Hoa Thi Le

A biotin-guided fluorescent-peptide drug delivery system for cancer treatment.

Herein, we present a fluorescent-peptide drug delivery system composed of biotin-naphthalimide-HJ inhibitor peptide2, prodrug 1. Treatment of 1 to biotin receptor-positive HepG2 cells, which are resistant to high concentrations of the HJ inhibitor peptide2, decreased cell viability and increased intracellular fluorescence.

Antibody functionalization with a dual reactive hydrazide/click crosslinker.

A water-soluble, dual reactive hydrazide/click crosslinker (ethynyl hydrazide, EH) was synthesized and characterized. A model antibody, human immunoglobulin G (hIgG), was ethynylated by conventional oxidation/hydrazide reactions with the hydrazide moiety of EH. The terminal alkyne conjugated to the glycan of hIgG was easily functionalized by quantitative and bioorthogonal Cu(I)-catalyzed azide-alkyne cycloaddition. The potential of the hydrazide/click crosslinker as a reagent to functionalize antibodies was demonstrated with fluorophore labeling and antibody immobilization.

6-Triazolyl-6-deoxy-β-cyclodextrin derivatives: synthesis, cellular toxicity, and phase-solubility study

Heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (HTβCD) and heptakis{6-(4-sulfonylmethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (STβCD) were prepared using copper(I)-catalyzed azide-alkyne cycloaddition between 6-azido-6-deoxy-β-CD and one of two alkynes, propargyl alcohol, and sodium propargyl sulfonate, respectively. The structures of HTβCD and STβCD were characterized by NMR techniques. NMR interpretations and computer modeling suggested that the limited freedom of rotation of the triazole moieties keeps HTβCD and STβCD rigid and compact. Water solubility tests of HTβCD and STβCD showed that the minimum water solubility of HTβCD and STβCD is at least 20times higher than that of β-CD. MTT assay showed that HTβCD and STβCD did not influence the cell viability under 1mM. A phase-solubility study of prednisolone with the CD derivatives showed increased solubility of prednisolone in the presence of increasing concentrations of HTβCD and STβCD.

Small molecular weight PEGylation of diosgenin in an in vivo animal study for diabetic auditory impairment treatment

Diosgenin was modified to control its in vivo bioavailability by conjugating a hydrophilic unit, tetraethylene glycol. The diosgenin-tetraethylene glycol conjugate (TE) was orally administered in streptozotocin induced diabetic mice for this auditory protection study. The bioactivity improvement of TE for in vivo diabetic auditory impairment treatment was clearly observed in three different auditory tests and compared with that of diosgenin. The improvement in in vivo efficacy suggests that the small molecular weight PEGylation of diosgenin is a synthetically robust and systematically applicable strategy to reform the poor pharmacokinetics of a hydrophobic aglycone.

Enhanced antidiabetic efficacy and safety of compound K⁄β-cyclodextrin inclusion complex in zebrafish

Background 20(S)-Protopanaxadiol 20-O-D-glucopyranoside, also called compound K (CK), exerts antidiabetic effects that are mediated by insulin secretion through adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic β-cells. However, the antidiabetic effects of CK may be limited because of its low bioavailability. Methods In this study, we aimed to enhance the antidiabetic activity and lower the toxicity of CK by including it with β-cyclodextrin (CD) (CD-CK), and to determine whether the CD-CK compound enhanced pancreatic islet recovery, compared to CK alone, in an alloxan-induced diabetic zebrafish model. Furthermore, we confirmed the toxicity of CD-CK relative to CK alone by morphological changes, mitochondrial damage, and TdT-UTP nick end labeling (TUNEL) assays, and determined the ratio between the toxic and therapeutic dose for both compounds to verify the relative safety of CK and CD-CK. Results The CD-CK conjugate (EC50 = 2.158μM) enhanced the recovery of pancreatic islets, compared to CK alone (EC50 = 7.221μM), as assessed in alloxan-induced diabetic zebrafish larvae. In addition, CD-CK (LC50 = 20.68μM) was less toxic than CK alone (LC50 = 14.24μM). The therapeutic index of CK and CD-CK was 1.98 and 9.58, respectively. Conclusion The CD-CK inclusion complex enhanced the recovery of damaged pancreatic islets in diabetic zebrafish. The CD-CK inclusion complex has potential as an effective antidiabetic efficacy with lower toxicity.

Regulatory effect of hydroquinone–tetraethylene glycol conjugates on zebrafish pigmentation

We synthesized two hydroquinone-tetraethylene glycol conjugates (HQ-TGs) and investigated their logP, photophysical stability, and redox chemical stability. HQ-TGs are a little more hydrophilic than hydroquinone (HQ) and show an enhanced photophysical and redox chemical stability compared with HQ. In addition we studied the effect of HQ-TGs on cell viability and on zebrafish pigmentation. MTT assay in HF-16 cells showed HQ-TGs are less cytotoxic than HQ. The phenotype-based image analysis of zebrafish larvae suggests that HQ-TGs suppress the pigmentation of zebrafish in a dose-dependent manner. The comparative experiments on stability, cytotoxicity, and zebrafish pigmentation between HQ and HQ-TGs suggest that mono tetraethylene glycol-functionalization of HQ is an alternative solution to overcome the adverse effect of HQ.

Synthesis, Cytotoxicity, and Phase-Solubility Study of Cyclodextrin Click Clusters

To explore the possibility of cyclodextrin click clusters (CCCs) as a new cyclodextrin-based excipient, we prepared three different CCCs; heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (HT-β-CD), heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}{2,3-di-O-methyl}-β-cyclodextrin (HT-β-CD(OMe)2 ), and heptakis{6-(4-sulfonylmethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-β-cyclodextrin (ST-β-CD). The CCCs were prepared using copper(I)-catalyzed azide-alkyne cycloaddition from 6-azido-6-deoxy-β-CD and their water solubility, cytotoxicity, and drug-solubilizing effect were investigated. Water turbidity testing of the CCCs showed that the minimum water solubility of the CCCs is at least 20 times higher than that of β-CD. An MTT cell viability assay performed on HeLa cells demonstrated a low cytotoxicity of the CCCs compared with 2,6-dimethyl-β-cyclodextrin. HT-β-CD(OMe)2 and ST-β-CD did not demonstrate any cytotoxicity within the experimental concentration (∼5 mM) like 2-hydroxypropyl-β-CD. A phase-solubility study of prednisolone with the CCCs suggested that CCCs showed increased solubility of prednisolone in the presence of increasing concentrations of the CCCs. The comparison between the conventional CD derivatives and CCCs on solubility, cytotoxicity, and binding property implies that CCCs are alternative cyclodextrin derivatives useful for overcoming the restrictions of conventional cyclodextrin chemistry.

Modulating the GSH/Trx selectivity of a fluorogenic disulfide-based thiol sensor to reveal diminished GSH levels under ER stress

We synthesized a fluorogenic disulfide-based naphthalimide thiol probe (ER-Naph) with a hydrophilic endoplasmic reticulum (ER)-guiding glibenclamide unit. Its ER targeting ability and high selectivity to GSH over thioredoxin, a potent competitor, were clearly demonstrated, both in solution and in vitro. Finally, a confocal microscopic investigation revealed that GSH levels in the ER were dramatically decreased under thapsigargin, brefeldin A, and tunicamycin-induced ER stress models.