A new peptide ligand for colon cancer targeted delivery of micelles

Abstract

Ligands are an imperative part of targeted drug delivery systems, and choosing a ligand with high affinity is a subject of considerable interest. In this study, we first synthesized a 12-residue peptide (TK) that interacts with integrin α₆β₁ overexpressed on colonic cancer cells. The molecular binding affinity assay indicated that TK had a high binding affinity for integrin α₆β₁. The results of cellular and tumor spheroid uptake suggested that TK peptide not only increases Caco-2 cells uptake, but also effectively increases penetration of the tumor spheroids. TK-conjugated PEG-PLA was synthesized to prepare a novel PEG-PLA micelles loading DOX or coumarin-6 (TK-MS/DOX or TK-MS/C6). The obtained TK-MS/DOX exhibited uniform, spherical shape with a size of 23.80?±?0.32?nm and zeta potential of 12.21?±?0.31 mV. The release behavior of DOX from micelles were observed no significant changes after TK modification, however, the release profile exhibited pH-sensitive properties. Compared with MS/DOX, TK-MS/DOX exhibited significantly stronger cytotoxicity for Caco-2. Confocal laser microscopy and flow cytometry data further indicated that the targeting micelles not only had higher uptake by Caco-2 cells, but also more effectively penetrated the tumor spheroids. Therefore, TK peptide appears to be suitable as a targeting ligand with potential applications in colonic targeted therapy.     

Tumor-targeted Gd-doped mesoporous Fe3O4 nanoparticles for T1/T2 MR imaging guided synergistic cancer therapy

In this study, a novel intelligent nanoplatform to integrate multiple imaging and therapeutic functions for targeted cancer theranostics. The nanoplatform, DOX@Gd-MFe₃O₄ NPs, was constructed Gd-doped mesoporous Fe₃O₄ nanoparticles following with the doxorubicin (DOX) loading in the mesopores of the NPs. The DOX@Gd-MFe₃O₄ NPs exhibited good properties in colloidal dispersity, photothermal conversion, NIR triggered drug release, and high T₁/T₂ relaxicity rate (r₁=9.64 mM⁻¹s⁻¹, r₂= 177.71 mM⁻¹s⁻¹). Benefiting from the high MR contrast, DOX@Gd-MFe₃O₄ NPs enabled simultaneous T₁/T₂ dual-modal MR imagining on 4T1 bearing mice in vivo and the MR contrast effect was further strengthened by external magnetic field. In addition, the DOX@Gd-MFe₃O₄ NPs revealed the strongest inhibition to the growth of 4T1 in vitro and in vivo under NIR irradiation and guidance of external magnetic field. Moreover, biosafety was also validated by in vitro and in vivo tests. Thus, the prepared DOX@Gd-MFe₃O₄ NPs would provide a promising intelligent nanoplatform for dual-modal MR imagining guided synergistic therapy in cancer theranostics.     

Identification of cytochromes<Emphasis Type="Italic"> P</Emphasis><Subscript>450</Subscript> 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro

Objective This in-vitro study aimed at an identification of cytochrome P₄₅₀ (CYP) enzymes catalysing the (S)- and (R)-hydroxylation of the widely used anticoagulant phenprocoumon (PPC) to its major, inactive metabolites.Methods Relevant catalysts were identified by kinetic, correlation and inhibition experiments using human liver microsomes and recombinant enzymes.Results Kinetics revealed (S)-7-hydroxylation as quantitatively most important. Biphasic Eadie-Hofstee plots indicated more than one catalyst for the 4-, 6- and 7-hydroxylation of both enantiomers with mean K_m1 and K_m2 of 144.5±34.9 and 10.0±6.49 µM, respectively. PPC hydroxylation rates were significantly correlated with CYP2C9 and CYP3A4 activity and expression analysing 11 different CYP-specific probes. Complete inhibition of PPC hydroxylation was achieved by combined addition of the CYP3A4-specific inhibitor triacetyloleandomycin (TAO) and a monoclonal, inhibitory antibody (mAb) directed against CYP2C8, 9, 18 and 19, except for the (R)-4-hydroxylation that was, however, inhibited by ~80% using TAO alone. (S)-PPC hydroxylation was reduced by ~2/3 and ~1/3 using mAb2C8–9-18–19 and TAO, respectively, but (R)-6- and 7-hydroxylation by ~50% each. Experiments with mAbs directed against single CYP2C enzymes clearly indicated CYP2C9 as a major catalyst of the 6- and 7-hydroxylation for both enantiomers. However, CYP2C8 was equally important regarding the (S)-4-hydroxylation. Recombinant CYP2C8 and CYP2C9 were high-affinity catalysts (K_m <5 µM), whereas CYP3A4 operated with low affinity (K_m >100 µM).Conclusion CYP2C9 and CYP3A4 are major catalysts of (S)- and (R)-PPC hydroxylation, while CYP2C8 partly catalysed the (S)-4-hydroxylation. Increased vigilance is warranted when PPC treatment is combined with substrates, inhibitors, or inducers of these enzymes.Part of this work was presented at the 6th Congress of the European Association for Clinical Pharmacology and Therapeutics, Istanbul, June 2003.     

Multi-walled carbon nanotube increases the excitability of hippocampal CA1 neurons through inhibition of potassium channels in rat's brain slices

This study was to investigate the neurotoxicity of multi-walled carbon nanotube (MWCNT) by measuring neuronal excitability in rat hippocampal neurons and exploring the underlying mechanism. Whole cell patch-clamp technique was used. Action potential properties and the pattern of repetitive firing rate were assessed. Our data showed that spike half-width and repetitive firing rate were significantly increased in a concentration-dependent manner. Furthermore, voltage-activated potassium currents were recorded. It was found that MWCNT produced a concentration-dependent inhibition in amplitudes of I_A and I_K. In addition, MWCNT had effect on the activation kinetics of I_A and I_K with V_h being shifted to the negative potential at high concentration, while I_A inactivation curve was considerably shifted to the hyperpolarize potential with V_h being increased. However, no effect was found on the recovery from inactivation of I_A. The results suggest that MWCNT increases the excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium current.     

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

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Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy

Tumour angiogenesis is a complex mechanism consisting of multi-step events including secretion or activation of angiogenic factors by tumour cells, activation of proteolytic enzymes, proliferation, migration and differentiation of endothelial cells. Both primary and metastatic tumours in the breast are dependent on angiogenesis. In the present study, 84 breast cancer patients were randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg (CoRN), one dosage per day along with tamoxifen (TAM) 10 mg twice a day. Serum pro-angiogenic levels were elevated in untreated breast cancer patients (Group II) and their levels were found to be reduced in breast cancer patients undergoing TAM therapy for more than 1 year (Group III). When these group III breast cancer patients were supplemented with CoRN for 45 days (Group IV) and 90 days (Group V) along with TAM, a further significant reduction in pro-angiogenic marker levels were observed. Supplementing CoRN to breast cancer patients has found to decrease the levels of pro-angiogenic factors and increase the levels of anti-angiogenic factors. A reduction in pro-angiogenic marker levels attributes to reduction in tumour burden and may suggest good prognosis and efficacy of the treatment, and might even offer protection from cancer metastases and recurrence.     

Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core

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少腹逐瘀颗粒联合甲羟孕酮治疗子宫内膜异位症的临床研究

目的探讨少腹逐瘀颗粒联合醋酸甲羟孕酮片治疗子宫内膜异位症的临床效果。方法选取2015年2月—2016年6月绵阳市中心医院收治的子宫内膜异位症患者98例作为研究对象,所有患者随机分为对照组和治疗组,每组各49例。对照组患者口服醋酸甲羟孕酮片,1片/次,1次/d。治疗组在对照组治疗的基础上口服少腹逐瘀颗粒,1袋/次,3次/d。两组均连续治疗6个月。评估两组患者的临床疗效,同时比较两组患者的盆腔包块大小、VAS评分、糖类抗原125(CA125)、雌二醇(E2)、卵泡刺激素(FSH)、黄体生成素(LH)、超敏C反应蛋白(hs-CRP)白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、复发率和痛觉发生情况。结果治疗后,治疗组的总有效率为93.9%,显著高于对照组的73.5%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者盆腔包块大小、VAS评分和CA125均较治疗前均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);治疗后,治疗组盆腔包块大小、VAS评分和CA125显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者E2水平较治疗前均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);治疗后,治疗组E2水平明显低于对照组,两组间比较差异具有统计学意义(P0.05)。治疗后,两组患者hs-CRP、IL-6和TNF-α水平较治疗前均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);治疗后,治疗组炎症指标水平明显低于对照组,两组比较差异具有统计学意义(P0.05)。随访1年后,治疗组患者复发率明显低于对照组(P0.05),且痛觉人数明显少于对照组(P0.05)。结论少腹逐瘀颗粒联合醋酸甲羟孕酮片治疗子宫内膜异位症具有较好的临床疗效,有助于缓解患者临床症状、降低机体炎症反应、降低复发率,且安全性高,具有一定的临床推广价值。     

灵芪胶囊对S180荷瘤小鼠IL-1和IL-6蛋白表达的影响

目的:研究灵芪胶囊对S₁₈₀荷瘤小鼠的抗肿瘤作用,并探讨其可能的作用机制。方法:将S₁₈₀瘤株接种于小鼠右前肢腋部皮下建立动物模型,并采用ELISA法检测小鼠外周血IL-1和IL-6蛋白含量。结果:灵芪胶囊能明显增加S₁₈₀荷瘤小鼠外周血IL-1和IL-6蛋白含量,能改善和增强荷瘤小鼠的免疫功能。结论:灵芪胶囊对S₁₈₀荷瘤小鼠有明显抑瘤作用,其作用机制可能是通过改善小鼠免疫功能而实现的。     

Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis

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Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs

BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. KEY RESULTS: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. CONCLUSIONS AND IMPLICATIONS: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.     

Synergistic dual-modified liposome improves targeting and therapeutic efficacy of bone metastasis from breast cancer

Breast cancer frequently metastasizes to bone, where it leads to poor clinical prognosis. Due to the peculiarity of the bone microstructure, the uptake of drugs often happens at non-targeted sites, which produces a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both an octapeptide with eight repeating sequences of aspartate (Asp₈) and folate to create a more selective and efficient drug delivery system to target cancer cells in bone tissue. Asp₈ and folate were conjugated to the distal ends of DSPE-PEG₂₀₀₀-maleimide and DSPE-PEG₂₀₀₀-amine to create DSPE-PEG₂₀₀₀-Asp₈ and DSPE-PEG₂₀₀₀-Folate, respectively, which were incorporated onto the surface of a doxorubicin (DOX)-loaded liposomes (A/F-LS). Asp₈, similar to the hydroxyapatite-binding domains of osteopontin and osteocalcin, has been used as bone-targeting moieties for exclusive delivery of drugs to bone. The folate moiety binds selectively to folate receptor-positive tumors. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. By taking advantages of dual-targeting drug delivery, the dual-modified liposomal drug system could relieve pain and improve survival. Inspired by its enhanced therapeutic efficacy and low toxicity, DOX-loaded A/F-LS could serve as an effective drug system for targeted therapy of bone metastases.     

Discovery of CS-0777: A Potent,Selective, and Orally Active S1P1 Agonist

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Discovery of PIPE-359, a Brain-Penetrant,Selective M1 Receptor Antagonist with Robust Efficacy in Murine MOG-EAE

The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M₁ antagonist, linker replacement and structure–activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.     

Prostaglandin E<Subscript>2</Subscript>-mediated dysregulation of proinflammatory cytokine production in pristane-induced lupus mice

Systemic lupus erythematosus (SLE) is characterized by inflammatory and dysregulatory immune responses including overactive B cells, overproduction of proinflammatory cytokines, and T cell hyperactivity. PGE₂ modulates a variety of immune processes at sites of inflammation, including production of inflammatory cytokines. However, the role of PGE₂ in dysregulatory inflammatory and immune responses in lupus remains unclear. We investigated whether PGE₂ mediates production of inflammatory cytokines in pristane-induced lupus BALB/c mice. Our results showed that levels of serum and BAL PGE₂ and LPS-stimulated production of PGE₂ by peritoneal macrophages were remarkably increased in pristane-induced lupus mice compared to healthy controls. Exogenous PGE₂ enhanced production of IL-6, IL-10, and NO but decreased TNF-α by macrophages and augmented IFN-γ, IL-6, and IL-10 by splenocytes from pristane-induced lupus mice compared to healthy controls. Exogenous PGE₂ also enhanced production of IFN-γ, IL-6, and IL-10 by thymocytes from pristane-induced lupus mice. Indomethacin (Indo), a PGE₂ synthesis inhibitor, greatly inhibited LPS-induced production of IL-6 and IL-10 by macrophages from pristane-induced lupus mice, while enhanced TNF-α. Indo remarkably inhibited Con A-increased production of IFN-γ, IL-6, and IL-10 by splenocytes and thymocytes from pristane-induced lupus mice. Therefore, our findings suggest that endogenous PGE₂ may mediate dysregulation of production of proinflammatory cytokines, such as IL-6, IL-10, and IFN-γ, and NO in pristane-induced lupus mice.     

Discovery of a Potent Thiadiazole Class of Histamine H3 Receptor Antagonist for the Treatment of Diabetes

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Discovery of a Potent,S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)

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Cardiovascular effects of the adenosine A<Subscript>1</Subscript> receptor agonist<Emphasis Type="Italic"> N</Emphasis><Superscript>6</Superscript>-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 µg/kg s.c., ~2×LD₅₀) in rats is completely prevented by treatment with the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A₁ receptor antagonist 8-p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A₁ receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.     

伊立替康联合顺铂治疗复发卵巢癌40例的临床疗效

目的:观察伊立替康联合顺铂治疗复发卵巢癌的效果。方法:将82例复发卵巢癌病人分成2组,试验组(40例)和对照组(42例),试验组每个疗程给予伊立替康200mg,在化学治疗(化疗)的d1,8静脉滴注(静滴);顺铂100mg,d1～5静滴;对照组氟尿嘧啶1500mg和顺铂100mg,按常规剂量给予。观察2组卵巢癌上皮抗原(CA125)值、病灶缩小情况、生存率、不同病理类型对其敏感度以及不良反应的差异。结果:试验组CA125下降率22%,病灶缩小率28%,1年生存率70%,对照组分别为10%,7%,33%,差异有显著意义(P<0.05)。透明细胞癌较浆液性癌对伊立替康更敏感。试验组的不良反应主要是腹泻、呕吐、中性粒细胞减少和肠梗阻。结论:伊立替康联合顺铂可成为一种有效的、优于对照组的治疗复发卵巢癌的药物。