant vanillyl alcohol-incorporated copolyoxalate (PVAX) which is designed to rapidly scavenge H2O2 and release bioactive vanillyl alcohol and CO2 in a H2O2-triggered manner. In this work, we developed curcumin-loaded PVAX (CUR-PVAX) nanoparticles as contrast-enhanced ultrasound imaging agents as well as on-demand therapeutic agents for ischemic injuries based on the hypothesis that PVAX nanoparticles generate echogenic CO2 bubbles through H2O2-triggered oxidation of peroxalate esters and the merger of curcumin and PVAX exerts H2O2-activatable synergistic therapeutic actions. CUR-PVAX nanoparticles also displayed the drastic ultrasound signal in ischemic areas by generating CO2 bubbles. CUR-PVAX nanoparticles exhibited significantly higher antioxidant and anti-inflammatory activities than empty PVAX nanoparticles and equivalent curcumin in vascular endothelial cells. A mouse model of ischemic injury was used to evaluate the potential of CUR-PVAX nanoparticles as ultrasound imaging agents and on-demand therapeutic agents. CUR-PVAX nanoparticles significantly suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Moreover, CUR-PVAX nanoparticles significantly enhanced the level of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31), leading to blood perfusion into ischemic tissues. We, therefore, believe that CUR-PVAX nanoparticles hold great translational potential as novel theranostic agents for ischemic diseases such as PAD.