Other articles by Xueming Wu on PubMed

• The Effect of Citric Acid Added to Hydroxypropyl Methylcellulose (HPMC) Matrix Tablets on the Release Profile of Vinpocetine Drug Development and Industrial Pharmacy. Jul, 2004  |   Pubmed ID: 15285336 Vinpocetine is a pH-dependent experimental drug with a short half-life. The sustained-release matrix tablets of vinpocetine were prepared by direct compression using hydroxypropyl methylcellulose (HPMC) and different amounts of citric acid to set up a system bringing about gradual release of this drug. In order to investigate the influence of citric acid and the pH value of medium on the drug release from HPMC matrix tablets, an in vitro release test was carried out in either phosphate buffer pH 6.8 [0.5% sodium dodecyl sulfate (SDS)] for 12 hr or in 0.1 N HCl (0.5% SDS) (0-2 hr) and phosphate buffer pH 6.8 (0.5% SDS) (2-12 hr). Dissolution curves were described by the Peppas equation: M(t)/M(inf)=ktn, and the influence of citric acid on the dissolution mechanism was estimated according to the regression parameter-n and k values. The addition of citric acid and the pH value of medium could notably influence the dissolution behavior and mechanism of drug-release from matrices. Increasing the amounts of citric acid produced an increase in drug release rate, which showed a good linear relationship between contents of citric acid and drug accumulate release (%) in phosphate buffer pH 6.8 (0.5% SDS) (r>0.99). Moreover, a higher drug release rate could be found in 0.1 N HCl (0.5% SDS) than that in phosphate buffer pH 6.8 (0.5% SDS) during the first two hours when the content of citric acid added to matrices was lower than 45 mg/tab., but no significant difference could be found when the content of citric acid was above that value. Increasing amounts of citric acid produced decreasing values of n and increasing values of k, in a linear relationship, which indicated there was a trend favoring the mechanism of diffusion with the addition of increasing quantities of citric acid.
• A Peptide Targeted Contrast Agent Specific to Fibrin-fibronectin Complexes for Cancer Molecular Imaging with MRI Bioconjugate Chemistry. Dec, 2008  |   Pubmed ID: 19053180 A peptide targeted contrast agent, CLT1-(Gd-DTPA), was synthesized for molecular imaging of fibronectin-fibrin complexes in tumor tissue with magnetic resonance imaging (MRI). The T(1) and T(2) relaxivities of CLT1-(Gd-DTPA) were 4.22 and 4.45 mM(-1) s(-1) at 3 T, respectively. The targeted contrast agent specifically bound to tumor tissue and resulted in significant tumor contrast enhancement at a dose of 0.1 mmol Gd/kg for at least 60 min in mice bearing HT-29 human colon carcinoma xenografts as shown in dynamic MR images. In contrast, a control nontargeted contrast agent, Gd(DTPA-BMA), was cleared rapidly with little tumor enhancement 60 min postinjection. Tumor enhancement with CLT1-(Gd-DTPA) was significantly reduced after coinjection with a 3-fold excess of free CLT1 peptide. The preliminary study has shown that CLT1-(Gd-DTPA) can specifically bind to the fibrin-fibronectin complexes in tumor tissues, resulting in significant tumor enhancement. The targeted contrast agent has a potential for cancer molecular imaging with MRI.
• Targeted Systemic Delivery of a Therapeutic SiRNA with a Multifunctional Carrier Controls Tumor Proliferation in Mice Molecular Pharmaceutics. May-Jun, 2009  |   Pubmed ID: 19296675 In this study, novel peptide-targeted delivery systems were developed for systemic and targeted delivery of therapeutic siRNA based on a multifunctional carrier, (1-aminoethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), which showed pH-sensitive amphiphilic cell membrane disruption. EHCO formed stable nanoparticles with siRNA. Targeted siRNA delivery systems were readily formed by surface modification of the nanoparticles. PEGylation of the siRNA/EHCO nanoparticles significantly reduced nonspecific cell uptake. The incorporation of a bombesin peptide or RGD peptide via a PEG spacer resulted in receptor-mediated cellular uptake and high gene silencing efficiency in U87 cells. Fluorescence confocal microscopic studies demonstrated that EHCO/siRNA nanoparticles and PEG modified EHCO/siRNA nanoparticles were able to facilitate endosomal escape of the siRNA delivery systems. Systemic administration of a therapeutic anti-HIF-1alpha siRNA with the peptide-targeted delivery systems resulted in significant tumor growth inhibition than a nontargeted delivery system or free siRNA via intravenous injection in nude mice bearing human glioma U87 xenografts. The results indicate a great promise of the multifunctional carrier EHCO for systemic and targeted delivery of therapeutic siRNA to treat human diseases with RNAi.
• Tumor Characterization with Dynamic Contrast Enhanced Magnetic Resonance Imaging and Biodegradable Macromolecular Contrast Agents in Mice Pharmaceutical Research. Sep, 2009  |   Pubmed ID: 19597972 To investigate the efficacy of polydisulfide-based biodegradable macromolecular contrast agents of different degradability and molecular weight for tumor characterization based on angiogenesis using dynamic contrast enhanced MRI (DCE-MRI).
• Noninvasive Evaluation of Antiangiogenic Effect in a Mouse Tumor Model by DCE-MRI with Gd-DTPA Cystamine Copolymers Molecular Pharmaceutics. Feb, 2010  |   Pubmed ID: 19958031 The efficacy of polydisulfide-based biodegradable macromolecular Gd(III) complexes, Gd-DTPA cystamine copolymers (GDCC), for assessing tumor microvascular characteristics and monitoring antiangiogenesis therapy was investigated in a mouse model using dynamic contrast-enhanced MRI (DCE-MRI). The mice bearing human colon tumor xenografts were intraperitoneally injected with an antiangiogenesis agent Avastin three times in a week at a dose of 200 mug/mouse. DCE-MRI with GDCC of 40 kDa (GDCC-40) was performed before and at 36 h after the first treatment with Avastin and at the end of treatment (7 days). Gd(DTPA-BMA) was used as a low molecular weight control. The tumor vascular parameters, endothelial transfer coefficient K(trans) and factional plasma volume f(PV), were calculated from the DCE-MRI data with a two-compartment model. The K(trans) and f(PV) in tumor periphery estimated by DCE-MRI with GDCC-40 before and after the antiangiogenesis treatment correlated well to tumor growth before and after the treatment in the tumor model. In contrast, the parameters estimated by Gd(DTPA-BMA) did not show significant correlation to the therapeutic efficacy. This study demonstrates that DCE-MRI with the biodegradable macromolecular MRI contrast agent can provide effective assessment of the antiangiogenic efficacy of Avastin in the animal tumor model based on measured vascular parameters in tumor periphery.
• Peptide-targeted Nanoglobular Gd-DOTA Monoamide Conjugates for Magnetic Resonance Cancer Molecular Imaging Biomacromolecules. Mar, 2010  |   Pubmed ID: 20131758 Effective imaging of a cancer molecular biomarker is critical for accurate cancer diagnosis and prognosis. CLT1 peptide was observed to specifically bind to the fibrin-fibronectin complexes presented in tumor extracellular matrix. In this study, we synthesized and evaluated CLT1 peptide-targeted nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance (MR) imaging of the fibrin-fibronectin complexes in tumor. The targeted nanoglobular contrast agents were prepared by conjugating peptide CLT1 to G2 and G3 nanoglobule (lysine dendrimers with a cubic silsesquioxane core) Gd-DOTA monoamide conjugates via click chemistry. The T(1) relaxivities of peptide-targeted G2 and G3 nanoglobules were 7.92 and 8.20 mM(-1) s(-1) at 3T, respectively. Approximately 2 peptides and 25 Gd-DOTA chelates were conjugated onto the surface of 32 amine groups of G2 nanoglobule, and 3 peptides and 43 Gd-DOTA chelates onto the surface of 64 amine groups of G3 nanoglobule. The peptide-targeted nanoglobular contrast agents showed greater contrast enhancement than the corresponding nontargeted agents in tumor at a dose of 0.03 mmol-Gd/kg in female athymic mice bearing MDA-MB-231 human breast carcinoma xenografts. The targeted MRI contrast agents have a potential for specific cancer molecular imaging with MRI.
• Stability and Biodistribution of a Biodegradable Macromolecular MRI Contrast Agent Gd-DTPA Cystamine Copolymers (GDCC) in Rats Pharmaceutical Research. Jul, 2010  |   Pubmed ID: 20393871 The aim of this study was to evaluate stability and Gd tissue distribution of a biodegradable macromolecular MRI contrast agent, GDCC.
• An Effective Targeted Nanoglobular Manganese(II) Chelate Conjugate for Magnetic Resonance Molecular Imaging of Tumor Extracellular Matrix Molecular Pharmaceutics. Aug, 2010  |   Pubmed ID: 20481565 Stable manganese(II) chelates are of great interest for the design and development of safe and effective non-gadolinium(III)-based targeted MRI contrast agents for MR cancer molecular imaging. In this study, a CLT1 peptide targeted G3 nanoglobular Mn(II)-DOTA monoamide conjugate was designed and synthesized as a targeted MRI contrast agent for molecular imaging of the fibrin-fibronectin complexes or oncofetal fibronectin in tumor stroma. The targeted contrast agent comprised 2 peptides and 42 Mn(II)-DOTA chelates on the surface of the G3 nanoglobule. The T(1) and T(2) relaxivities of the targeted agent at room temperature were 3.13 and 8.74 mM(-1) s(-1) per Mn(II) chelate at 3 T (tesla), respectively. It had a well-defined nanosize (5.2 nm) and could be readily excreted via renal filtration. The targeted nanoglobular contrast agent specifically bound to tumor tissue, resulting in significant tumor contrast enhancement with minimal nonspecific enhancement in the liver of tumor bearing mice as compared to a nontargeted control at a dose as low as 0.03 mmol-Mn/kg. The targeted G3 nanoglobular Mn(II)-DOTA conjugate is promising as a targeted non-gadolinium(III)-based MRI contrast agent for MR cancer molecular imaging.
• Polydisulfide Based Biodegradable Macromolecular Magnetic Resonance Imaging Contrast Agents Israel Journal of Chemistry. Aug, 2010  |   Pubmed ID: 21331318 Macromolecular Gd(III) complexes are advantageous over small molecular Gd(III) complexes in contrast enhanced magnetic resonance imaging (MRI) because of their prolonged blood circulation and preferential tumor accumulation. However, macromolecular contrast agents have not been approved for clinical applications because of the safety concerns related to their slow body excretion. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular MRI contrast agents to alleviate the concerns by facilitating the clearance of Gd(III) complexes from the body. These agents initially behave as macromolecular agents and result in superior contrast enhancement in the vasculature and tumor tissues. They can then be readily degraded in vivo into small molecular chelates that can rapidly excrete from the body via renal filtration after the MRI examinations. Various polydisulfide Gd(III) complexes have been prepared as biodegradable macromolecular MRI contrast agents. These agents have resulted in strong contrast enhancement in the vasculature and tumor tissue in animal models with minimal long-term tissue accumulation comparable to small molecular contrast agents. Polydisulfide Gd(III) complexes are promising for further clinical development as safe and effective biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging. The review summarizes the chemistry and properties of polydisulfide Gd(III) complexes.
• Synthesis and Evaluation of Nanoglobular Macrocyclic Mn(II) Chelate Conjugates As Non-gadolinium(III) MRI Contrast Agents Bioconjugate Chemistry. May, 2011  |   Pubmed ID: 21473650 Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-1) per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less nonspecific liver enhancement than MnCl(2) and were effective for contrast-enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising nongadolinium based MRI contrast agents.
• Ocular Pharmacokinetic Study Using T₁ Mapping and Gd-chelate- Labeled Polymers Pharmaceutical Research. Dec, 2011  |   Pubmed ID: 21691891 Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo.
• Polydisulfide Manganese(II) Complexes As Non-gadolinium Biodegradable Macromolecular MRI Contrast Agents Journal of Magnetic Resonance Imaging : JMRI. Mar, 2012  |   Pubmed ID: 22031457 To develop safe and effective manganese(II) -based biodegradable macromolecular MRI contrast agents.
• MR Molecular Imaging of Prostate Cancer with a Peptide-targeted Contrast Agent in a Mouse Orthotopic Prostate Cancer Model Pharmaceutical Research. Apr, 2012  |   Pubmed ID: 22139536 To study the effectiveness of a peptide targeted nanoglobular Gd-DOTA complexes for MR molecular imaging of prostate cancer in a mouse orthotopic PC-3 prostate cancer model.
• Synthesis and Evaluation of a Peptide Targeted Small Molecular Gd-DOTA Monoamide Conjugate for MR Molecular Imaging of Prostate Cancer Bioconjugate Chemistry. Aug, 2012  |   Pubmed ID: 22812444 Tumor extracellular matrix has an abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. Innovative design and development of safe and effective targeted contrast agents to these biomarkers would allow effective MR cancer molecular imaging with high spatial resolution. In this study, we synthesized a low molecular weight CLT1 peptide targeted Gd(III) chelate CLT1-dL-(Gd-DOTA)(4) specific to clotted plasma proteins in tumor stroma for cancer MR molecular imaging. CLT1-dL-(Gd-DOTA)(4) was synthesized by conjugating four Gd-DOTA monoamide chelates to a CLT1 peptide via generation 1 lysine dendrimer. The T(1) relaxivity of CLT1-dL-(Gd-DOTA)(4) was 40.4 mM(-1) s(-1) per molecule (10.1 mM(-1) s(-1) per Gd) at 37 °C and 1.5 T. Fluorescence imaging showed high binding specificity of CLT1 to orthotopic PC3 prostate tumor in mice. The contrast agent resulted in improved tumor contrast enhancement in male athymic nude mice bearing orthotopic PC3 prostate tumor xenograft at a dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for high-resolution MR molecular imaging of prostate tumor.
• An Efficient Novel Glycosylation of Flavonoid by β-fructosidase Resistant to Hydrophilic Organic Solvents Bioresource Technology. Feb, 2013  |   Pubmed ID: 23298773 An effective approach was successfully developed to isolate glycosidase with resistance of hydrophilic organic solvent, simultaneously with acceptor specificity of the target substrate. By this approach, an efficient solvent tolerant glycosidase producing bacterium Arthrobacter nicotianae XM6 was obtained. The β-fructosidase from strain XM6 shows high activity and stability in 10-25% DMSO and 10-20% methanol with 90-99% yields of puerarin glycosides. The addition of hydrophilic solvents not only greatly promoted the solubility of puerarin, but also regulated main products from multifructosyl puerarin to monofructosyl puerarin with increasing solvent concentration. Extraordinary highly efficient synthesis of puerarin glycosides (111.3 g/L of monofructosyl puerarin and 35.6 g/L of difructosyl puerarin) was attained in 25% DMSO solvent system from 110.4 g/L puerarin, which resulted a great facility for purification in large-scale process. The most novelty was that the β-fructosidase did not hydrolyze almost the newly formed glycosides using simply sucrose as donor.
• Synthesis and Evaluation of a Polydisulfide with Gd-DOTA Monoamide Side Chains As a Biodegradable Macromolecular Contrast Agent for MR Blood Pool Imaging Contrast Media & Molecular Imaging. May-Jun, 2013  |   Pubmed ID: 23606425 Macromolecular Gd(III)-based contrast agents are effective for contrast-enhanced blood pool and cancer MRI in preclinical studies. However, their clinical applications are impeded by potential safety concerns associated with slow excretion and prolonged retention of these agents in the body. To minimize the safety concerns of macromolecular Gd contrast agents, we have developed biodegradable macromolecular Gd contrast agents based on polydisulfide Gd(III) complexes. In this study, we designed and synthesized a new generation of the polydisulfide Gd(III) complexes containing a macrocyclic Gd(III) chelate, Gd-DOTA monoamide, to improve the in vivo kinetic inertness of the Gd(III) chelates. (N6-Lysyl)lysine-(Gd-DOTA) monoamide and 3-(2-carboxyethyldisulfanyl)propanoic acid copolymers (GODC) were synthesized by copolymerization of (N6-lysyl)lysine DOTA monoamide and dithiobis(succinimidylpropionate), followed by complexation with Gd(OAc)3. The GODC had an apparent molecular weight of 26.4 kDa and T1 relaxivity of 8.25 mM(-1) s(-1) per Gd at 1.5 T. The polymer chains of GODC were readily cleaved by L-cysteine and the chelates had high kinetic stability against transmetallation in the presence of an endogenous metal ion Zn(2+). In vivo MRI study showed that GODC produced strong and prolonged contrast enhancement in the vasculature and tumor periphery of mice with breast tumor xenografts. GODC is a promising biodegradable macromolecular MRI contrast agent with high kinetic stability for MR blood pool imaging.
• Peptide Targeted Tripod Macrocyclic Gd(III) Chelates for Cancer Molecular MRI Biomaterials. Oct, 2013  |   Pubmed ID: 23863450 Rational design and develop of targeted contrast agents binding to cancer-related proteins will achieve more accurate cancer diagnosis and prognosis by magnetic resonance (MR) imaging. CREKA is a tumor-homing pentapeptide (Cys-Arg-Glu-Lys-Ala) specifically homes to fibrin-fibronectin complexes abundantly expressed in tumor microenvironment. In this study, we developed and evaluated a CREKA peptide targeted multiplexed Gd-MR probe (CREKA-Tris-Gd(DOTA)3) for MR imaging of breast tumors. CREKA and azide bearing Gd(III) was attached to a maleimide-functional trialkyne scaffold via thiol-maleimide and azide-alkyne click chemistry, respectively. CREKA-Tris-Gd(DOTA)3 has a well-defined structure with a molecular weight of 2914 Da. The T1 relaxivity of CREKA-Tris-Gd(DOTA)3 is 8.06 mm(-1) s(-1) per Gd (24.18 mm(-1) s(-1) per molecule) at room temperature and 3 T. Fluorescence imaging showed high binding specificity of CREKA to a 4T1 breast tumor model in mice while it was not found for the scrambled CREKA (CERAK). The CREKA peptide-targeted contrast agent resulted in greater contrast enhancement than the corresponding CERAK agent and the commercialized contrast agent ProHance(®) in tumor at a dose of 0.1 mmol Gd/kg in female athymic mice bearing 4T1 breast carcinoma xenograft. This small molecular contrast agent was easily excreted from body after imaging indicated low toxicity. The targeted MRI contrast agent has a potential for specific cancer molecular imaging with MRI.
• Isolation, Identification and Pharmacokinetic Analysis of Fructosyl Puerarins from Enzymatic Glycosylation Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. Sep, 2013  |   Pubmed ID: 23948238 A method of using high-speed counter-current chromatography (HSCCC) was established for preparative isolation and purification of puerarin glycosides from the crude sample after enzymatic glycosylation of puerarin. Four fructosyl puerarins were successfully purified for the first time by HSCCC with a two-phase-solvent system composed of n-butanol-acetic acid-water (4:1.5:6, v/v/v). A total of 5mg of puerarin (1), 20mg of β-d-fructofuranosyl-(2→6)-puerarin (2), 41mg of β-d-difructofuranosyl-(2→6)-puerarin (3), 18mg of β-d-trifructofuranosyl-(2→6)-puerarin (4) and 15mg β-d-tetrafructofuranosyl-(2→6)-puerarin (5) were obtained in one-step separation from 100mg of the crude sample with purities of 98.5%, 98.3%, 98.9%, 97.8%, 97.5% and 97.2%, respectively. Among them, compounds 2-5 are novel compounds, and their chemical structures were identified by HRMS, (1)H NMR, (13)C NMR and 2D NMR. Pharmacokinetic analysis showed that β-d-fructofuranosyl-(2→6)-puerarin (2) was able to maintain higher plasma concentrations and have a longer mean residence time in the blood than puerarin.