Biodegradable self-assembled nanoparticles of poly (d,l-lactide-co-glycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer

To develop biodegradable docetaxel-loaded self-assembled nanoparticles of poly (d,l-lactide-co-glycolide)/hyaluronic acid block copolymers were successfully synthesized. These copolymers could form nanoparticles with small size (<200 nm), an acceptable CMC (∼7.9 mg/L), typical core/shell structure and superior stability in one week. DTX-loaded PLGA_502H-b-HA_5.6k nanoparticles (DTX/SANPs) showed a biphasic release pattern within 120 h, and exhibited enhanced cytotoxicity toward CD44-overexpressing MDA-MB-231 cells. Cellular uptake study indicated that PLGA_502H-b-HA_5.6k nanoparticles (SANPs) were taken up in MDA-MB-231 cells by CD44-mediated endocytosis. Pharmacokinetics study revealed DTX/SANPs could prolong the circulation of DTX in the blood. In vivo studies demonstrated that SANPs exhibited enhanced tumor targeting and antitumor activity with lower systemic toxicity. In conclusion, DTX/SANPs have great potential for targeted chemotherapy for CD44-overexpressing breast cancer.     

多西紫杉醇纳米结构脂质载体中主药含量及包封率测定

目的:建立测定多西紫杉醇(DTM)纳米结构脂质载体(NLC)中主药含量及包封率的方法。方法:采用高效液相色谱法测定药物含量,色谱柱为DiamonsilTMODS,流动相为乙腈-水(55:45),流速为1.0mL.min-1,检测波长为228nm;分别采用超速离心法及超滤法分离DTX-NLC中游离药物以测定包封率。结果:DTM检测浓度的线性范围为0.024～2.4μg.mL-1(r=0.9996),平均回收率为99.29%(RSD=0.37%);2种方法所测药物的平均包封率均>96.5%。结论:本方法简便、准确、可靠,灵敏度高,可用于该制剂的质量控制。     

多西他赛联合奥沙利铂/卡培他滨治疗晚期胃癌47例临床观察

目的观察多西他赛联合奥沙利铂/卡培他滨治疗晚期胃癌的近期疗效和不良反应。方法47例晚期胃癌患者采用多西他赛60 mg/m~2,静脉滴注,第1天;奥沙利铂85 mg/m~2,静脉滴注,第2天;卡培他滨2000 mg/m~2,bid,口服,服10 d停4 d,14 d为1周期。3周期后评价疗效和不良反应。结果全组47例患者均可评价疗效,其中CR 4例(8.5%),PR 24例(51.1%),SD 12例(25.5%),PD 7例(14.9%),总有效率59.6%,Ⅲ/Ⅳ度中性粒细胞减少发生率51.1%。中位TTP为6.2个月(3.4～11.6个月),中位OS为11.3个月(5.9～14.6个月)。结论多西他赛联合奥沙利铂/卡培他滨治疗晚期胃癌有效率较高,血液学毒性低,近期疗效较好,用药方便、安全,明显提高了患者的生活质量。     

多西紫杉醇联合氟尿嘧啶及顺铂治疗晚期胃癌

 目的 观察国产多西紫杉醇（TAT）联合亚叶酸钙／5-氟尿嘧啶（CF／5Fu）及顺铂（DDP）治疗晚期胃癌的临床疗效与不良反应。方法 41例晚期胃癌患者接受TAT与CF／5-Fu及DDP联合化疗：TAT75mg／m2，静滴1h，d1；CF100mg，静滴2h，d1-5；5-Fu500mg／m2，22h微泵持续静滴，d1-5；DDP25mg／m2，静滴，d，1-3。28天为一个周期。治疗2个周期后评价疗效和不良反应。结果 41例患者均可评价疗效。完全缓解2例，部分缓解23例，有效率61．0％。中位疾病进展时间7．5个月，中位生存期10．6个月，1年生存率41．5％。主要不良反应为骨髓抑制，脱发和周围神经炎。结论 国产多西紫杉醇联合亚叶酸钙／5-氟尿嘧啶及顺铂治疗晚期胃癌缓解率高，毒副反应可以耐受。     

Docetaxel and oxaliplatin combination in second-line treatment of patients with advanced gastric cancer

Background In advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy. Methods Patients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m² on day 1 and oxaliplatin 80 mg/m² on day 2, every 3 weeks, until progression or unacceptable toxicity. Results Between May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median number of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2–8 months) and median overall survival was 8.1 months (range, 3–26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months) Conclusion The combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room for optimizing the schedule as well as for planning sequential treatments in gastric cancer.     

多西他赛联合顺铂和氟尿嘧啶治疗晚期胃癌疗效观察

目的观察多西他赛联合顺铂、氟尿嘧啶(DCF方案)治疗晚期胃癌的疗效和不良反应。方法采用DCF方案治疗33例晚期胃癌患者。多西他赛75 mg/m2,d1;顺铂75 mg/m2,d1;氟尿嘧啶750 mg/m2,持续静脉滴注,d1~5,3周1个周期,至少2个周期。结果33例晚期胃癌中,完全缓解(CR)0例,部分缓解(PR)18例(54.5%),稳定(SD)8例(24.2%),进展(PD)7例(21.2%)。中位肿瘤进展时间为6.1个月(3.5~11.5个月),中位总生存期为11.2个月(6.0~14.5个月)。最常见的不良反应为骨髓抑制、消化道反应及可逆性体液潴留,不良反应多为Ⅰ~Ⅱ度,无Ⅳ度不良反应发生。骨髓抑制以白细胞减少为特点,血小板减少及贫血较轻。消化道反应主要表现为恶心呕吐、腹泻、便秘,无Ⅳ度腹泻发生。无治疗相关性死亡。结论DCF方案是治疗晚期胃癌安全有效的化疗方案。     

多西他赛联合顺铂治疗晚期食管鳞癌

目的:探讨多西他赛联合顺铂治疗晚期食管鳞癌的疗效和不良反应。方法:30例晚期食管癌患者,期中20例为初次化疗患者,10例为曾接受手术后辅助化疗。中位年龄54岁。多西他赛75mg/m2,d1、静脉滴注1小时;顺铂40mg/m2,d2,d3;21天为1周期。结果:30例患者共完成93个化疗周期。在可评价的28例患者中,完全缓解4例(14.2%),部分缓解13例(42.8%),有效率为(57.1%),中位疾病进展时间为5.2个月,中位生存时间为9.5个月。可评价不良反应28例,其中主要的不良反应为脱发,有4例(14.2%),患者出现Ⅲ～Ⅳ度粒细胞降低。结论:多西他赛联合顺铂治疗晚期食管癌疗效肯定,可以考虑作为治疗晚期食管癌的主要治疗方案。     

Modeling therapy resistance in genetically engineered mouse cancer models

Resistance to anti-cancer drugs is a major obstacle in successful treatment of cancer. Multidrug resistance is not only observed with clinically established chemotherapeutics, but also with novel targeted therapies. Although a range of drug resistance mechanisms have been identified up till now, for most drugs it is still controversial which mechanisms are responsible for resistance and therapy failure in patients. Hence, the development of strategies to circumvent drug resistance is often unfocused. Since several years genetically engineered mouse models have been generated which develop tumors that closely resemble cancer in humans. We argue that such models can be used to investigate relevant in vivo mechanisms of resistance. This includes the analysis of intrinsic and acquired resistance, and the characterization of residual cells which survive the treatment. In such model systems different drugs and therapy combinations can be optimized prior to clinical trials.     

多西紫杉醇白蛋白纳米粒的制备及体外评价

目的：制备多西紫杉醇白蛋白纳米粒，考察白蛋白和多西紫杉醇的处方量及乙醇加入量等因素对其形态、粒径、Zeta电位、收率、包封率、载药量和体外释药特性的影响，并对处方工艺进行优化。方法：采用去溶剂化-化学交联法制备多西紫杉醇白蛋白纳米粒，透射电镜观察纳米粒形态，马尔文激光粒度仪测定其粒径分布及Zeta电位，考马斯亮兰-酶标仪法测定纳米粒收率，HPLC法测定纳米粒包封率和载药量；以累积释药百分率为指标，通过方程拟合释药曲线，考察制剂的体外释药特性。处方优化采用星点设计-效应面优化法，应用SAS统计软件对数据进行处理。结果：优化处方制得的纳米粒为类球形，平均粒径65．3nm，Zeta电位-31．4mV，纳米粒收率95．0％，包封率74．3％，载药量4．65％，制剂24小时体外累积释药百分率为74．4％。结论：难溶性抗癌药物多西紫杉醇可以采用去溶剂化-化学交联法制备成白蛋白纳米粒，其粒径小，稳定性高，可显著提高多西紫杉醇在水相中的浓度。其优化处方中药物的释放显著慢于原料药磷酸盐缓冲溶液的释放，具有缓释效果。