Optimization on biodistribution and antitumor activity of tripterine using polymeric nanoparticles through RES saturation

Systemic delivery of tripterine (TPR) is challenged by its insoluble property and unsuitable pharmacokinetics. This work aimed to develop polymeric nanoparticles (NPs) combined with the reticuloendothelial system (RES) saturation to improve the in vivo distribution and antitumor activity of TPR. TPR-loaded nanoparticles (TPR-NPs) were prepared by the low-energy emulsification/evaporation method and characterized with particle size, entrapment efficiency, and morphology. The resulting TPR-NPs were 75?nm around in particle size and displayed a sustained drug release in pH 7.4 medium. Pharmacokinetic studies revealed that TPR-NPs had the advantage in bettering the pharmacokinetic properties of TPR over the solution formulation. However, the ameliorative effect on pharmacokinetics was more significant in the case of RES saturation (i.e. preinjection of blank NPs). Preinjection of blank NPs followed by injection of TPR-NPs resulted in higher distribution of TPR into the tumor due to reduced sequestration of TPR-NPs by RES. In tumor-bearing mice (prostatic cancer model), TPR-NPs treatment with RES saturation exhibited a superior antitumor efficacy to free TPR and TPR-NPs alone. It can be concluded that formulating TPR into polymeric NPs in combination with RES saturation is an effective means to address the systemic delivery of TPR.     

药用真菌杨树菇肽脯氨酰顺反异构酶基因及抗肿瘤活性初步鉴定

目的：鉴定克隆杨树菇抗肿瘤相关蛋白基因活性。方法：构建cDNA文库,随机测序得到脯氨酰顺反异构酶（Peptidyl-prolyl cis/trans isomerase,PPIase）基因,并对其进行生物信息学分析,通过检测其在HeLa细胞中表达引起的细胞凋亡及衰老的变化,初步鉴定其抗肿瘤活性。结果：得到杨树菇PPIase cDNA序列,其氨基酸序列在真菌中十分保守。PPIase基因在真核细胞中表达没有引起肿瘤细胞的凋亡和衰老。结论：杨树菇PPIase序列具有PPIase保守序列模式,是PPIase家族的成员。     

Comparison of in vitro and in vivo biological effects of trabectedin,lurbinectedin (PM01183) and Zalypsis® (PM00104)

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non‐homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150–200‐fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host‐mediated effects are involved in the in vivo pharmacological effects.     

Antitumor conjugates with polyamine vectors and their molecular mechanisms

Importance of the field: A polyamine conjugate is a special polyamine derivative composed of polyamine vectors appended directly or by a linker to a cargo with specific biological functions. In recent years, extensive researches have emphasized the fact that polyamine conjugates acting as promising antitumor candidates are becoming increasingly important in the polyamine field.

Areas covered in this review: Two key subjects are illustrated in this review. First, various drug-polyamine conjugates and relevant structure–activity relationships are discussed with a focus on the molecular recognition of polyamine transport system (PTS). Second, the design of polyamine conjugates is following a rational mechanism-based strategy. Therefore, it is critically important to understand the intrinsic properties of PTS on the cell membrane, enhanced pharmacological effects of polyamine vector on cellular components, and resulting comprehensive signaling networks.

What the reader will gain: A general design strategy of polyamine conjugates as well as recent progress in both fundamental mechanism studies and preclinical therapies are provided for the readers.

Take home message: The multiple functions of polyamine moieties in objective conjugates furnish broad development space for more efficacious antitumor agents.     

蛇毒毒素的抗肿瘤作用及其在医药领域的应用

目的 探讨蛇毒毒素的抗肿瘤作用及其在医药领域的应用。方法 综述蛇毒毒素的抗肿瘤组分、抗肿瘤作用及其机制的研究进展。结果 蛇毒毒素对多种肿瘤均有抑制作用,具有直接杀伤肿瘤细胞、诱导肿瘤细胞凋亡、抑制血管再生等作用。结论 对蛇毒毒素抗肿瘤组分及其作用机制进行深入研究,是当前抗肿瘤药物研究的重要方向。     

Toxic optic neuropathies: an updated review

Toxic optic neuropathy (TON) is caused by the damage to the optic nerve through different toxins, including drugs, metals, organic solvents, methanol and carbon dioxide. A similar clinical picture may also be caused by nutritional deficits, including B vitamins, folic acid and proteins with sulphur‐containing amino acids. This review summarizes the present knowledge on disease‐causing factors, clinical presentation, diagnostics and treatment in TON. It discusses in detail known and hypothesized relations between drugs, including tuberculostatic drugs, antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfiram, halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodiesterase type 5 inhibitors and optic neuropathy.     

一株红树内生真菌BY5的鉴定及生物活性研究△

目的对分离自红树植物海马齿(Sesuvium portulacastrum)的1株内生真菌BY5进行鉴定,并对其发酵产物的生物活性进行研究。方法采用形态学、28SrDNA序列对红树内生真菌BY5进行鉴定;采用滤纸片琼脂扩散法、自由基清除法(DPPH、·OH和ABTS+)和MTT法对其发酵液上清乙酸乙酯抽提物的抗菌、抗氧化和抗肿瘤活性进行研究。结果菌株BY5的菌落形态和显微形态与曲霉属的基本相同,其28SrDNA序列与塔宾曲霉(Aspergillus tubingensis)的相似度达100%,确定该菌株为塔宾曲霉;其发酵液上清乙酸乙酯抽提物对金黄色葡萄球菌、枯草芽孢杆菌有较强抑制作用;对DPPH自由基、·OH自由基和ABTS+自由基具有较强清除作用(0mg/mL相似文献   

Synthesis and biological properties of antitumor-active conjugates of ADR with dextran

Three kinds of polymeric adriamycin (ADR) conjugates of dextran were synthesized, namely a dextran–Gly-Leu-Gly-ADR (DGLGA) conjugate with a lysosomally degradable tripeptide spacer group, a dextran–Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga) conjugate with a targeting moiety of galactosamine on DGLGA, and a dextran–C₆H₁₀-ADR (DC₆A) conjugate with a hexamethylen spacer group. The content of the ADR moiety in the polymeric-drug conjugate was about 3 mol%. Enzyme hydrolysis of DGLGA and DC₆A was carried out by incubation with papain. The total amount of ADR released after 48 h was 43 mol% for DGLGA and less than 1 mol% for DC₆A. In an in vitro cytotoxicity experiment, the DGLGA-Ga conjugate has higher cytotoxic efficacy than the other conjugates for incubation with Hep-3B cells and consequently, the capability of targeting hepatoma cells of the galactosamine residue was determined. In contrast, for the incubation with SiHa cells of these conjugates, there was no significant cytotoxicity effect. The in vivo cytotoxic efficacy of each conjugate (20 mg ADR equiv./kg) against CT-26 mice colon cells implanted subcutaneously in Balb-C mice was studied. The DGLGA conjugate generated the best therapeutic effect with the presence of long-term survival (LTS) at day 50 (2/6).     

Antitumor Effect of Embryonic Stem Cells in a Non-Small Cell Lung Cancer Model: Antitumor Factors and Immune Responses

Research in recent years has revealed that embryonic stem cells (ESCs) could generate obvious antitumor effects in both vitro and vivo. In vitro, ESCs could secrete soluble factors that are capable of blocking cancer cells proliferation, moreover, embryonic microenvironments could effectively inhibit tumorigenesis and metastasis; while in vivo, administration of ESCs in tumor-bearing mice could generate significant antitumor effects by indirectly activating the antitumor immune system. In this study, non-small cell lung cancer cells (Lewis Lung Carcinoma cells, LLCs) and ESCs were co-injected together into mice, after that subcutaneous tumor growth was monitored, cellular and humoral immune responses were detected, and different control groups were set to compare the results in different conditions. Our results suggested that compared to be injected alone, ESCs co-injected with cancer cells could inhibit cancer cell growth more efficiently in vivo, with more CD8+ lymphocytes generated in both peripheral circulation and spleen, and with higher serum anticancer cytokine level (interleukin (IL)-2 and interferon (IFN)-γ). We conclude that the boosted antitumor effects induced by ESCs and cancer cells co-injection may be both the effects of antitumor factors secreted by ESCs and immune responses induced by ESCs in vivo.     

二氢卟吩p6醚类光敏剂的合成及光动力抗癌活性研究

目的 基于前期研究表明二氢卟吩f的3-乙烯基成醚修饰具有更强的光敏抗肿瘤活性而设计合成二氢卟吩p₆醚类光敏剂（1）,研究其初步体外光动力抗癌活性。方法 以蚕沙叶绿素a粗提物酸水解产物脱镁叶绿酸a（5）经碱及空气氧化降解制得的紫红素-18（4）为先导物,通过碱水解和CH₂N₂甲基化制得二氢卟吩p₆三甲酯（2）,2与33% HBr加成后再和烷氧醇发生亲核取代反应生成目标化合物（1）,并评价其对黑色素瘤B16-F10细胞的光动力杀伤效应。结果 6个目标化合物1a-1f对黑色素瘤B16-F10细胞的体外光动力抗癌活性均优于同类阳性对照药他拉泊芬和维替泊芬,其结构经电喷雾质谱（ESI-MS）、氢谱（¹H NMR）、碳谱（¹³C NMR）及电喷雾高分辨质谱（ESI-HRMS）确证。结论 二氢卟吩p₆醚类光敏剂具有光动力抗癌活性强、治疗指数（暗毒/光毒比）高等优点,值得进一步开发研究。