Ho Sang Jung

Nanographene oxide-hyaluronic acid conjugate for photothermal ablation therapy of skin cancer.

Melanoma skin cancer is one of the most dangerous skin cancers and the main cause of skin-cancer-related mortality. Hyaluronic acid (HA) has been used as an effective transdermal delivery carrier of chemical drugs and biopharmaceuticals. In this work, a nanographene oxide-HA conjugate (NGO-HA) was synthesized for photothermal ablation therapy of melanoma skin cancer using a near-infrared (NIR) laser. Confocal microscopy and ex vivo bioimaging clearly visualized the remarkable transdermal delivery of NGO-HA to tumor tissues in the skin of mice, which might be ascribed to highly expressed HA receptors and relatively leaky structures around tumor tissues, enabling the enhanced permeation and retention of nanoparticles. The NIR irradiation resulted in complete ablation of tumor tissues with no recurrence of tumorigenesis. The antitumor effect was confirmed by ELISA for caspase-3 activity and histological and immunohistochemical analyses with TUNEL assay for tumor apoptosis. Taken together, we could confirm the feasibility of transdermal NGO-HA for photothermal ablation therapy of melanoma skin cancers.

Bioimaging of hyaluronic acid derivatives using nanosized carbon dots.

Fluorescent nanosized carbon dots (Cdots) are an emerging bioimaging agent with excellent chemical inertness and marginal cytotoxicity in comparison to widely used semiconductor quantum dots. In this work, we report the application of Cdots for real time bioimaging of target specific delivery of hyaluronic acid (HA) derivatives. Polyethylene glycol (PEG) diamine-capped Cdots were synthesized by the pyrolysis of citric acid in a hot solvent. The synthesized Cdots showed strong fluorescence under UV excitation with emission properties dependending on the excitation wavelength. HA-Cdot conjugates were synthesized by amide bond formation between amine groups of Cdot and carboxylic groups of HA. After confirmation of the negligible cytotoxicity of Cdots and HA-Cdot conjugates, in vitro bioimaging was carried out for target specific intracellular delivery of the HA-Cdot conjugates by HA receptor-mediated endocytosis. Furthermore, in vivo real-time bioimaging of Cdots and HA-Cdot conjugates exhibited the target specific delivery of HA-Cdot conjugates to the liver with abundant HA receptors. Taken together, we could confirm the feasibility of HA derivatives as a target-specific drug delivery carrier for the treatment of liver diseases and Cdots as a promising bioimaging agent.

Photodynamic therapy of melanoma skin cancer using carbon dot - chlorin e6 - hyaluronate conjugate.

UNLABELLED Despite wide application of photodynamic therapy (PDT) for the treatment of melanoma skin cancers, there are strong biomedical unmet needs for the effective generation of singlet oxygen after targeted delivery of photosensitizers. Here, we investigated a facile PDT of melanoma skin cancer using transdermal carbon dot - chlorine e6 - hyaluronate (Cdot-Ce6-HA) conjugates. The Cdot-Ce6-HA conjugate was synthesized by the coupling reaction of diaminohexane modified HA (DAH-HA) with the carboxylic group of Ce6. The singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6. The enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice were corroborated by confocal microscopy and two-photon microscopy. The laser irradiation after topical treatment with Cdot-Ce6-HA conjugates resulted in complete suppression of melanoma skin cancers. The antitumor effect was confirmed by histological analysis with H&E staining and TUNEL assay for tumor apoptosis. Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers. STATEMENT OF SIGNIFICANCE To our knowledge, this is the first report on a facile transdermal photodynamic therapy (PDT) of melanoma skin cancer using carbon dot - chlorine e6 - hyaluronate (Cdot-Ce6-HA) conjugates. We found that the singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6. Confocal microscopy and two-photon microscopy clearly confirmed the enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice. Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers.

Surface modification of multipass caliber-rolled Ti alloy with dexamethasone-loaded graphene for dental applications.

Titanium (Ti) and its alloys with a high mechanical strength and a small diameter can be effectively exploited for minimally invasive dental implantation. Here, we report a multipass caliber-rolled Ti alloy of Ti13Nb13Zr (MPCR-TNZ) with a high mechanical strength and strong fatigue characteristics. For further dental applications, MPCR-TNZ was surface-modified with reduced graphene oxide (RGO) and loaded with osteogenic dexamethasone (Dex) via π-π stacking on the graphitic domain of RGO. The Dex-loaded RGO-MPCR-TNZ (Dex/RGO-MPCR-TNZ) resulted in significantly enhanced growth and differentiation of MC3T3-E1 cells into osteoblasts, which was confirmed by Alizarin red staining, alkaline phosphatase activity test, immunocytochemistry, and real-time PCR. Moreover, we could confirm the feasibility of Dex/RGO-MPCR-TNZ from the implantation test of a prototype of a dental implant to an artificial bone block for clinical dental applications.

Nano graphene oxide–hyaluronic acid conjugate for target specific cancer drug delivery

A nano graphene oxide–hyaluronic acid (NGO–HA) conjugate was successfully prepared for target specific delivery of an anti-cancer drug loaded by π–π stacking via HA receptor mediated endocytosis. In vitro tests confirmed the pH dependent drug release and target specific anti-cancer effect of the complex.

Nanoscale graphene coating on commercially pure titanium for accelerated bone regeneration

Titanium (Ti) is one of the representative biocompatible metallic materials which has been widely exploited for various implants and bone replacements. Here, commercially pure Ti (CP Ti) was surface-modified with reduced graphene oxide (RGO) for accelerated bone regeneration and osseointegration. Nanoscale RGO coating on CP Ti was clearly confirmed by SEM, AFM, EDS, XPS, HR-TEM and EELS. In addition, pre-osteoblast cells cultured on RGO-CP Ti showed higher cell viability and cell attachment than those on CP Ti. After confirmation of the drug loading capability of RGO-CP Ti, osteogenic dexamethasone loaded RGO-CP Ti (Dex/RGO-CP Ti) was implanted on calvarial bone defects in rats. Synchrotron X-ray imaging successfully visualized more effective bone regeneration on Dex/RGO-CP Ti than CP Ti and RGO-CP Ti after 8 weeks.

Enhancing the transdermal penetration of nanoconstructs: could hyaluronic acid be the key?

Nanoconstructs, such as liposomes, polymeric micelles, gold nanoparticles, carbon nanomaterials and nanocrystalline quantum dots, have been widely investigated for diagnostic, bioimaging and therapeutic applications [1]. Nanoconstructs have been also extensively explored in the field of dermatology. For example, liposomes and polymeric nanoparticles loaded with drugs were applied as topical administration agents for the treatment of skin diseases such as psoriasis, dermatitis and skin cancer [2,3]. Titanium dioxide and zinc oxide (ZnO) nanoparticles have been used as sun-screen formulation for the protection of skin from UV by the scattering, absorption and reflection of UV [4]. Silver nanoparticles are commercially used as wound and burn dressing agents with antibacterial effects [5]. Quantum dots and ZnO nanoparticles were utilized as bioimaging agents for the diagnosis of skin diseases [6,7]. Moreover, gold nanoconstructs and carbon nanomaterials have been actively investigated as promising agents for the photothermal ablation therapy of skin cancers due to their high light-to-heat conversion capability [8,9]. For further applications of nanoconstructs in dermatology, we need efficient transdermal delivery carriers of the nanoconstructs. The transdermal delivery has several advantages over other administration routes, such as oral delivery and needle based injection. The advantages include noninvasive treatment, self-administration, improved patient compliance and avoidance of hepatic first-pass metabolism or digestion system [10]. Despite these benefits, the low skin permeability of nanoconstructs such as polymers, proteins, hydrophilic drugs and nanoparticles limited their wide applications to the transdermal delivery. To facilitate the transdermal delivery of nanoconstructs, additional treatments have been adopted using penetration enhancers, iontophoresis, ultrasound and microneedles [11]. However, these methods require physical perturbations to the skin tissue, causing skin damage in some cases [12]. A noninvasive molecular carrier for transdermal delivery would have compelling advantages. The understanding for the characteristics of skin layers can be a good starting point for the development of transdermal delivery carriers of nanoconstructs. Stratum corneum (SC), the outermost skin layer, is the main barrier composed of densely packed dead cells forming hydrophobic surfaces. For the penetration of hydrophobic SC, hydrophobic molecules have clear benefits over hydrophilic molecules. The hydrophobic molecules can infiltrate into densely packed lipid layers in SC. However, nanoconstructs are usually formulated to have hydrophilic surfaces enhancing the physiological stability in the biological conditions. This contradicting requirement of hydrophobicity and hydrophilicity for transdermal delivery should be reconciled to enhance the physiological stability and the skin permeability by lipid disruption in SC. Recently, hyaluronic acid (HA) has been investigated as a promising transdermal delivery carrier. HA is a naturally occurring linear polysaccharide composed of repeating units of d-glucuronic acid and N-acetylEnhancing the transdermal penetration of nanoconstructs: could hyaluronic acid be the key?

Microneedle Biosensor for Real-Time Electrical Detection of Nitric Oxide for In Situ Cancer Diagnosis During Endomicroscopy

A dual-diagnostic system of endom-icroscope and microneedle sensor is developed to demonstrate high-resolution imaging combined with electrical real-time detection of NO released from cancer tissues. The dual-diagnostic system can be a new platform for facile, precise, rapid, and accurate detection of cancers in various biomedical applications.

Superior Pre-Osteoblast Cell Response of Etched Ultrafine-Grained Titanium with a Controlled Crystallographic Orientation

Ultrafine-grained (UFG) Ti for improved mechanical performance as well as its surface modification enhancing biofunctions has attracted much attention in medical industries. Most of the studies on the surface etching of metallic biomaterials have focused on surface topography and wettability but not crystallographic orientation, i.e., texture, which influences the chemical as well as the physical properties. In this paper, the influences of texture and grain size on roughness, wettability, and pre-osteoblast cell response were investigated in vitro after HF etching treatment. The surface characteristics and cell behaviors of ultrafine, fine, and coarse-grained Ti were examined after the HF etching. The surface roughness during the etching treatment was significantly increased as the orientation angle from the basal pole was increased. The cell adhesion tendency of the rough surface was promoted. The UFG Ti substrate exhibited a higher texture energy state, rougher surface, enhanced hydrophilic wettability, and better cell adhesion and proliferation behaviors after etching than those of the coarse- and fine-grained Ti substrates. These results provide a new route for enhancing both mechanical and biological performances using etching after grain refinement of Ti.

Hyaluronic acid–siRNA conjugates complexed with cationic solid lipid nanoparticles for target specific gene silencing

Despite extensive investigations on siRNA delivery systems for the past decade, there has been no clinically available product until now. In this work, reducible hyaluronic acid (HA)–siRNA conjugate was successfully synthesized and used to make a complex with cationic solid lipid nanoparticles (CSLNs) for the development of a liver specific siRNA delivery system. The reducible HA–siRNA conjugate was synthesized by the disulfide–thiol exchange reaction between pyridyldithiol modified HA and thiolated siRNA. The remaining pyridyldithiol was further blocked with cysteine. The biomimetic CSLNs were prepared by reconstituting the composition of natural apolipoprotein-free low density lipoproteins (LDLs). The formation of the HA–siRNA/CSLN complex was confirmed by gel electrophoresis (GE), dynamic light scattering (DLS), and atomic force microscopy (AFM). The HA–siRNA/CSLN complex showed remarkably low cytotoxicity and high transfection efficiency in the presence of serum. The therapeutic index (LC50/IC50) of the HA–siRNA/CSLN complex was statistically much higher than that of a HA–siRNA conjugate or siRNA complexed with commercially available siRNA transfection reagents like in vivo jetPEI and INTERFERin, as well as an siRNA/CSLN complex. The HA–siRNA/CSLN complex can be effectively applied as a model system for the treatment of liver diseases, such as liver fibrosis and liver cancer.