Non-invasive endotracheal delivery of paclitaxel-loaded alginate microparticles

Aerosolized chemotherapeutics leads to higher, localized and continuous concentrations of active agents in lung tissue with lower side effects for other organs. The present study was performed on jugular vein cannulated rats which endothracheally received 4 mg/kg of free paclitaxel powder (Free-PTX), paclitaxel-loaded alginate microparticles (PTX-ALG-MPs) and i.v. paclitaxel (Anzatax^®). Pharmacokinetic parameters for Free-PTX and PTX-ALG-MPs contain higher AUC, mean residence time (MRT),half-life and bioavailability, with lower elimination constant (k_e). Statistical analysis showed that the amount of paclitaxel per gram of lung tissue after 0.5, 6 and 24 h after administration of Free-PTX was lower than PTX-ALG-MPs. Lung tissue AUC for Free-PTX was lower than PTX-ALG-MPs. According to the obvious advantages obtained, such as dose lowering and increasing paclitaxel residence time and half-life. It should be noted that cell cytotoxicity test on normal airway cell lines was not examined in this study but due to previous reports on safety of inhaled paclitaxel, it can be suggested that pulmonary delivery of paclitaxel can be a useful non-invasive route of administration compared with i.v administration.     

异黏蛋白调控鼻咽癌细胞增殖及紫杉醇耐药的研究

 目的 探讨异黏蛋白（Metadherin, MTDH）对鼻咽癌细胞增殖及紫杉醇耐药的影响。方法 采用慢病毒介导的MTDH cDNA和MTDH-shRNA转染鼻咽癌细胞，分别上调和抑制MTDH的表达。CCK-8法、流式细胞实验分别检测细胞增殖能力、细胞周期及凋亡改变。CCK-8法确定紫杉醇对鼻咽癌细胞的IC₃₀、IC₅₀、IIC₇₀，并检测IC₃₀、IC₅₀、IC₇₀浓度下MTDH过表达组与沉默组细胞生存率改变。结果 MTDH上调后5-8F、HNE-1细胞的增殖能力均增强，而沉默MTDH后细胞的增殖能力均降低。MTDH沉默组的G1期细胞比例明显增加。MTDH过表达组细胞凋亡率降低，MTDH沉默组细胞凋亡率增加。MTDH表达上调之后，鼻咽癌细胞对紫杉醇的敏感度降低，在IC₇₀、IC₅₀浓度下，MTDH过表达组细胞的生存率高于对照组细胞。沉默MTDH之后，鼻咽癌细胞对紫杉醇的敏感度升高，在IC₅₀、IC₃₀浓度下，MTDH沉默组细胞的生存率低于对照组细胞。结论 MTDH在促进鼻咽癌细胞增殖中起重要作用，其高表达可促进鼻咽癌细胞紫杉醇耐药性的产生。     

Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non‐MDR paclitaxel resistant ovarian cancer lines ES‐2/TP, MES‐OV/TP and OVCAR‐3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti‐human CCL2 antibody CNTO 888 and the anti‐mouse MCP‐1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.     

Succès du traitement par paclitaxel d’une rechute viscérale d’un sarcome de Kaposi après transplantation rénale

We report the observation of a patient who presented with post-transplant Kaposi's sarcoma after a delay of eight months with a dual cutaneous and palatal localisation. The reduction in immunosuppressive treatment and the introduction of Rapamune® allowed good clinical progress initially with regression of the skin lesions. He subsequently presented later a skin relapse with visceral localisation. Chemotherapy was conducted based on weekly paclitaxel infusions allowing partial remission and maintenance of renal graft function with good clinical tolerance.     

Improved anticancer delivery of paclitaxel by albumin surface modification of PLGA nanoparticles

Background

Nanoparticles (NPs) play an important role in anticancer delivery systems. Surface modified NPs with hydrophilic polymers such as human serum albumin (HSA) have long half-life in the blood circulation system.

Methods

The method of modified nanoprecipitation was utilized for encapsulation of paclitaxel (PTX) in poly (lactic-co-glycolic acid) (PLGA). Para-maleimide benzoic hydrazide was conjugated to PLGA for the surface modifications of PLGA NPs, and then HSA was attached on the surface of prepared NPs by maleimide attachment to thiol groups (cysteines) of albumin. The application of HSA provides for the longer blood circulation of stealth NPs due to their escape from reticuloendothelial system (RES). Then the physicochemical properties of NPs like surface morphology, size, zeta potential, and in-vitro drug release were analyzed.

Results

The particle size of NPs ranged from 170 to 190 nm and increased about 20–30 nm after HSA conjugation. The zeta potential was about -6 mV and it decreased further after HSA conjugation. The HSA conjugation in prepared NPs was proved by Fourier transform infrared (FT-IR) spectroscopy, faster degradation of HSA in Differential scanning calorimetry (DSC) characterization, and other evidences such as the increasing in size and the decreasing in zeta potential. The PTX released in a biphasic mode for all colloidal suspensions. A sustained release profile for approximately 33 days was detected after a burst effect of the loaded drug. The in vitro cytotoxicity evaluation also indicated that the HSA NPs are more cytotoxic than plain NPs.

Conclusions

HSA decoration of PLGA NPs may be a suitable method for longer blood circulation of NPs.     

紫杉醇联合替吉奥胶囊治疗晚期食管癌的临床疗效观察

目的观察紫杉醇联合替吉奥胶囊治疗晚期食管癌的临床疗效和不良反应。方法选择37例晚期食管癌患者,予紫杉醇175 mg/m2,d1,静脉滴注3 h;替吉奥胶囊服用剂量按体表面积<1.25 m2者剂量40毫克/次;体表面积1.25~1.5 m2者剂量50毫克/次;体表面积>1.5 m2者剂量60毫克/次;均每日2次,早晚餐后口服,连服14 d,21 d为1个周期。结果疗效可评价患者36例,其中完全缓解(CR)1例,部分缓解(PR)14例,病情稳定(SD)11例,病情进展(PD)10例,有效率(CR+PR)为41.7%;疾病控制率(CR+PR+SD)为72.2%;中位疾病进展时间(m TTP)及中位生存时间分别为7.4个月、10.6个月,1年生存率为36.1%。化疗的主要不良反应为脱发及骨髓抑制,其中Ⅲ~Ⅳ度中性粒细胞减少发生率为16.7%。结论紫杉醇联合替吉奥胶囊治疗晚期食管癌疗效肯定,且耐受性较好。     

紫杉醇通过mTOR信号通路影响乳腺癌细胞的增殖迁移

目的 探讨紫杉醇通过雷帕霉素靶蛋白(mTOR)信号通路影响乳腺癌MCF-7细胞的增殖迁移.方法 实验分为4组,分别为对照组,紫杉醇低剂量组(0.25 μmol/L),紫杉醇中剂量组(0.5 μmol/L),紫杉醇高剂量组(1μmol/L).MTT法检测各组MCF-7细胞活力;流式细胞术检测各组MCF-7细胞周期变化;Transwell迁移实验检测各组MCF-7细胞迁移能力;Western blot检测各组mTOR信号通路相关蛋白表达水平.结果 与对照组比较,紫杉醇低、中、高剂量组能显著抑制MCF-7细胞活力(P＜0.05),且在48 h抑制程度最高(P＜0.05),紫杉醇低、中、高剂量组都能使穿过滤膜进入下腔的乳腺癌MCF-7细胞数目显著减少[(98 ±9.78) vs (86.21 ±6.58)、(53.41 ±3.16)及(42.00 ±4.69),P＜0.05];紫杉醇低、中、高剂量组能使G1期的细胞明显增多[(52.14±6.13)％vs (67.93±8.16)％、(72.32±3.67)％及(78.53±6.28)％,P＜0.01],使G2期的细胞明显减少[(13.68±0.85)％vs(8.57±1.03)％、(5.30±0.89)％及(3.46±0.78)％,P＜0.01];紫杉醇低、中、高剂量组中4E结合蛋白1(4EBP1)及mTOR磷酸化水平下降,细胞周期蛋白D1(Cyclin D1)及基质金属蛋白酶-9(MMP-9)表达量也降低(P＜0.01).结论 紫杉醇抑制乳腺癌MCF-7细胞的增殖迁移,与mTOR信号通路有关.