载多西他赛的聚乙二醇-聚赖氨酸-维生素E聚合物胶束的制备及体内实体瘤分布研究

紫杉烷类化疗药物用于实体瘤化疗时肿瘤递送效率低、不良反应较大,本研究合成了聚乙二醇-b-聚-L-赖氨酸-g-维生素E (PEG-PLL-VE)两亲性共聚物,并作为载体制备成聚合物胶束包载紫杉烷类药物多西他赛,通过流式细胞术、体外细胞毒性试验和体内活体成像考察该多西他赛聚合物胶束的MDA-MB-231乳腺癌细胞摄取效率、...     

肝癌靶向的阳离子脂质体共递送多西他赛和siRNA的研究

肝细胞癌是全世界最常见的恶性肿瘤之一,居癌症相关死亡原因第三位。通过存纳米载体系统上修饰靶向配体可将药物主动靶向至肿瘤细胞。随着药物制剂学的发展,采用纳米给药系统共递送化疗药物与基因药物成为了治疗肿瘤的一种手段。本研究通过薄膜超声法制备了共包载多西他赛（DTx）和小干扰RNA（siRNA）的脂质体,并用SP94对其进行修饰。血清稳定性试验表明,脂质体能较好地保护siRNA免受血清中核酸酶的降解。与未修饰的阳离子脂质体相比,SP94修饰的阳离子脂质体显著增强了制剂的在肿瘤细胞内的摄取和对肿瘤细胞的抗增殖作用,表明了SP94的主动靶向作用。本课题成功构建了主动靶向肝癌的共包载DTx和siRNA的阳离子纳米粒给药系统,为肝细胞癌的治疗提供了新的研究思路。     

纳米制剂中7-表多西他赛的体内外抗肿瘤作用研究

目的:研究7-表多西他赛体内外抗肿瘤活性.方法:建立动物荷瘤模型,以多西他赛为阳性对照,考察7-表多西他赛抗肿瘤活性;通过体外细胞实验,考察7-表多西他赛的毒性.结果:7-表多西他赛在动物实验中,对肿瘤有一定抑制作用,但其抑制作用弱于多西他赛;在体外细胞实验中,7-表多西他赛毒性与多西他赛相当.结论:7-表多西他赛作为多西他赛的主要杂质,毒性与多西他赛相当,抗肿瘤活性弱于多西他赛,为确保多西他赛抗肿瘤活性,应对7-表多西他赛进行含量控制.     

胃癌患者首次使用多西他赛化疗发生过敏反应的护理及分析

化学治疗是目前治疗肿瘤的重要手段之一,能够有效制肿瘤的生长、转移和扩散,但是大多数化疗药物都存在一些明显的毒副反应,如过敏反应、胃肠道反应、肝脏毒性、心脏毒性、脱发等。多西他赛是一种抗肿瘤药物,主要作用于细胞周期的M期,可抑制微管的解聚,抑制血管生成,影响肿瘤细胞的凋亡过程,有效率可达75％。但是多西他赛能够引发部分患者发生严重的过敏反应,本文首次使用多西他赛的胃癌患者进行临床护理及观察分析,将化疗发生过敏反应的处理经验和护理体会报告如下。     

共载多西他赛和IR820的化疗/光热/光动纳米粒的抗肿瘤增殖及转移作用考察

本课题采用改进的乳化溶剂蒸发法制备聚乳酸-羟基乙酸共聚物(PLGA)-聚乙烯亚胺(PEI)纳米粒,并通过亲疏水作用力和电性吸附原理分别将多西他赛(1)和光敏剂IR820共同装载于PLGA内核和PEI阳离子亲水外壳中。为使纳米粒具有长循环功能,选用负电性肝素(heparin,H)修饰在纳米粒表面使电荷翻转,得到共载药纳米粒(1@IR820/H NPs),从而实现将化疗/光热/光动3种肿瘤治疗相结合,达到理想的抗乳腺癌细胞增殖和转移的治疗效果。制备并表征了所得纳米粒的物理化学性质,并考察了其在体外经近红外光(808 nm)照射处理后对乳腺癌细胞4T1增殖和转移的影响。结果显示,所得的1@IR820/H NPs的粒径为(192.7±4.1)nm,ζ电位为(-22.6±1.9)mV。细胞摄取试验表明,与1@IR820/H NPs共孵育的4T1细胞经近红外光照射处理后,明显增强了摄取能力。体外活性氧试验表明,细胞摄取的增强可提高光动治疗效果。另外,共载药纳米粒的细胞毒性明显高于游离药物。抗肿瘤转移试验表明IR820及共载药纳米粒可抑制肿瘤细胞转移,并且Western Blot技术表征显示抗转移作用与基质金属蛋白酶-9(MMP-9)的表达减少有关。     

莪术有效成分联合多西他赛抗肺部肿瘤最佳配比初步研究

目的初步确定莪术中有效抗癌成分姜黄素和β-榄香烯联合多西他赛对肺癌细胞生长抑制的最佳质量浓度配比。方法体外培养LLC细胞,通过MTT实验研究不同质量浓度姜黄素和β-榄香烯联合多西他赛单独及配伍对LLC细胞的生长抑制作用。采用金氏公式计算q值研究药物联用后的协同效果。结果质量浓度为10mg·L-1的β-榄香烯与质量浓度为40mg·L-1的姜黄素联用,再配伍质量浓度为800μg·L-1的多西他赛后q值最大,即联用后协同效果最明显。结论实验初步筛选出姜黄素和β-榄香烯合用后再与多西他赛联用对LLC细胞生长抑制率最明显的质量浓度组。     

多西他赛他莫昔芬复方脂质体逆转乳腺癌细胞耐药性的研究

目的 在体外考察多西他赛(Docetaxel, DTX)他莫昔芬(Tamoxifen, TMX)复方脂质体对乳腺癌细胞耐药性的逆转作用。方法 在体外,利用乳腺肿瘤细胞MCF-7和耐药乳腺肿瘤细胞MCF-7/ADR,通过MTU实验和中效原理评价多西他赛和他莫昔芬不同浓度时的协同作用。通过薄膜分散法制备具有协同作用的多西他赛他莫昔芬复方脂质体。在体外通过MTT实验考察复方脂质体细胞毒性和逆转肿瘤耐药作用。结果 在MCF-7细胞和MCF-7/ADR细胞,TMX-DUX混合物(M∶M=7∶1)的中效原理联合指数值都小于1,具有协同作用。对MCF-7细胞,游离药物DTX在浓度0.001 nM到50 nM有细胞毒性,游离TMX没有细胞毒性,DTX-TMX复方脂质体具有细胞毒性。对耐药MCF-7/ADR细胞,游离药物DTX在浓度0.001 nM到50 nM没有细胞毒性,游离TMX没有细胞毒性,DTX-TMX复方脂质体具有细胞毒性,并且细胞毒性强度大于对MCF-7细胞。结论 DTX-TMX复方脂质体能够逆转肿瘤耐药性。     

多西他赛联合洛铂治疗卵巢恶性肿瘤的护理

目的 总结多西他赛联合洛铂治疗卵巢恶性肿瘤患者的护理体会.方法 选取2010月3至2013月6在我院妇科多西他赛联合洛铂治疗卵巢恶性肿瘤94例的临床资料为研究对象.总结不良反应的发生率,对其化疗方案的护理方法进行分析,探讨护理体会.结果 94例患者全部有不同程度的脱发及血液系统毒性,出现消化道症状46例,过敏反应3例,血压变化6例,肝功能损伤11例,肾功能损伤4例,口腔炎23例,神经毒性18例.经处理并予以精心护理后,患者病情基本得到缓解.结论 采取预防性护理干预措施,可减轻多西他赛联合洛铂治疗卵巢恶性肿瘤的化疗药物不良反应,保证化疗的顺利完成.     

肿瘤治疗的细胞药物递送系统的研究进展

目前,肿瘤的临床治疗主要以手术、化疗和放射疗法为主,但仍存在复发和不良反应明显等问题。细胞药物递送系统不仅可以避免纳米颗粒药物的毒性,又可以增加药物的生物利用度,提高生物相容性、靶向性。总结了活细胞、死细胞、外泌体及其药物递送系统的载药特点和在肿瘤治疗中的应用,为肿瘤治疗提供了更多的治疗手段。     

多西他赛抑制小鼠肺癌血管生成分析

目的探讨常用化疗药物多西他赛化疗抑制肿瘤血管生成的作用。方法选择Lewis肺癌细胞荷瘤小鼠50只,随机分成多西他赛不同剂量治疗3组、生理盐水组和对照组,观察4周后5组最终肿瘤体积、质量以及移植瘤血管生成抑制情况。结果多西他赛组小鼠皮下移植瘤质量与体积明显小于其他组,其微血管数（MVD）亦明显低于其他组。结论多西他赛能明显抑制小鼠肺癌血管生成。     

Co-delivery of curcumin and STAT3 siRNA using deformable cationic liposomes to treat skin cancer

Skin cancer is one of the most widely prevalent cancer types with over expression of multiple oncogenic signaling molecules including STAT3. Curcumin is a natural compound with effective anti-cancer properties. The objective of this work was to investigate the liposomal co-delivery of curcumin and STAT3 siRNA by non-invasive topical iontophoretic application to treat skin cancer. Curcumin was encapsulated in cationic liposomes and then complexed with STAT3 siRNA. The liposomal nanocomplex was characterized for particle size, zeta-potential, drug release and stability. Human epidermoid (A431) cancer cells were used to study the cell uptake, growth inhibition and apoptosis induction of curcumin-loaded liposome–siRNA complex. Topical iontophoresis was applied to study the skin penetration of nanocomplex in excised porcine skin model. Results showed that curcumin-loaded liposome–siRNA complex was rapidly taken up by cells preferentially through clathrin-mediated endocytosis pathway. The co-delivery of curcumin and STAT3 siRNA using liposomes resulted in significantly (p?<?.05) greater cancer cell growth inhibition and apoptosis events compared with neat curcumin and free STAT3 siRNA treatment. Furthermore, topical iontophoresis application enhanced skin penetration of nanocomplex to penetrate viable epidermis. In conclusion, cationic liposomal system can be developed for non-invasive iontophoretic co-delivery of curcumin and siRNA to treat skin cancer.     

Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells.     

共载多西他赛和维拉帕米脂质体逆转肿瘤耐药性的研究

研究共载多西他赛(docetaxel, DTX)和维拉帕米(verapamil, VRP)组成的脂质体(DTX-VRP liposome,DTX-VRP LP)对人乳腺癌化疗多药耐药性的逆转作用。采用薄膜分散法制备DTX-VRP LP;用激光粒度仪考察了其粒径大小和zeta电位;用超滤法测定了载药量和包封率;动态透析法考察脂质体在pH值7.4和6.8的磷酸盐缓冲液(PBS)中体外累积释放率;以DTX诱导的多药耐药人源乳腺癌(MCF-7/DTX)细胞株研究脂质体的体内外药效学。动物实验获得上海交通大学动物伦理委员会批准(批准号:2019-06^-172)。结果表明, DTX-VRP LP平均粒径约为140.9 nm, zeta电位约在-28.7 mV。DTX-VRP LP中DTX及VRP包封率和载药量分别是(81.7±3.9)%、(2.9±0.3)%和(59.6±0.6)%、(1.6±0.5)%;在pH 7.4和6.8 PBS中, 0～4 h内DTX-VRP LP组累积释放率分别约为40%和70%,相较于其他实验组, DTX-VRP LP组累积释放率稍慢些。体外药效学...     

整合素配体RGD修饰的阳离子脂质体作为siRNA输送载体的体外研究

本研究构建了能够靶向肿瘤新生血管的RGD修饰阳离子脂质体（RGD-Lipo），作为靶向耐药相关基因MDR1的siRNA输送载体并评价其相关的药剂学性质。该脂质体与siRNA形成的复合物粒径控制在200nm以内，并且对其中所包载的siRNA具有一定的保护作用。体外实验结果表明，经RGD修饰的脂质体（RGD-Lipo）细胞粘附能力显著增强，并可增加细胞内siRNA的转染效果。与利用前插法进行靶向修饰相比，利用后插法进行RGD修饰可有效地改善siRNA的溶酶体释放效率。细胞毒试验结果表明，后插法制备的pRGD-Lipo-siRNA能够有效逆转人卵巢癌SKV03／A细胞的耐药性，并增加阿霉素药物在细胞内的蓄积。体外研究结果证实，使用pRGD-Lipo-siRNA有利于提高耐药细胞对化疗药阿霉素的敏感度，并将有可能应用于临床耐药肿瘤的治疗。     

基于碳纳米角的荧光标记载药体系的构建、表征及体外释放

目的考察碳纳米角(CNHox)经不同浓度壳聚糖(CS)修饰后在水和磷酸缓冲溶液(PBS)中的分散性;构建以CNHox为载体装载多烯紫杉醇(DTX)并通过CS连接CdTe量子点荧光探针的载药体系;考察载药体系体外药物释放行为。方法测定经不同浓度CS修饰的CNHox在水中和PBS中的zeta电位,静置观察分散液的聚沉情况;饱和溶液结晶法装载DTX,热重法测定载药量;以EDC、NHS为交联剂共价连接CdTe量子点与CS,修饰到载有DTX的CNHox表面,构建新型荧光标记抗肿瘤载药体系,对该载药体系进行系列表征;考察药物体外溶出情况,高效液相色谱法测定溶出DTX的含量,并绘制体外释放曲线。结果 CS浓度达到2.50mg·mL-1时,CNHox在PBS中的分散性良好;CNHox装载DTX载药量可以达到1.170 mg·mg-1;载药体系成功标记荧光量子点,且在PBS中的分散性良好;体外累积药物释放量为54.8%,释放曲线有明显缓释行为。结论 CS修饰可提高CNHox在盐溶液中的分散性;载药体系具有较高载药量;量子点成功标记载药体系,为该载药体系的体外示踪研究奠定基础;该载药体系的体外释放试验证实具有缓释效果。     

Increase of therapeutic activity of doxorubicin by long circulating liposomes in combination with curcumin

In this study, doxorubicin (DOX)-loaded long circulating liposomes combined with curcumin (CUR) (DOX-CUR-LCLs) were successfully prepared as a novel formulation for cancer treatment. The particle size and distribution, zeta potential, drug loading capacity, and entrapment efficiency (EE) of the preparation were characterized. The in vitro anti-tumor activities of DOX-CUR-LCLs and DOX-LCLs against A549 cells were then evaluated and compared with that of free DOX. Cytotoxicity evaluation showed that DOX-CUR-LCLs had a significantly higher antitumor activity than other DOX preparations. These results suggest that novel DOX-CUR-LCLs, combination of DOX and CUR administered in long-circulating liposomes, could improve antitumor activity.     

DCF方案辅加复方丹参液治疗中晚期胃癌的临床观察

目的观察复方丹参注射液联合化疗对中晚期胃癌患者疗效、生活质量及不良反应的影响。方法 78例中晚期非小细胞胃癌患者随机分为丹参注射液化疗、单纯化疗两组,观察组(39例)采用复方丹参注射液加DCF方案[多西他赛(DTX)+顺铂(DDP)+5-氟尿嘧啶(5-Fu)]治疗,对照组(39例)采用单纯DCF方案化疗。结果观察组和对照组总有效率分别为59.0%和51.3%(P<0.05),观察组毒副反应如血色素、白细胞及血小板的降低及恶心、呕吐等轻于对照组(P<0.05)。结论复方丹参液能够提高DCF化疗的有效率,减轻化疗某些不良反应,值得进一步研究应用。     

牛血清白蛋白阳离子微球的制备及体外评价

目的制备牛血清白蛋白（BSA）口服阳离子微球,考察天然阳离子物质壳聚糖（CHS）的加入对蛋白微球的粒径、电动电势、包封率、载药量及体外释放情况的影响。方法以乳酸／羟基乙酸共聚物（PLGA）和壳聚糖（CHS）为载体材料,采用W／O／W复乳-溶剂挥发法制备牛血清白蛋白乳酸／羟基乙酸共聚物-壳聚糖（PLGA／CHS）阳离子微球。通过正交设计优化制备工艺,确定最佳处方。建立准确而简便的蛋白含量测定方法,并对微球进行体外评价。结果最佳处方为：BSA浓度为150g·L^-1、PLGA浓度为8％、外水相体积为80mL、壳聚糖浓度为0．2％。制得的微球形态圆整,平均粒径为（6．9±5．5）μm,为表面荷正电的阳离子微球[ζ电势=00．0±0．6）mV],包封率为（75．4±4．6）％,载药量为（9．3±0．2）％。体外释放结果表明,在模拟胃液和模拟肠液中,壳聚糖的加入均能减少突释,延缓药物的释放。结论与PLGA微球相比,制得的PLGA／CHS阳离子微球表面带正电,具有较高的包封率和载药量,可以延缓药物释放,同时减少突释现象。     

Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy

Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.