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1.
J Control Release ; 370: 626-642, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38734314

ABSTRACT

Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.


Subject(s)
Amphotericin B , Antifungal Agents , Fungemia , Prodrugs , Animals , Amphotericin B/administration & dosage , Amphotericin B/pharmacology , Amphotericin B/chemistry , Amphotericin B/pharmacokinetics , Prodrugs/administration & dosage , Prodrugs/chemistry , Prodrugs/pharmacology , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/therapeutic use , Humans , Fungemia/drug therapy , Nanoparticles/chemistry , Drug Liberation , Micelles , Mice , Female , Click Chemistry , Candida albicans/drug effects , Polyethylene Glycols/chemistry , Polyethylene Glycols/administration & dosage
2.
Exp Biol Med (Maywood) ; 247(4): 300-309, 2022 02.
Article in English | MEDLINE | ID: mdl-34861117

ABSTRACT

Carbon "quantum" dots or carbon dots (CDots) exploit and enhance the intrinsic photoexcited state properties and processes of small carbon nanoparticles via effective nanoparticle surface passivation by chemical functionalization with organic species. The optical properties and photoinduced redox characteristics of CDots are competitive to those of established conventional semiconductor quantum dots and also fullerenes and other carbon nanomaterials. Highlighted here are major advances in the exploration of CDots for their serving as high-performance yet nontoxic fluorescence probes for one- and multi-photon bioimaging in vitro and in vivo, and for their uniquely potent antimicrobial function to inactivate effectively and efficiently some of the toughest bacterial pathogens and viruses under visible/natural or ambient light conditions. Opportunities and challenges in the further development of the CDots platform and related technologies are discussed.


Subject(s)
Nanoparticles , Nanostructures , Quantum Dots , Carbon/pharmacology , Fluorescence , Nanostructures/chemistry , Quantum Dots/chemistry
3.
Ann Hum Genet ; 84(4): 339-344, 2020 07.
Article in English | MEDLINE | ID: mdl-31853946

ABSTRACT

Osteogenesis imperfecta (OI) is a rare heritable disease with systemic connective tissue disorder. Most of the patients represent autosomal dominant form of OI, and are usually resulting from the mutations in type I collagen genes. However, the gene mutations reported previously only account for ∼70% of the OI cases. Here, in a Chinese OI family, we examined seven patients and nine normal individuals using the whole genome sequencing and molecular genetic analysis. The mutation of rs66612022 (COL1A2:p.Gly328Ser) related to glycine substitution was found in the seven patients. Moreover, we identified a novel missense mutation (HMMR:p.Glu2Gln). Interestingly, the individuals of this family with both the mutations were suffering from OI, while the others carried one or none of them are normal. The mutations of COL1A2 and HMMR and their combined effect on OI would further expand the genetic spectrum of OI.


Subject(s)
Collagen Type I/genetics , Extracellular Matrix Proteins/genetics , Hyaluronan Receptors/genetics , Osteogenesis Imperfecta/genetics , Asian People/genetics , China , Female , Humans , Male , Mutation, Missense , Pedigree , Polymorphism, Single Nucleotide , Whole Genome Sequencing
4.
J Bone Miner Metab ; 34(1): 23-32, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25511080

ABSTRACT

Osteoporosis is a systemic and metabolic bone disease. New drugs with good curative effect, fewer side effects, and high safety need to be developed urgently. Recently, simvastatin has been used to treat osteoporosis more frequently; however, its clinical effect and treatment mechanism are still unknown. With the use of animal models, the treatment effectiveness of simvastatin on experimental osteoporosis was investigated and the functional mechanism was preliminarily explored. The results show that simvastatin significantly increased the mechanical parameters such as maximum load, stiffness, and energy-absorbing capacity, and improved the microarchitecture. They indicated that the antiosteoporosis activity of simvastatin may be due to the promotion of proliferation and differentiation of osteoblasts. Simvastatin was effective in treating experimental osteoporosis. This study provides necessary experimental evidence for the clinical application of simvastatin in osteoporosis treatment.


Subject(s)
Osteoporosis/prevention & control , Simvastatin/therapeutic use , Animals , Bone Density/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoporosis/drug therapy , Simvastatin/pharmacology
5.
Langmuir ; 30(23): 6878-88, 2014 Jun 17.
Article in English | MEDLINE | ID: mdl-24849780

ABSTRACT

A series of telodendrimer (a linear polyethyelene glycol-block-dendritic oligo-cholic acid) have been synthesized via a bottom-up approach to optimize the hemocompatibility of the nanocarrier. Numbers of hydrophilic glycerol groups were introduced onto the polar surface of cholic acid to reduce the plasma membrane lytic activity of telodendrimers. An interesting result was observed: only an optimum number of glycerol introduced could reduce the hemolytic properties of the nanocarrier; on the contrary, more glycerols or the amino-glycerol substitution onto cholic acid significantly increased the hemolytic properties of the nanocarriers. To further elucidate the structure-property relationship, the molecular dynamic approach was used to simulate the conformation of the subunits of telodendrimers with different glycerol substitution, and the binding energies and the polar surface areas of the hairpin conformations were calculated to explain the membrane activities of nanocarriers. In addition, these telodendrimer subunits were synthesized and their membrane activities were tested directly, which validated the computational prediction and correlated with the observed hemolytic activity of nanocarriers. The glycerol substitution sustained the facial amphiphilicity of cholic acid, maintaining the superior drug loading capacity (paclitaxel and doxorubicin), stability, cell uptake, and anticancer efficacy of payloads. The in vivo optical imaging study indicated that the optimized nanocarriers can specifically deliver drug molecules to the tumor sites more efficiently than free drug administration, which is essential for the enhanced cancer treatment.


Subject(s)
Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Drug Delivery Systems/methods , Nanostructures/chemistry , Polymers/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Drug Carriers/adverse effects , Drug Delivery Systems/adverse effects , Female , HT29 Cells , Hemolysis/drug effects , Humans , Mice , Mice, Nude , Micelles , Molecular Dynamics Simulation , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Paclitaxel/therapeutic use , Polymers/adverse effects , Xenograft Model Antitumor Assays
6.
Neural Regen Res ; 7(15): 1138-44, 2012 May 25.
Article in English | MEDLINE | ID: mdl-25722706

ABSTRACT

A contusive model of spinal cord injury at spinal segment T8-9 was established in rats. Huantiao (GB30) and Huatuojiaji (Ex-B05) were punctured with needles, and endogenous neural stem cells were labeled with 5-bromo-2'-deoxyuridine (BrdU) and NG2. Double immunofluorescence staining showed that electroacupuncture markedly increased the numbers of BrdU(+)/NG2(+) cells at spinal cord tissue 15 mm away from the injury center in the rostral and caudal directions. The results suggest that electroacupuncture promotes the proliferation of endogenous neural stem cells and oligodendrocytes in rats with spinal cord injury.

7.
Bioorg Med Chem ; 16(17): 8178-86, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18693018

ABSTRACT

Twenty-four purine derivatives bearing aryl groups at N9 position were designed and synthesized as HIV-1 Tat-TAR interaction inhibitors. All the compounds showed high antiviral activities in inhibiting the formation of SIV-induced syncytium in CEM174 cells. Ten of them with low cytotoxicities were evaluated by Tat dependent HIV-1 LTR-driven CAT gene expression colorimetric enzyme assay in human 293T cells at a concentration of 30 microM, indicating effective inhibitory activities of blocking the Tat-TAR interaction. The aryl groups at N9 position affected the binding affinities between compounds and TAR RNA, showing some specificities of aryl groups to TAR RNA.


Subject(s)
Anti-HIV Agents/chemical synthesis , Gene Products, tat/antagonists & inhibitors , Purines/chemical synthesis , Purines/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Design , Gene Products, tat/genetics , Gene Products, tat/metabolism , HIV Long Terminal Repeat/drug effects , HIV-1/drug effects , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Purines/chemistry , RNA/drug effects , RNA/genetics , Stereoisomerism , Structure-Activity Relationship
8.
Bioorg Med Chem ; 16(8): 4538-44, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18331796

ABSTRACT

A series of novel 2-oxocycloalkylsulfonamides (4) were synthesized and their structures confirmed by IR, (1)H NMR, and elemental analysis. The bioassay showed that they have fair to excellent fungicidal activities against Botrytis cinerea Pers and Sclerotinia sclerotiorum. Among them, compounds 4A(10), 4A(11), 4A(12), 4B(2), and 4B(3), the EC(50) values of which were 2.12, 3.66, 3.96, 2.38, and 2.43 microg/mL, respectively, displayed excellent fungicidal activity against B. cinerea Pers, and are comparable with commercial fungicide procymidone (the EC(50) value is 2.45 microg/mL). 3D QSAR against B. cinerea Pers was studied, a statistically significant and chemically meaningful CoMFA model was developed and some compounds which have a high predicted activity were forecasted. In addition, the bioassay also showed that the compounds have good inhibitory activities against human tumor cells HL-60, BGC-823, Bel-7402 and KB. It is interesting to point out that the antitumor activities of compounds 4 are in accordance with their fungicidal activity to a great extent: compounds having relatively best antitumor activities (4A(10), 4A(11), 4A(12), and 4B(3)) also displayed excellent fungicidal activity.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Alkylation , Antifungal Agents/chemistry , Antineoplastic Agents/chemistry , Ascomycota/drug effects , Botrytis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cyclization , Humans , Molecular Structure , Quantitative Structure-Activity Relationship , Sulfonamides/chemistry
9.
Bioorg Med Chem ; 15(1): 265-72, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17055732

ABSTRACT

A series of novel substituted purines containing a side chain with a terminal amino or guanidyl group were designed and synthesized as HIV-1 Tat-TAR inhibitors. All the compounds could effectively block the TAR transactivation in human 293T cells with the CAT expression percentage ranging from 34.4% to 65.7% and showed high antiviral effects with low cytotoxicities in inhibiting the formation of SIV-induced syncytium in CEM174 cells. Molecular modeling studies by Auto-dock process suggest that the compounds bind to TAR RNA in two different modes.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Gene Products, tat/antagonists & inhibitors , HIV Long Terminal Repeat/drug effects , Purines/chemical synthesis , Purines/pharmacology , Animals , Anti-HIV Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Drug Design , Giant Cells/drug effects , Humans , Magnetic Resonance Spectroscopy/methods , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Structure, Tertiary , Purines/chemistry , Sensitivity and Specificity , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effects
10.
Bioorg Med Chem Lett ; 15(17): 3978-81, 2005 Sep 01.
Article in English | MEDLINE | ID: mdl-16039124

ABSTRACT

Four new isoquinoline derivatives bearing guanidinium group or amino group-terminated side chain were synthesized to target the HIV-1 TAR element. Their abilities to bind TAR RNA and inhibit Tat-TAR RNA interaction were determined by CE analysis, a Tat-dependent HIV-1 LTR-driven CAT assay and SIV-induced syncytium evaluation.


Subject(s)
Anti-HIV Agents/chemical synthesis , Gene Products, tat/drug effects , HIV Long Terminal Repeat/drug effects , Isoquinolines/chemical synthesis , Anti-HIV Agents/pharmacology , Cell Line , Electrophoresis, Capillary , Gene Products, tat/metabolism , Humans , Isoquinolines/pharmacology , Protein Binding/drug effects , Structure-Activity Relationship
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