新型药物载体“脂质乳剂”的药剂学定义辨析及其意义

目的经典药剂学著作中无脂质乳剂和脂肪乳剂等乳剂剂型定义,造成文献中出现产品剂型相同但剂型名称不同的混淆现状。本文作者对新型药物载体'脂质乳剂'的药剂学定义进行了辨析。方法查阅了国内外有代表性的相关文献并进行比较、归纳和分析。结论本文作者提出了新的脂质乳剂定义,并建议营养型脂肪乳定义为'脂肪乳剂',载药型脂肪乳定义为'脂质乳剂',希望能引起学术界进一步的重视与研究。

注射用水飞蓟宾脂质纳米乳中水飞蓟宾含量测定

目的 建立直接紫外分光光度法 ,测定最新研制的注射用水飞蓟宾脂质纳米乳中水飞蓟宾含量的方法。方法 选用 1mol·L-1的NaOH碱溶液破乳 ,弃去以氯仿为萃取剂提取的纳米乳油相 ,水相层由纳米乳中释放出的水飞蓟宾以无水乙醇溶解 ,HCl中和 ,于 2 88nm处直接测定吸光度 ,计算水飞蓟宾的含量。结果 水飞蓟宾在 0 .2 970～ 1.784mg·mL-1浓度范围内呈线性 ,r =0 .9999;高、中、低 3种浓度的萃取回收率和方法回收率分别为 96 .0 8%～ 98.95 %和 99.72 %～ 10 0 .5 % ,n =3;日内和日间RSD分别为 0 .37%和 3.6 % ,n =5。结论 建立的方法准确度高 ,重现性好 。

鸦胆子油乳脂质纳米粒对A549细胞抑制作用的研究

目的探讨鸦胆子油乳脂质纳米粒对人非小细胞肺癌A549细胞株的抑制、凋亡作用及其机制。方法用MTT法检测设不同浓度实验组(30、60、90、120 mg/L)及不同作用时间(24、48、72 h)药物对细胞的抑制率;用流式细胞仪检测药物浓度60 mg/L作用24、48、72 h后实验组细胞的凋亡率;RTPCR检测Caspase-3 mRNA的表达。结果不同浓度、时间鸦胆子油乳脂质纳米粒对A549细胞增殖的影响:细胞增殖抑制率在一定剂量范围内随浓度的增加而增加,具有剂量依赖性,用相同浓度鸦胆子油乳脂质纳米粒(60 mg/L)干预A549人肺腺癌细胞24、48、72 h,抑制率在一定时间范围内随时间的延长而增加,具有时间依赖性。用相同浓度鸦胆子油乳脂质纳米粒(60 mg/L)干预A549人肺腺癌细胞24、48、72 h凋亡率分别是:48.67%±1.42,64.82%±1.46,68.25%±1.32。RT-PCR结果提示鸦胆子油乳脂质纳米粒上调了Caspase-3 mRNA的表达。结论鸦胆子油乳脂质纳米粒可以抑制人肺腺癌A549细胞增殖和诱导凋亡,并呈时间-剂量关系,其机制可能与上调Caspase-3的表达有关。

同步荧光法监控人乳脂质替代品氧化过程

以市售大豆油、玉米油、椰子油、葵花籽油和鱼油为原料油脂,通过气相色谱仪检测其脂肪酸含量,并根据原料油脂的脂肪酸特点和GB 10765-2010的相关规定,通过Matlab软件和Excel线性规划求解,设计出6种人乳脂质替代品样品,采用Schaal烘箱加速氧化法,研究同步荧光技术结合传统化学试剂法(氧化指标:过氧化值、茴香胺值、总氧化值)监控6种样品的氧化过程,通过统计学分析数据,探索荧光强度和氧化指标之间的统计学关系。结果表明:椰子油的主要脂肪酸为月桂酸和肉豆蔻酸,其饱和脂肪酸含量最高(93.75%±0.06%);而其余油脂主要由棕榈酸、亚油酸等组成,其中鱼油的不饱和脂肪酸最高。随着氧化时间的延长,荧光强度逐渐减弱,氧化指标数值不断增大;相关分析和回归分析结果表明,6种样品的氧化指标与荧光强度的变化均呈负相关,R^2均大于0.9。

牛乳和母乳中脂质的比较

母乳和牛乳中都含有大约3～5％的总脂质。它们以直径2～4μm的乳脂肪球存在,并含有从分泌细胞衍生来的膜。脂肪球中约98％或更多的脂质是甘油三酸酯。磷脂约占总脂质的0.5～1％,固醇约占0.2～0.5％,主要分布在脂肪球膜中。胆固醇是主要的固醇。母乳和牛乳的主要不同之处在于脂肪酸的组成,甘油三酸酯的结构及母乳中脂肪酸随母亲的饮食而改变。牛乳含有大量的碳4:0—10:0脂肪酸,碳18:2脂肪酸约为2％;几乎不含有其它长链多重不饱和脂肪酸,脂肪酸的组成不随日常饲料而变。母乳含有极少量的碳4:0—10:0脂肪酸,10～14％的碳18:2脂肪酸及少量的其他多重不饱和脂肪酸。他们的甘油三酸酯的结构不同。母乳中的位置sn—2被碳16:0占据,而牛乳中多数的sn—3位置被碳4:0～10:0占据。文中还讨论了乳胆固醇和脂肪酸对人的血胆固醇水平的影响。

乳极性脂质组成及其功能性研究进展

乳中含有2%~5%的脂质,乳中的脂质由乳腺上皮细胞分泌并以乳脂肪球的形式分散在乳中。大部分乳脂(约98%)以甘油酯的形式存在于乳脂肪球内部,其余(约2%)包括甘油磷脂、鞘脂、糖脂等在内的少部分极性脂质则主要分布在乳脂肪球膜表面。乳极性脂质虽然在乳脂中占比较少,但却对哺乳动物的生长发育有着不可或缺的作用。本文首先介绍乳中极性脂质的种类,比较奶牛乳、水牛乳、牦牛乳、绵羊乳、山羊乳、驴乳、骆驼乳、人乳等不同乳源的乳极性脂质种类及含量差异,随后探讨乳极性脂质的生理功能,包括抑制中性脂肪吸收、调节肠道微生物群落组成、预防心血管疾病、预防非酒精性脂肪肝、促进认知功能与神经系统发育、抗炎作用等,以期为功能性乳脂产品的研发提供参考。

乳脂分离与检测分析技术研究进展

乳是一种含有脂质、蛋白质、碳水化合物和矿物质等成分的复杂的生物流体,同时对于哺乳动物新生儿的生长发育具有重要作用。乳脂质仅占乳中总成分的2%~5%,但却占哺乳动物新生儿每日能量摄入的50%以上。乳脂大部分以甘油脂的形式存在(约98%),而极性脂质(如甘油磷脂和鞘脂等)则是其中的次要成分(约2%)。近年来,随着脂质组学技术的不断完善,乳中脂质的定性与定量研究已经取得了长足进步,为婴幼儿配方乳粉的研制与开发提供了重要的信息。首先介绍了脂质的分类及乳中的常见脂质,探讨了乳中甘油脂、甘油磷脂、鞘脂与糖脂的分离方法的优缺点,总结了常见的乳脂检测及分析方法,随后对乳脂质组学的生物信息学分析进行了介绍,最后对乳脂质组学研究目前的热点与难点问题进行了展望与讨论,以期为脂质组学在乳脂的应用提供借鉴与参考。

氧化苦参碱磷脂复合物纳米结构脂质载体的制备

目的:采用微乳法制备氧化苦参碱磷脂复合物纳米结构脂质载体(OMT-PC-NLC)。方法:通过伪三元相图考察OMT-PC-NLC初乳处方,再将初乳分散于冰水中固化,以包封率为指标,考察固化时间、外水相体积、搅拌速度对OMT-PC-NLC制备工艺的影响。结果:以硬脂酸为固态脂质,油酸为液态脂质,吐温/泊洛沙姆组成的复合乳化剂比例为2∶1,乙醇为助乳化剂,乳化剂与助乳化剂的比例(Km)为1∶1,油相Km为1∶9,固化时间为10 min,外水相体积为175 m L,将初乳在1 750 r/min搅拌状态下分散于冰水中、固化,制备得到OMT-PC-NLC平均粒径为315 nm,粒径范围为161~650 nm。结论:采用微乳法成功制备OMT-PC-NLC,制备工艺简单、操作方便。

替米考星固体脂质纳米乳的制备及体外抗菌效果研究

为了解决替米考星现存制剂不足现状,开发出新型制剂,并对其理化特性进行研究,试验采用热均质超声法制备替米考星固体脂质纳米乳,并通过光学显微镜及纳米粒度仪观察、测定其理化特性;通过纳米乳的体外释放及抗菌试验,用细菌生长抑制和菌落计数法评价其对金黄色葡萄球菌的体外抗菌效果。结果表明:替米考星固体脂质纳米乳的粒径、Zeta电位、多分散系数分别(421.3±26.4)nm、(-10.3±0.3)mv,(0.30±0.09);替米考星固体脂质纳米乳在体外显示良好的缓释效果及持续的抑菌作用。说明替米考星固体脂质纳米乳是一种有前景的新制剂。

石蒜碱脂质纳米乳的制备及抗肿瘤活性的初步研究

目的制备石蒜碱脂质纳米粒,考察体外抗肿瘤活性。方法制备石蒜碱-油酸复合物,溶剂注入法制备纳米乳,超滤法测定包封率,MTT法初步考察纳米乳的抗肿瘤活性。结果制备的纳米乳颗粒圆整均匀,形态良好,包封率为82%±1.4%,粒径为91.9±4.0 nm,PDI为0.171±0.013,Zeta电位为-50.4±5.4 mV。纳米乳较原药能更好抑制肿瘤细胞增殖。结论溶剂注入法制备的石蒜碱脂质纳米乳包封率较高,粒径大小分布均匀,较原药具有更强的抗肿瘤活性。

乳腺癌新辅助化疗的新方案——脂质纳米乳病灶内注射

巴西圣保罗大学心脏病研究所脂质代谢实验室的研究人员通过先前的实验已发现，静脉注射脂质纳米乳后在乳腺癌组织和其他实体肿瘤中会出现聚集，以此可携带药物直接作用到肿瘤组织中去。使用纳米乳液可在减少化疗药物不良反应的同时不减少抗肿瘤的活性。最近，研究人员又测试了纳米乳液在乳腺癌组织局部注射后的聚集情况，结果发表在Gynecol Oncol上。

Study on Preparation of Waterproofing Agent for Mineral Wool Board from Modified C_9 Petroleum Resin

The modified petroleum resin emulsion prepared from the C9petroleum resin was modified with maleic anhydride.The effects of maleic rosin and maleic anhydride addition level,the modification time and the alkali liquor on the properties of the emulsion were discussed.The results showed that the optimum process conditions covered:a maleic anhydride mass fraction of 1.5%,a maleic rosin mass fraction of 10%,a KOH mass fraction of 1%,a petroleum resin modification temperature of 200℃,a petroleum resin modification duration of 3 h,and a modified petroleum resin emulsion/wax emulsion mixing ratio of 1:1.The particle size of modified petroleum resin emulsion prepared under these conditions was equal to 104.166μm.

Neoadjuvant Combination Chemotherapy with Pegylated Liposomal Doxorubicin and Vinorelbine for Locally Advanced Breast Cancer

OBJECTIVE In China, vinorelbine plus an anthracycline is a common neoadjuvant regimen for locally-advanced breast cancer （LABC）. Pegylated liposomal doxorubicin （PLD） is an alternate anthracycline formulation with a more favorable safety profile compared with conventional anthracyclines. METHODS In this open-label trial, 61 women with LABC received up to 6 cycles of PLD 30 mg/m2 on Day 1 and vinorelbine 25 mg/m2 on Days 1 and 8 every 21 days. Hormone receptor and/or HER2 status was not routinely available. RESULTS The overall clinical response rate （primary efficacy endpoint） was 80% （95% CI： 68%-89%）. Two patients achieved a pathological complete response （3%）, with 75% having their tumor down-staged, and 89% proceeding to tumor resection. The most frequent nonhematologic adverse events were stomatitis, fever, rash, and palmar-plantar erythrodysesthesia, with none considered serious. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 10% and 2% of patients, respectively. CONCLUSION PLD plus vinorelbine demonstrated comparable efficacy to conventional anthracyclines plus vinorelbine in the neoadjuvant treatment of LABC, but may offer safety advantages.

Local injection of liposomal adriamycin to inhibit metastatic cell proliferation in axillary nodes in rabbits bearing breast tumors

Objective: To assess the inhibitory effects of local injection of liposomal adriamycin (LADR) on the proliferation of lymph node metastases in rabbits bearing VX2 carcinoma in the mammary gland. Methods:Thirty female New Zealand white rabbits were divided into 3 groups, with 10 in each. VX2 tumor mass suspensions were injected into the breast tissues of rabbits. Treatment initiated once the axillary lymph node reached 5 mm in the maximum diameter. Group 1 received a sham treatment. Group 2 received a subcutaneous injection of LADR adjacent to tumor. Group 3 received an intravenous injection of free ADR (FADR) at the same dose and concentration to group 2. The breast tumors and axillary lymph nodes were resected after the treatment was repeated 3 times. The tumor and node sizes before and after treatment were measured. PCNA mRNA expressions in breast tumors and axillary nodes were determined using RT-PCR. Results: The mean growth ratios of lymph nodes after treatment were 3. 70, 1. 55, and 2. 89,respectively, in groups 1,2, and 3. The slowest node growth was observed in animals of group 2, with significant differences from group 1 (P<0. 001) and group 3 (P = 0. 002). The relative values of PCNA mRNA expression in lymph nodes were 0. 541, 0. 329,and 0. 450, respectively, in groups 1,2, and 3. Group 2 exhibited a significantly reduced PCNA mRNA expression in metastatic lymph node, as compared to group 1 (P<0. 001) and group 3 (P = 0. 004). Intravenous FADR injection effectively lowered the mRNA expressions of PCNA in breast tumors, which were not apparently altered after local LADR injection. Conclusion: Local injection of LADR holds a strong inhibitory effect on the proliferation of metastatic tumor cells in lymph nodes and appears to be an effective method for the treatment of lymphatic metastases of breast cancer.

3种前列地尔新型制剂理化性质对比研究

目的:系统比较3种前列地尔新型制剂的理化性质,探讨结构组成与稳定性的关系。方法:采用透射电子显微镜和激光散射仪考察3种前列地尔新型制剂的形态、粒径以及p H值、离子强度和血清对其稳定性的影响;采用傅立叶红外光谱和差示量热扫描技术分析制剂的结构组成;采用超滤法测定3种制剂中前列地尔的包封率。结果:脂质乳呈现出较强的膜结构,有清晰膜边界,粒径约为150 nm;脂微球呈现出鹅卵石状结构,粒径约为200 nm;干乳剂经去离子水复溶后,颗粒无明显膜结构,粒径为200 nm。稳定性实验结果表明,在不同离子强度、p H值和血清影响下,制剂的稳定性顺序为:脂质乳>脂微球>干乳剂。在处方组成上,脂质乳与脂微球基本一致,但处方含量不同,而干乳剂在处方组成与含量上,均与前两者有明显差异;3种制剂的包封率分别为(92.06±1.49)%(脂质乳)、(83.08±6.05)%(脂微球)和(81.99±6.90)%(干乳剂)。结论:3种前列地尔新型制剂的结构和理化性质存在异同,脂质乳和脂微球制剂结构和组成相近,与干乳剂明显不同。与脂微球比较,脂质乳具有更好的稳定性和较高的包封率。

A novel type of functional epirubicin liposomes modified with DSPE-PEG_(2000)-cyclopamine conjugate for eliminating heterogeneous breast cancer cells

Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells （such as cancer stem-like cells）, resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog （Hh） signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of fimctional drug liposomes for eliminating heterogeneous cancer, The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol （DSPE-PEG2000）-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epimbicin liposomes were successful constructed by modifying with DSPE-PEG2o00-cyclopamine, displaying a particle size in nano-scale （approximately 98 nm） and a high epirubicin encapsulation （〉97%）. The CD44＋/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, fimctional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.

Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice

Breast cancer is one of the malignant tumors with the highest morbidity and mortality. It is helpful to reduce the rate of tumor recurrence and metastasis by treating breast cancer with adjuvant chemotherapy, so as to increase the cure rate or survival of patients. In recent years, liposomes have been regarded as a kind of new carrier for targeted drugs. Being effective for enhancing drug efficacy and reducing side effects, they have been widely used for devel- oping anticancer drugs. As a kind of anthracycline with high anticancer activity, doxorubicin can treat or alleviate a variety of malignant tumors effectively when it is used on its own or in combination with other anticancer drugs~ Alt- hough liposomal doxorubicin has been extensively used in the adjuvant chemotherapy of breast cancer, its exact therapeutic efficacy and side effects have not been definitely proven. Various clinical studies have adopted different combined regimes, dosages, and staging, so their findings differ to certain extent. This paper reviews the clinical application of liposomal doxorubicin in the adjuvant chemotherapy of breast cancer and illustrates therapeutic effects and side effects of pegylated liposomal doxorubicin （PLD） and non-PLD （NPLD） in clinical research, in order to discuss the strategies for applying these drugs in such adjuvant chemotherapy, looking forward to providing references for related research and clinical treatment in terms of dosage, staging, combined regimes, and analysis methods and so on.

Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG_(2000)-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro

Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was synthesized from DSPE-PEG2000-NH2 and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG20o0-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG2000-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF-MS）. The concentrations of sunitinib and vinorelbine were measured simultaneously by high performance liquid chromatography （HPLC）. The analysis was performed on an ODS column at 30℃ at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH2PO4 （pH 3.5） and triethylamine （35：65：0.3, v/v/v）. The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25μg/mL. Two drugs were linearly correlated in the range of 0.5-25.0 μg/mL. For varying types of liposomes, the encapsulation efficiencies were 〉90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adr cells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared to non-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast cancer cells, thereby inhibiting proliferation of the resistant cancer cells. Accordingly, the targeted sunitinib plus vinorelbine liposomes may provide a new strategy for circumventing the drug resistance in the resistant breast cancer.