Sukmo Kang

Gold Nanoparticles Displaying Tumor‐Associated Self‐Antigens as a Potential Vaccine for Cancer Immunotherapy

Golden vaccine for cancers. Gold nanoparticles enable efficient antigen delivery to dendritic cells and then activate the cells to facilitate cross-presentation, inducing antigen-specific cytotoxic T-lymphocyte responses for effective cancer therapy.

Bilirubin Nanoparticles as a Nanomedicine for Anti-inflammation Therapy

Despite the high potency of bilirubin as an endogenous anti-inflammatory compound, its clinical translation has been hampered because of its insolubility in water. Bilirubin-based nanoparticles that may overcome this critical issue are presented. A polyethylene glycol compound (PEG) was covalently attached to bilirubin, yielding PEGylated bilirubin (PEG-BR). The PEG-BR self-assembled into nanoscale particles with a size of approximately 110 nm, termed bilirubin nanoparticles (BRNPs). BRNPs are highly efficient hydrogen peroxide scavengers, thereby protecting cells from H2 O2 -induced cytotoxicity. In a murine model of ulcerative colitis, intravenous injection of BRNPs showed preferential accumulation of nanoparticles at the sites of inflammation and significantly inhibited the progression of acute inflammation in the colon. Taken together, BRNPs show potential for use as a therapeutic nanomedicine in various inflammatory diseases.

Effects of gold nanoparticle-based vaccine size on lymph node delivery and cytotoxic T-lymphocyte responses

Abstract Although it has been shown that the size of nanoparticle‐based vaccines is a key determining factor for the induction of immune responses, few studies have provided detailed analyses of thresholds or critical sizes of nanoparticle vaccines. Here we report effects of the size of gold nanoparticle (GNP)‐based vaccines on their efficiency of delivery to lymph nodes (LNs) and induction of CD8+ T‐cell responses. We further propose a threshold size of GNPs for use as an effective vaccine. To examine the effects of GNP size, we synthesized GNPs with diameters of 7, 14 and 28 nm, and then conjugated them with recombinant ovalbumin (OVA) as a model antigen. The resulting OVA‐GNPs had hydrodynamic diameter (HD) of ˜ 10, 22, and 33 nm for 7, 14 and 28 nm GNPs, respectively and exhibited a size‐dependent increase in cellular uptake by dendritic cells (DCs) and subsequent T‐cell cross‐priming and activation. Upon injection into a mouse footpad, both 22‐ and 33‐nm OVA‐GNPs showed much higher delivery efficiency to draining LNs than did 10‐nm OVA‐GNPs. An ex vivo restimulation assay using OVA as an antigen revealed that frequencies of OVA‐specific CD8+ T cells were higher in mice immunized with 22‐ and 33‐nm OVA‐GNPs than in those immunized with 10‐nm OVA‐GNPs; moreover, these cells were shown to be poly‐functional. In a tumor‐prevention study, 22‐nm OVA‐GNPs showed greater antitumor efficacy, and higher infiltration of CD8+ T‐cells and greater tumor cell apoptosis and cell death than 10‐nm OVA‐GNPs. Taken together, our results suggest that the size threshold for induction of potent cellular responses and T‐cell poly‐functionality by GNPs lies between 10 nm and 22 nm, and highlight the importance of nanoparticle size as a critical parameter in designing and developing nanoparticle‐based vaccines. Graphical abstract Figure. No Caption available.

Photo-decomposable Organic Nanoparticles for Combined Tumor Optical Imaging and Multiple Phototherapies

Combination of photodynamic therapy (PDT) with photothermal therapy (PTT) has achieved significantly improved therapeutic efficacy compared to a single phototherapy modality. However, most nanomaterials used for combined PDT/PTT are made of non-biodegradable materials (e.g., gold nanorods, carbon nanotubes, and graphenes) and may remain intact in the body for long time, raising concerns over their potential long-term toxicity. Here we report a new combined PDT/PTT nanomedicine, designated SP3NPs, that exhibit photo-decomposable, photodynamic and photothermal properties. SP3NPs were prepared by self-assembly of PEGylated cypate, comprising FDA-approved PEG and an ICG derivative. We confirmed the ability of SP3NPs to generate both singlet oxygen for a photodynamic effect and heat for photothermal therapy in response to NIR laser irradiation in vitro. Also, the unique ability of SP3NPs to undergo irreversible decomposition upon NIR laser irradiation was demonstrated. Further our experimental results demonstrated that SP3NPs strongly accumulated in tumor tissue owing to their highly PEGylated surface and relatively small size (~60 nm), offering subsequent imaging-guided combined PDT/PTT treatment that resulted in tumor eradication and prolonged survival of mice. Taken together, our SP3NPs described here may represent a novel and facile approach for next-generation theranostics with great promise for translation into clinical practice in the future.

Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy

Significance Tumor tissues have formidable physiological barriers, such as a high interstitial pressure and a densely entangled ECM. Most synthetic nanomaterials used for drug delivery fail to penetrate tumor tissues deeply and localize only in perivascular areas, thereby limiting their therapeutic efficacy. This report describes bioengineered yeast-derived natural nanocarriers for cancer-specific targeting and drug delivery. Budding yeast was genetically engineered to produce large numbers of nanosized compartments—vacuoles that display cancer—targeting ligands on their surface. The nanosized vacuoles significantly enhanced drug penetration in tumor xenografts, and consequently prevented tumor growth without eliciting immune responses. This result shows that the biological nanocarriers overcome the limitations associated with synthetic cancer-targeting nanomaterials, and thus can be used to treat various cancers. Despite the appreciable success of synthetic nanomaterials for targeted cancer therapy in preclinical studies, technical challenges involving their large-scale, cost-effective production and intrinsic toxicity associated with the materials, as well as their inability to penetrate tumor tissues deeply, limit their clinical translation. Here, we describe biologically derived nanocarriers developed from a bioengineered yeast strain that may overcome such impediments. The budding yeast Saccharomyces cerevisiae was genetically engineered to produce nanosized vacuoles displaying human epidermal growth factor receptor 2 (HER2)-specific affibody for active targeting. These nanosized vacuoles efficiently loaded the anticancer drug doxorubicin (Dox) and were effectively endocytosed by cultured cancer cells. Their cancer-targeting ability, along with their unique endomembrane compositions, significantly enhanced drug penetration in multicellular cultures and improved drug distribution in a tumor xenograft. Furthermore, Dox-loaded vacuoles successfully prevented tumor growth without eliciting any prolonged immune responses. The current study provides a platform technology for generating cancer-specific, tissue-penetrating, safe, and scalable biological nanoparticles for targeted cancer therapy.

Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion injury (IRI) remains a major concern in liver transplantation and resection, despite continuing efforts to prevent it. Accumulating evidence suggests that bilirubin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. We recently developed bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol (PEG)-conjugated bilirubin. Here, we sought to investigate whether BRNPs protect against IRI in the liver by preventing oxidative stress. BRNPs exerted potent antioxidant and anti-apoptotic activity in primary hepatocytes exposed to hydrogen peroxide, a precursor of reactive oxygen species (ROS). In a model of hepatic IRI in mice, BRNP preconditioning exerted profound protective effects against hepatocellular injury by reducing oxidative stress, pro-inflammatory cytokine production, and recruitment of neutrophils. They also preferentially accumulated in IRI-induced inflammatory lesions. Collectively, our findings indicate that BRNP preconditioning provides a simple and safe approach that can be easily monitored in the blood like endogenous bilirubin, and could be a promising strategy to protect against IRI in a clinical setting.

Mono-arginine Cholesterol-based Small Lipid Nanoparticles as a Systemic siRNA Delivery Platform for Effective Cancer Therapy.

Although efforts have been made to develop a platform carrier for the delivery of RNAi therapeutics, systemic delivery of siRNA has shown only limited success in cancer therapy. Cationic lipid-based nanoparticles have been widely used for this purpose, but their toxicity and undesired liver uptake after systemic injection owing to their cationic surfaces have hampered further clinical translation. This study describes the development of neutral, small lipid nanoparticles (SLNPs) made of a nontoxic cationic cholesterol derivative, as a suitable carrier of systemic siRNA to treat cancers. The cationic cholesterol derivative, mono arginine-cholesterol (MA-Chol), was synthesized by directly attaching an arginine moiety to cholesterol via a cleavable ester bond. siRNA-loaded SLNPs (siRNA@SLNPs) were prepared using MA-Chol and a neutral helper lipid, dioleoyl phosphatidylethanolamine (DOPE), as major components and a small amount of PEGylated phospholipid mixed with siRNA. The resulting nanoparticles were less than ~50 nm in diameter with neutral zeta potential and much lower toxicity than typical cationic cholesterol (DC-Chol)-based lipid nanoparticles. SLNPs loaded with siRNA against kinesin spindle protein (siKSP@SLNPs) exhibited a high level of target gene knockdown in various cancer cell lines, as shown by measurement of KSP mRNA and cell death assays. Furthermore, systemic injection of siKSP@SLNPs into prostate tumor-bearing mice resulted in preferential accumulation of the delivered siRNA at the tumor site and significant inhibition of tumor growth, with little apparent toxicity, as shown by body weight measurements. These results suggest that these SLNPs may provide a systemic delivery platform for RNAi-based cancer therapy.

Coupled model for simulation of landslides and debris flows at local scale

This research connects different but sequential processes of slope failure: landslide occurrence, debris-flow initiation from landslides, and debris-flow propagation to lowlands. The coupled model presented in this study consists of a deterministic landslide susceptibility model that estimates the landslide source and local geomorphological mobilization criteria for selecting debris-flow initiation points, and an empirical debris-flow model that simulates the transport and propagation of failed materials from the identified source areas. The debris flow initiation in the spreading analysis was estimated from the landslide source by landslide analysis. Then, its inspection using the mobilization criteria was used to determine if the landslide transformed into a debris flow. While the geomorphological criteria were calibrated using data obtained from Gyeong-gi Province, the validation of the coupled approach was done at Mt. Woomyeon. In comparison with a landslide inventory map, the model simulations resulted in reasonable estimates of all the mountain hazards caused by slope failures as a sequential process on a local scale. The coupled analysis proposed in this study affirms that it is important to manage them together because of the correlation between landslides and debris flows. Thus, if it is parameterized and calibrated for local conditions the suggested model, linking landslides and debris flows with the mobilization analysis, provides a powerful tool for decision makers in territorial planning and disaster preparedness.

Targeted cancer therapy using a fusion protein of TNFα and a tumor-associated fibronectin-specific aptide

Tumor necrosis factor-α has shown potent antitumor effects in preclinical and clinical studies. However, severe side effects at less than therapeutic doses have limited its systemic delivery, prompting the need for a new strategy for targeted delivery of the protein to tumors. Here, we report a fusion protein of mouse tumor necrosis factor (TNF)-α (mTNFα) and a cancer-targeting, high-affinity aptide and investigate its therapeutic efficacy in tumor-bearing mice. A fusion protein consisting of mTNFα, a linker, and an aptide specific to extra domain B (EDB) of fibronectin (APTEDB), designated mTNFα-APTEDB, was successfully produced by expression in Escherichia coli. mTNFα-APTEDB retained specificity and affinity for its target, EDB. In mice bearing EDB-overexpressing fibrosarcomas, mTNFα-APTEDB showed greater efficacy in inhibiting tumor growth than mTNFα alone or mTNFα linked to a nonrelevant aptide, without causing an appreciable loss in body weight. Moreover, in vivo antitumor efficacy was further significantly increased by combination treatment with the chemotherapeutic drug, melphalan, suggesting a synergistic effect attributable to enhanced drug uptake into the tumor as a result of TNFα-mediated enhanced vascular permeability. These results suggest that a fusion protein of mTNFα with a cancer-targeting peptide could be a new anticancer therapeutic option for ensuring potent antitumor efficacy after systemic delivery.

Magnetic Resonance Imaging‐Guided Drug Delivery to Breast Cancer Stem‐Like Cells

The feasibility of detecting breast cancer stem-like cells (BCSCs) with magnetic resonance imaging using extradomain-B of fibronectin (EDB-FN)-specific peptide (APTEDB )-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (APTEDB -TCL-SPIONs) is previously demonstrated. Here, doxorubicin (Dox)-loaded APTEDB -TCL-SPIONs (Dox@APTEDB -TCL-SPIONs) are generated and their theranostic ability in a BCSC xenograft mouse model is assessed. The Dox@APTEDB -TCL-SPIONs enable more efficient delivery of Dox to tumors than nontargeted Dox@TCL-SPIONs. Much greater inhibition of BCSC tumor growth is observed after treatment with the Dox@APTEDB -TCL-SPIONs than with either Dox@TCL-SPIONs or free Dox. Hypointense signals are observed in the majority of the mice in postcontrast but not precontrast T2*-weighted MR images of tumors 7 days after treatment with Dox@APTEDB -TCL-SPIONs. An inverse correlation is observed between signal intensity and both EDB-FN expression and response to chemotherapy. The data indicate Dox@APTEDB -TCL-SPIONs can detect BCSCs within tumors by targeting EDB-FN-expressing cells. These nanoparticles thus have theranostic potential in breast cancer.