Seonju Lee

Validation of international consensus guidelines for the resection of branch duct‐type intraductal papillary mucinous neoplasms

Classifications of intraductal papillary mucinous neoplasm (IPMN) remain ambiguous, especially for the mixed type. Factors predicting malignancy remain unclear. The aim of this study was to evaluate the usefulness of factors predicting malignancy in the new international consensus guidelines for resection of branch duct‐type (BD)‐IPMN and to compare them with those in the previous version.

Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation

Failure of chromosome–spindle attachment and a weakened spindle assembly checkpoint lead to genetic instability and cancer in mice expressing acetylation-deficient BubR1.

Preparation of non-aggregated fluorescent nanodiamonds (FNDs) by non-covalent coating with a block copolymer and proteins for enhancement of intracellular uptake

Fluorescent nanodiamonds (FNDs) are very promising fluorophores for use in biosystems due to their high biocompatibility and photostability. To overcome their tendency to aggregate in physiological solutions, which severely limits the biological applications of FNDs, we developed a new non-covalent coating method using a block copolymer, PEG-b-P(DMAEMA-co-BMA), or proteins such as BSA and HSA. By simple mixing of the block copolymer with FNDs, the cationic DMAEMA and hydrophobic BMA moieties can strongly interact with the anionic and hydrophobic moieties on the FND surface, while the PEG block can form a shell to prevent the direct contact between FNDs. The polymer-coated FNDs, along with BSA- and HSA-coated FNDs, showed non-aggregation characteristics and maintained their size at the physiological salt concentration. The well-dispersed, polymer- or protein-coated FNDs in physiological solutions showed enhanced intracellular uptake, which was confirmed by CLSM. In addition, the biocompatibility of the coated FNDs was expressly supported by a cytotoxicity assay. Our simple non-covalent coating with the block copolymer, which can be easily modified by various chemical methods, projects a very promising outlook for future biomedical applications, especially in comparison with covalent coating or protein-based coating.

Apoptosis inducing, conformationally constrained, dimeric peptide analogs of KLA with submicromolar cell penetrating abilities.

The apoptosis inducing KLA peptide, (KLAKLAK)2, possesses an ability to disrupt mitochondrial membranes. However, this peptide has a poor eukaryotic cell penetrating potential and, as a result, it requires the assistance of other cell penetrating peptides for effective translocation in micromolar concentrations. In an effort to improve the cell penetrating potential of KLA, we have created a library in which pairs of residues on its hydrophobic face are replaced by Cys. The double Cys mutants were then transformed to bundle dimers by oxidatively generating two intermolecular disulfide bonds. We envisioned that once transported into cells, the disulfide bonds would undergo reductive cleavage to generate the monomeric peptides. The results of these studies showed that one of the mutant peptides, dimer B, has a high cell penetrating ability that corresponds to 100% of fluorescence positive cells at 250 nM. Even though dimer B induces disruption of the mitochondrial potential and cytochrome c release followed by caspase activation at submicromolar concentrations, it displays an LD50 of 1.6 μM under serum conditions using HeLa cells. Taken together, the results demonstrate that the strategy involving formation of bundle dimeric peptides is viable for the design of apoptosis inducing KLA peptide that translocate into cells at submicromolar concentrations.

Cell-Penetrating, Dimeric α-Helical Peptides: Nanomolar Inhibitors of HIV-1 Transcription†

We constructed dimeric α-helical peptide bundles based on leucine (L) and lysine (K) residues for both efficient cell penetration and inhibition of the Tat-TAR interaction. The LK dimers can penetrate nearly quantitatively into eukaryotic cells and effectively inhibit the elongation of the TAR transcript at low nanomolar concentrations. The effective inhibition of HIV-1 replication strongly suggests that the LK dimer has strong potential as an anti-HIV-1 drug.

Alleviation of capsular formations on silicone implants in rats using biomembrane-mimicking coatings

Despite their popular use in breast augmentation and reconstruction surgeries, the limited biocompatibility of silicone implants can induce severe side effects, including capsular contracture - an excessive foreign body reaction that forms a tight and hard fibrous capsule around the implant. This study examines the effects of using biomembrane-mimicking surface coatings to prevent capsular formations on silicone implants. The covalently attached biomembrane-mimicking polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), prevented nonspecific protein adsorption and fibroblast adhesion on the silicone surface. More importantly, in vivo capsule formations around PMPC-grafted silicone implants in rats were significantly thinner and exhibited lower collagen densities and more regular collagen alignments than bare silicone implants. The observed decrease in α-smooth muscle actin also supported the alleviation of capsular formations by the biomembrane-mimicking coating. Decreases in inflammation-related cells, myeloperoxidase and transforming growth factor-β resulted in reduced inflammation in the capsular tissue. The biomembrane-mimicking coatings used on these silicone implants demonstrate great potential for preventing capsular contracture and developing biocompatible materials for various biomedical applications.

A medusa-like β-cyclodextrin with 1-methyl-2-(2′-carboxyethyl) maleic anhydrides, a potential carrier for pH-sensitive drug delivery

Abstract We developed a new pH-sensitive drug delivery carrier based on β-cyclodextrin (β-CD) and 1-methyl-2-(2′-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of β-CD were successfully attached to MCM residues to produce a medusa-like β-CD–MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency ( > 90%). More importantly, β-CD–MCM–CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5 h at pH 5.5. In addition, the inclusion complex between β-CD–MCM–CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, β-CD–MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery.

Systematic structure control of ammonium iodide salts as feasible UCST-type forward osmosis draw solutes for the treatment of wastewater

A variety of UCST-type thermoresponsive ammonium iodide salts is systematically designed and synthesised with desired aqueous solubility, phase-transition temperature, osmolality change, phase-transition concentration range, stability, and toxicity by controlling the ionic interactions, hydrophobicity, and symmetry of the salt structure. Suitable draw solutes can be selected based on the characteristics of the ammonium iodide salts as well as the feed solutions for feasible forward osmosis (FO)-based water purification. In this research, highly concentrated wastewater from a flue gas desulfuriser (FGD), with osmotic pressure three times higher than seawater, is targeted for purification by FO using the draw solutes. Two ammonium iodide salts (HM8I and HM10I) show a remarkable water flux from the wastewater samples and significantly lower salt leakage compared to conventional draw solutes. The osmolality of the phase-separated draw solution drops to less than one tenth of that of the initial feed solution, and reverse osmosis or nanofiltration can be applied to the solution with much lower external pressure for the final purification to produce fresh water. This systematic approach to the design and selection of suitable draw solutes can be an effective strategy for future practical FO-based wastewater treatment and seawater desalination.

Ring Opening Metathesis Polymerization of Bicyclic α,β-Unsaturated Anhydrides for Ready-to-be-grafted Polymers Having Tailored pH-Responsive Degradability

Polymers having α,β-unsaturated anhydrides as repeating units were synthesized by ring opening metathesis polymerization (ROMP). The anhydride moieties were ready-to-be-grafted with amines to form acid-labile cis-α,β-unsaturated acid amide linkages. The pH-responsive reversible de-grafting can be controlled by changing the intramolecular accessibility between acid and amide groups. The alendronate-grafted ROMP polymers showed distinct pH-dependent cytotoxicity according to the anhydride structures.