Tumor-targeted redox-regulating and antiangiogenic phototherapeutics nanoassemblies for self-boosting phototherapy.

Cancer cells are equipped with abundant antioxidants such as glutathione (GSH) that eliminate reactive oxygen species (ROS) to deteriorate the therapeutic efficacy of photodynamic therapy (PDT). Another challenge in PDT is circumventing PDT-induced hypoxic condition that provokes upregulation of pro-angiogenic factor such as vascular endothelial growth factor (VEGF). It is therefore reasonable to expect that therapeutic outcomes of PDT could be maximized by concurrent delivery of photosensitizers with GSH depleting agents and VEGF suppressors. To achieve cooperative therapeutic actions of PDT with in situ GSH depletion and VEGF suppression, we developed tumor targeted redox-regulating and antiangiogenic phototherapeutic nanoassemblies (tRAPs) composed of self-assembling disulfide-bridged borylbenzyl carbonate (ssBR), photosensitizer (IR780) and tumor targeting gelatin. As a framework of tRAPs, ssBR was rationally designed to form nanoconstructs that serve as photosensitizer carriers with intrinsic GSH depleting- and VEGF suppressing ability. tRAPs effectively depleted intracellular GSH to render cancer cells more vulnerable to ROS and also provoked immunogenic cell death (ICD) of cancer cells upon near infrared (NIR) laser irradiation. In mouse xenograft models, tRAPs preferentially accumulated in tumors and dramatically eradicated tumors with laser irradiation. The design rationale of tRAPs provides a simple and versatile strategy to develop self-boosting phototherapeutic agents with great potential in targeted cancer therapy.

Tumor-Targeting H2O2-Responsive Photosensitizing Nanoparticles with Antiangiogenic and Immunogenic Activities for Maximizing Anticancer Efficacy of Phototherapy.

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) uses photosensitizers and light to kill cancer cells and has become a promising therapeutic modality because of advantages such as minimal invasiveness and high cancer selectivity. However, PTT or PDT as a single treatment modality has insufficient therapeutic efficacy. Moreover, oxygen consumption by PDT activates angiogenic factors and leads to cancer recurrence and progression. Therefore, the therapeutic outcomes of phototherapy would be maximized by employing photosensitizers for concurrent PTT and PDT and suppressing angiogenic factors. Therefore, integrating photosensitive agents and antiangiogenic agents in a single nanoplatform would be a promising strategy to maximize the therapeutic efficacy of phototherapy. In this study, we developed hyaluronic acid-coated fluorescent boronated polysaccharide (HA-FBM) nanoparticles as a combination therapeutic agent for phototherapy and antiangiogenic therapy. Upon a single near-infrared laser irradiation, HA-FBM nanoparticles generated heat and singlet oxygen simultaneously to kill cancer cells and also induced immunogenic cancer cell death. Beside their fundamental roles as photosensitizers, HA-FBM nanoparticles exerted antiangiogenic effects by suppressing the vascular endothelial growth factor (VEGF) and cancer cell migration. In a mouse xenograft model, intravenously injected HA-FBM nanoparticles targeted tumors by binding CD44-overexpressing cancer cells and suppressed angiogenic VEGF expression. Upon laser irradiation, HA-FBM nanoparticles remarkably eradicated tumors and increased anticancer immunity. Given their synergistic effects of phototherapy and antiangiogenic therapy from tumor-targeting HA-FBM nanoparticles, we believe that integrating the photosensitizers and antiangiogenic agents into a single nanoplatform presents an attractive strategy to maximize the anticancer therapeutic efficacy of phototherapy.

Acid-activatable polymeric curcumin nanoparticles as therapeutic agents for osteoarthritis.

Curcumin, a primary active element of turmeric, has potent antioxidant and anti-inflammatory activity, but its low bioavailability is a major hurdle in its pharmaceutical applications. To enhance the therapeutic efficacy of curcumin, we exploited polymeric prodrug strategy. Here, we report rationally designed acid-activatable curcumin polymer (ACP), as a therapeutic prodrug of curcumin, in which curcumin was covalently incorporated in the backbone of amphiphilic polymer. ACP could self-assemble to form micelles that rapidly release curcumin under the acidic condition. The potential of ACP micelles as therapeutics for osteoarthritis was evaluated using a mouse model of monoidoacetic acid (MIA)-induced knee osteoarthritis. ACP micelles drastically protected the articular structures from arthritis through the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin 1ß (IL-1ß). Given their pathological stimulus-responsiveness and potent antioxidant and anti-inflammatory activities, ACP micelles hold remarkable potential as a therapeutic agent for not only osteoarthritis but also various inflammatory diseases.

Acid-sensitive oxidative stress inducing and photoabsorbing polysaccharide nanoparticles for combinational anticancer therapy.

Combination therapy, a treatment regimen that combines more than two therapeutic agents to diseased tissues has recently gained increasing attentions in anticancer therapy. As cancer cells are more vulnerable to oxidative stress and heat compared to normal cells, we developed hyperthermia- and oxidative stress-inducing maltodextrin (HTOM) nanoparticles as a platform of combinational photothermal/oxidative anticancer therapy. HTOM was designed to incorporate cinnamaldehyde as an oxidative stress inducer through acid-labile acetal linkage and IR780 as a photoabsorber. HTOM nanoparticles could generate excess reactive oxygen species (ROS) to kill cancer cells effectively. When exposed to near infrared (NIR) laser irradiation (808 nm), HTOM nanoparticles also increased temperature to destroy cancer cells. The combination of NIR laser irradiation with HTOM nanoparticles exhibited significantly higher anticancer activity than HTOM nanoparticles alone and NIR lasers irradiation alone. When combined with NIR laser irradiation on the tumor site, intravenously administrated HTOM nanoparticles effectively eradicated tumors in mouse xenograft models. Our strategy for combination of oxidative stress and photothermal heating may offer a new combinational treatment modality for cancer.

Hydrogen peroxide-activatable polymeric prodrug of curcumin for ultrasound imaging and therapy of acute liver failure.

Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2-associated diseases.

Dual Imaging-Guided Oxidative-Photothermal Combination Anticancer Therapeutics.

Heme oxygenase-1 (HO-1) is a stress-response protein with potent cytoprotective and antioxidant activity, and its expression in cancer cells is enhanced in response to chemotherapy and radiotherapy. HO-1 is known to serve as a shield to protect cancer cells from anticancer therapy and attenuate apoptotic signals. It can be therefore reasoned that inhibition of HO-1 reduces the antioxidant level, making cancer cells more sensitive to photothermal heating. In this work, we developed dual imaging-guided oxidative-photothermal combination nanotherapeutics (OPCN) consisting of amphiphilic polymers conjugated with zinc protoporphyrin as a HO-1 inhibitor and fluorescent IR820 as a photothermal agent. A combination of OPCN and near-infrared (NIR) laser irradiation markedly increased the temperature and exerted significant toxicity through induction of apoptosis. In a mouse model of xenografts, tumors were identified by the strong fluorescence and photoacoustic signals. OPCN combined with NIR laser irradiation resulted in effective and complete thermal ablation of tumors without discernable side effects and tumor recurrence. We believe that OPCN hold tremendous translational potential for dual imaging-guided oxidative-photothermal combination anticancer therapy.

Acid-triggered echogenic nanoparticles for contrast-enhanced ultrasound imaging and therapy of acute liver failure.

There has been increasing interest in the development of pathological stimulus-activatable nanoplatforms with theranostic functions. Here, we report ketalized maltodextrin (KMD) nanoparticles which are able to deliver therapeutic and imaging functions to the acidic conditions simultaneously, as may be found in the site of inflammation. KMD was synthesized as a platform of the theranostic nanoparticles by conjugating acid-cleavable hydrophobic moieties to maltodextrin through carbonate bonds. KMD nanoparticles could undergo acid-triggered hydrolytic degradation to generate carbon dioxide (CO2) bubbles, amplifying the ultrasound signal. The potential of KMD nanoparticles as a drug carrier was evaluated using silymarin as a model drug. KMD nanoparticles displayed significantly enhanced ultrasound contrast at acidic pH and released drug payloads in acid-triggered manners. The translational potential of silymarin-loaded KMD (s-KMD) nanoparticles as ultrasound contrast agents and therapeutic agents was thoroughly evaluated using cell culture models and mouse models of acetaminophen (APAP)-induced acute liver failure. s-KMD nanoparticles exhibited significantly enhanced ultrasound contrast in the APAP-intoxicated liver and also remarkably suppressed the hepatic damages by inhibiting the expression of pro-inflammatory cytokines. These results suggest that KMD nanoparticles hold tremendous potential as theranostic agents for various inflammatory diseases.

Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H2O2-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-1ß). 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.

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

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.