Su-Geun Yang

An acetylated polysaccharide-PTFE membrane-covered stent for the delivery of gemcitabine for treatment of gastrointestinal cancer and related stenosis

Gemcitabine (Gem) eluting metal stents were prepared for potential application as drug delivery systems for localized treatment of malignant tumors. Pullulan, a natural polysaccharide, was chemically acetylated (pullulan acetate; PA) by different degrees (1.18, 1.71, and 2.10 acetyl groups per glucose unit of pullulan), layered on polytetrafluoroethylene (PTFE), and applied as part of a Gem-loaded controlled-release membrane for drug-eluting non-vascular stents. PA with a higher degree of acetylation had greater drug-loading capacity with more extended release of Gem over 30 days. The released Gem accumulated in CT-26 colon cancer without systemic exposure inducing total regression of tumors. The long-term biological activity of the released Gem and apoptosis of tumor tissues following localized delivery were confirmed by annexin V binding assays and histology. The controlled release of Gem from PA-PTFE covered drug-eluting stents (DES) may increase the patency of these stents for the treatment of malignant gastrointestinal cancer as well as cancer-related stenosis.

Improved SERS Nanoparticles for Direct Detection of Circulating Tumor Cells in the Blood

The detection of circulating tumor cells (CTCs) in the blood of cancer patients is crucial for early cancer diagnosis, cancer prognosis, evaluation of the treatment effect of chemotherapy drugs, and choice of cancer treatment options. In this study, we propose new surface-enhanced Raman scattering (SERS) nanoparticles for the direct detection of CTCs in the blood. Under the optimized experimental conditions, our SERS nanoparticles exhibit satisfying performances for the direct detection of cancer cells in the rabbit blood. A good linear relationship is obtained between the SERS intensity and the concentration of cancer cells in the range of 5-500 cells/mL (R(2) = 0.9935), which demonstrates that the SERS nanoparticles can be used for the quantitative analysis of cancer cells in the blood and the limit of detection is 5 cells/mL, which is lowest compared with the reported values. The SERS nanoparticles also have an excellent specificity for the detection of cancer cells in the rabbit blood. The above results reinforce that our SERS nanoparticles can be used for the direct detection of CTCs in the blood with excellent specificity and high sensitivity.

Partially unzipped carbon nanotubes for high-rate and stable lithium–sulfur batteries

Lithium–sulfur (Li–S) batteries are attractive due to a high theoretical energy density and low sulfur cost. However, they have critical drawbacks such as drastic capacity fading during cycling, especially under high current density conditions. We report a suitable carbon matrix based on partially unzipped multi-walled carbon nanotubes (UZ.CNTs), which have favorable properties compared to multi-walled carbon nanotubes (MWCNTs) and fully unzipped nanoribbons (UZ.NRs). Partially unzipped walls of MWCNTs lead to increased surface area and pore volume with a retained electron conduction pathway. This also provides accessible inner pores as a stable reservoir for polysulfides. This reservoir is decorated with newly introduced oxygen containing functional groups, and affords a synergistic effect of shortening the depth that electrons penetrate and interacting with polysulfides for high-performance Li–S batteries. The synergistic effect is revealed by Monte Carlo simulations. The resulting partially unzipped MWCNT sulfur composite delivers 707.5 mA h g−1 at the initial discharge and retains 570.4 mA h g−1 after 200 cycles even at a high current rate of 5C (8375 mA g−1).

99mTc-hematoporphyrin linked albumin nanoparticles for lung cancer targeted photodynamic therapy and imaging

In this study, we fabricated albumin nanoparticles (ANP) using a solvent diffusion method and modified the surface of the ANP with hematoporphyrin (HP) which has been used for cancer photodynamic therapy. Hematoporphyrin linked albumin nanoparticles (HP-ANP) were further functionalized with gamma-emitting nuclides (99mTc) for scintigraphic imaging. The fabrication method for HP-ANP was optimized extensively to obtain HP-ANP particles within the size range of 100 to 200 nm. HP-ANP had enhanced accumulation in A549 and CT-26 cancer cell lines, and photodynamic activity against A549 cells after UV exposure. HP-ANP also showed increased accumulation in murine lung tumors, which was induced by CT-26 colon cancer cells, compared to normal lungs. Pharmacokinetics of 99mTc chelated HP-ANP (99mTc-HP-ANP) was estimated through scintigraphic imaging of rabbits. 99mTc-HP-ANP demonstrated good imaging properties in the rabbit with a much more extended biological half life compared to 99mTc-HP. 99mTc-HP-ANP could be utilized as a radio-diagnostic tool for cancer as well as the obvious application for photodynamic therapy.

Liver Cancer Targeting of Doxorubicin with Reduced Distribution to the Heart Using Hematoporphyrin-Modified Albumin Nanoparticles in Rats

ABSTRACTPurposeTo evaluate the usefulness of hematoporphyrin (HP)-modification of the surface of doxorubicin (DOX)-loaded bovine serum albumin (BSA) nanoparticles (NPs) in the liver cancer-selective delivery of DOX.MethodsHP-modified NPs (HP-NPs) were prepared by conjugation of amino groups on the surface of NPs with HP, a ligand for low density lipoprotein (LDL) receptors on the hepatoma cells. In vitro cellular accumulation of DOX, in vivo biodistribution of DOX, safety, and anti-tumor efficacy were evaluated for HP-NPs.ResultsCytotoxicity and accumulation of DOX were in the order of HP-NPs>NPs>solution form (SOL). Cellular uptake from HP-NPs was proportional to the expression level of LDL receptors on the cells, indicating possible involvement of LDL receptor-mediated endocytosis (RME) in uptake. The “merit index,” an AUC ratio of DOX in liver (target organ) to DOX in heart (major side effect organ) following iv administration of HP-NPs to hepatoma rats, was 132.5 and 4 times greater compared to SOL and NPs, respectively. The greatest suppression of body weight decrease and tumor size increase was observed for iv-administered HP-NPs in tumor-bearing mice.ConclusionsHP modification appears to be useful in selective delivery of NP-loaded DOX to tumors.

Polymeric nanocapsules with SEDDS oil-core for the controlled and enhanced oral absorption of cyclosporine

Self-microemulsifying drug delivery system (SEDDS) cored-polymeric nanocapsules (NC) were fabricated using emulsion diffusion method for the controlled oral absorption of the poorly water soluble drug, cyclosporine. Poly-dl-lactide (PDLLA) was used as the shell-forming polymer. The NCs in different polymer/oil ratios (from 25/125 to 125/125) were prepared following a solvent-diffusion method. Especially, the SEDDS oil-core compositions, which can form microemulsions on dispersion, were selected based on a pseudo-phase diagram study and further optimized based on the solubility and permeability studies. The prepared NCs were with a mean diameter of 150-220 nm and 9.4-4.5% w/w drug loading. In vivo study in rats showed that the optimized NC(50/125) and NC(100/125) released the drug in controlled way as well as enhanced the bioavailability significantly with AUC(0-24h) values of 14880.3±1470.6 and 12657.8±754.5 ng h/ml, respectively, compared to that of SEDDS-core solution (9878.9±409.6 ng h/ml). Moreover it was observed that the NCs maintained blood concentration of cyclosporine (>500 ng/ml) for 14-20 h but in the case of control formulation it was only 7.33 h. Our results suggest that the prepared NCs could be a potential carrier for the oral controlled release formulation of cyclosporine.

Gemcitabine-releasing polymeric films for covered self-expandable metallic stent in treatment of gastrointestinal cancer.

Non-vascular drug-eluting stents have been studied for the treatment of gastrointestinal cancer and cancer-related stenosis. In this study, we designed and evaluated a gemcitabine (GEM)-eluting covered nonvascular stent. Polyurethane (PU)/polytetrafluoroethylene (PTFE) film was selected for the drug loading and eluting membrane. The membrane was fabricated by dip-coating on a Teflon bar (∅; 10mm), air-dried, peeled off and applied to a self-expanding Nitinol stent. Various amounts of poloxamer 407 (PL, Lutrol F127, BASF) (8%, 10%, or 12% of PU by weight) were added to control the release of GEM from membranes. The membrane containing 12% PL (GEM-PU-PL12%) showed the most favourable release properties; 70% of the loaded GEM released within 35 days, including the 35% released during the initial burst. The biological activities of GEM-PU-PL12% were evaluated using human cholangiocarcinoma cells (SK-ChA-1). GEM-PU-PL12% most efficiently inhibited the proliferation of cholangiocarcinoma cells and most highly induced pro-inflammatory cytokines (TNF-α, IL-1β and IL-12) and p38 MAPKs in the cells. Subtumoural insertion of the GEM-PU-PL12% membrane more efficiently inhibited the growth of CT-26 colon cancer than other membranes. In this study, the GEM-eluting metal stents covered with PU-PL12% showed considerable feasibility for the treatment of malignant gastrointestinal cancer as well as cancer-related stenosis.

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC0→24h, Cmax and Tmax, respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

Rational design of exfoliated 1T MoS2@CNT-based bifunctional separators for lithium sulfur batteries

Lithium-sulfur (Li-S) batteries are experiencing a design shift from a closed structure to an open structure to further improve their performance, expanding the design realm from the development of nanostructured materials for the cathode to the production of functional separators. Rational guidelines for preparing a bifunctional separator with exfoliated MoS2 and CNTs are suggested to deal with two conflicting issues: guaranteeing the electron pathway while strongly trapping polysulfide species. In addition, various exfoliation methods ranging from mechanical to chemical were investigated to identify an adequate method for preparing exfoliated MoS2 based-bifunctional separators. The electrochemical exfoliation method was found to be effective in not only exfoliating high quality MoS2 in terms of the lateral size and number of layers, but also providing a favorable MoS2 phase, 1T metallic MoS2. A bifunctional separator of 1T exfoliated MoS2@CNT in a tandem configuration (layer-by-layer structure)-coated Celgard rather than a hetero-configuration delivered an excellent electrochemical performance of ∼670 mA h g−1 after 500 cycles at a high current density of 1C. In addition, the separator was highly effective in trapping polysulfide species and facilitating electron transfer to the irreversible discharge products. The rational guidelines suggested in this study will be extended to other two-dimensional transition-metal dichalcogenides, and applied to the development of other functional membranes.

Photo-cured PMMA/PEI core/shell nanoparticles surface-modified with Gd-DTPA for T1 MR imaging

Herein, we introduced amine-functionalized core-shell nanoparticles (Polymethyl methacrylate/Polyethyleneimine; PMMA/PEI) with surface primary amines (3.15×10(5) groups/particle) and uniform size distribution (150-200nm) that were prepared by one-step photo-induced emulsion polymerization. Further PEI-surface was modified with diethylenetriamine pentaacetic acid (DTPA) and introduced with Gd(III). The modified particles possessing DTPA can entrap a high content of Gd(III) ions of over 5.5×10(4)Gd/particle with stable chelation (no release of free Gd) at least 7h. The Gd-DTPA-conjugated core-shell nanoparticles (PMMA/PEI-DTPA-Gd NPs) enhanced the MRI intensity more than Primovist (a commercial hepatic contrast agent). Moreover, the PMMA/PEI-DTPA-Gd NPs showed non-cytotoxicity up to 250μM in normal liver cells. Thus, in vitro data suggested the PMMA/PEI-DTPA-Gd NPs is promising delivery system as a superior MRI contrast agent, especially for hepatic lesion targeted MR imaging.