载紫杉醇的聚乙二醇修饰的大黄酸偶联物胶束的体内安全性及抗肿瘤药效学研究

目的 探讨载紫杉醇(paclitaxel,PTX)的聚乙二醇修饰的羧甲基壳聚糖-大黄酸(CRmP)偶联物胶束(PTX/CRmP胶束)作为静脉注射给药制剂的安全性,并对PTX/CRmP胶束在小鼠体内的抗肿瘤效果进行研究。方法 测定PTX/CRmP胶束的pH值及渗透压。以新鲜兔血红细胞检测溶血性。新西兰白兔耳缘静脉注射PTX/CRmP胶束溶液、CRmP偶联物溶液,光镜下对血管连同周围组织切片进行组织学检查。建立H-22荷瘤小鼠模型,随机分组,分别尾静脉注射给予0.9%氯化钠注射液、注射用PTX脂质体、PTX注射液和PTX/CRmP胶束低、中、高剂量(5,10,15 mg·kg^-1)。给药过程中每天观察小鼠活动情况,记录小鼠体质量变化、肿瘤体积,绘制体质量变化曲线、肿瘤体积变化曲线,计算抑瘤率,HE染色观察肿瘤组织切片。结果 不同浓度PTX/CRmP胶束溶液的pH值与血液pH值相近,渗透压为286～292 mOsm·kg^-1。浓度在0.01～0.05mg·mL-1内,CRmP偶联物及PTX/CRmP胶束的溶血率<5%;经耳缘静脉注射后,注射部...     

载紫杉醇的PEG修饰的大黄酸偶联物胶束的表征、体外释放及药动学研究

目的 对载紫杉醇(paclitaxel,PTX)的聚乙二醇修饰的大黄酸偶联物[PEGylated carboxymethyl chiosan-rhein conjugate (polymeric),PTX/CRmP]胶束进行形态与结构表征,考察其体外(模拟血液环境中)释放情况及药动学特征。方法 通过透射电镜(transmission electron microscopy,TEM)、差示扫描量热法(differential scanning calorimetry,DSC)、X射线衍射(X-ray diffraction,XRD)对胶束的粒径、形态及结构等方面进行评价;在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中进行PTX/CRmP胶束的体外释放研究,计算PTX的累积释放率,绘制累积释放曲线;以大鼠为模型,尾静脉注射PTX/CRmP胶束后,通过药-时曲线、药动学参数等对其进行药动学研究。结果 TEM显示PTX/CRmP胶束呈类球形,粒径约160 nm,分布均匀;DSC和XRD显示PTX几乎全部被CPmP胶束包载入其内核中。PTX/CRmP胶束在pH 7.4磷酸盐缓冲液(含0.8 mol·L^-1水杨酸钠)中24 h内累积释放率为92.2%,药物释放速率显著慢于Taxol^®。药动学研究表明,与Taxol^®组相比,PTX/CRmP胶束中药物的分布和消除较慢,药-时曲线下面积显著增加,CRmP胶束能延长PTX半衰期及其在血液循环系统中的循环时间。结论 CRmP偶联物物理包载PTX于内核中所得的PTX/CRmP胶束,粒径小,在体外模拟血液pH环境中缓释,PTX生物利用度提高。     

PEG-PCL 纳米胶束用于肿瘤诊断治疗的靶向成像和药物输送(英文)

纳米胶束, 是由疏水性内核及亲水性外壳自组装形成的纳米粒子, 利用其在肿瘤部位增强的渗透和滞留效应(EPR效应), 已成功用作靶向药物输送载体。本研究将近红外荧光染料Cy7-NHS与NH2-PEG-b-PCL连接合成了Cy7-PEG-PCL,并将其组装修饰在胶束结构中, 作为紫杉醇药物的递送载体。研究结果显示, 当药物/载体比例确定为1/4, 由聚乙二醇-聚己内酯共聚物自组装形成的胶束粒径为30 nm左右, zeta电位为 -3 mV, 包封率可达95%以上。体外细胞毒实验表明,载紫杉醇胶束对人乳腺癌MCF-7细胞增殖的抑制能力与Taxol 制剂相似。活体成像实验结果显示Cy7标记的聚合物胶束在静脉注射后可以有效地被动靶向到肿瘤部位。另外, 以异位接种MCF-7细胞荷瘤裸鼠为模型的体内药效学实验中,载紫杉醇聚合物胶束显示出与Taxol 制剂相似的抗肿瘤活性。综上所述, 在肿瘤靶向成像和治疗方面, 本研究所构建的胶束载药系统显示出良好的潜力。     

新型抗淋巴瘤药物anti-CD19(Fab)-LDM的靶向分布研究

目的研究抗体毒素偶联新型药物anti-CD19(Fab)-LDM体内外靶向CD19+B淋巴瘤细胞的能力。方法制备Cy5标记的anti-CD19(Fab)-LDP(LDP为LDM辅基蛋白),体外流式细胞仪分析其与人淋巴瘤Raji细胞表面CD19抗原的结合能力;体内建立裸鼠淋巴瘤皮下移植瘤模型,应用活体动物成像系统观察Cy5标记的anti-CD19(Fab)-LDP在荷瘤小鼠体内的靶向分布。结果 Cy5标记的anti-CD19(Fab)-LDP能有效与淋巴瘤Raji细胞膜表面的CD19抗原结合;成功建立人淋巴瘤Raji细胞皮下移植瘤模型,体内活体成像结果表明,融合蛋白anti-CD19(Fab)-LDP可靶向定位到肿瘤部位。结论体内外实验证实anti-CD19(Fab)-LDP能很好的靶向CD19+的淋巴瘤细胞,此抗体毒素偶联药物anti-CD19(Fab)-LDM有希望成为治疗恶性淋巴瘤的新型药物。     

还原敏感型透明质酸-甘草次酸偶联物胶束的制备及评价

目的 合成还原敏感型透明质酸-甘草次酸(hyaluronic acid-glycyrrhetinic acid,HSG)偶联物,对其自组装行为及安全性进行评价,以它为胶束载体增溶化疗药紫杉醇(paclitaxel,PTX),并考察其体外释药行为、细胞摄取行为与细胞毒性。方法 以透明质酸(hyaluronic acid,HA)为亲水性骨架材料,通过还原敏感型胱胺连接臂引入疏水甘草次酸(glycyrrhetinic acid,GA)制备HSG偶联物,应用¹H-NMR与FT-IR表征验证HSG的结构;从粒径及分布、临界胶束浓度、形态3个方面对偶联物的自组装行为进行表征,考察疏水段GA取代度对HSG胶束粒径、分布及其增溶PTX性能的影响;通过溶血性初步评估HSG偶联物的安全性;采用透析法考察载药胶束PTX/HSG在不同浓度谷胱甘肽(glutathione,GSH)介质中的释放行为;流式细胞仪检测HA和GA预孵育对细胞摄取HSG胶束的影响;MTT法考察PTX/HSG对HepG2的细胞毒性。结果 成功合成了一系列两亲性还原敏感型HSG偶联物,随GA取代度提高,HSG胶束粒径降低,确定HA∶GA=1∶2为最佳投料比,此时偶联物GA摩尔取代度为(7.83±1.24)%,粒径为(209.7±10.4)nm,临界胶束浓度为50.1μg·mL^-1,透射电镜显示HSG胶束皆近似球形结构;HSG溶血性低于Tween 80,与聚氧乙烯蓖麻油相当。不同GA取代度的HSG偶联物对PTX均具有增溶效果,并随取代度增加,HSG胶束载体载药能力增强;HSG包载PTX后在高浓度GSH介质中有还原响应性快速释药能力;HSG与HA、GA预孵育后肿瘤细胞对其摄取量降低;PTX/HSG对HepG2的细胞毒性强于Taxol制剂。结论 所制HSG两亲性偶联物能形成胶束,安全系数高,具有还原触发快速释药与主动靶向的能力,可作为载体材料包载难溶性化疗药并有助于其疗效的发挥。     

仿生杂交膜纳米药物联合光动力治疗和化疗用于食管癌的研究

目的构建了具有靶向性的仿生纳米药物HASGA@TK-AKR(HG@TA),利用光动力治疗联合化疗策略治疗食管癌。通过对其理化性质、体外抗肿瘤活性、体内分布和成像等研究,验证该策略的抗肿瘤效果。方法(1)HG@TA的合成与表征:采用去溶剂交联法和膜融合技术制备纳米药物。观察其形貌特征及粒径,测定其包封率和释药率,检测其产生氧气的能力,测定其降低GSH的特性。(2)体外抗肿瘤活性研究:观察并定量分析食管癌细胞系AKR细胞对其摄取能力和胞内分布情况。考察了纳米药物对AKR细胞活力的影响。(3)体内分布和成像研究:考察纳米药物在小鼠体内的同源靶向功能及体内分布情况。结果成功构建HG@TA。体外产氧实验表明HG@TA表面的H2O2酶能催化H2O2生成大量O2。GSH实验结果表明,激光照射下HG@TA能显著降低细胞内GSH水平。体外抗肿瘤活性结果显示,激光照射下HG@TA能降低细胞活力,具有增强的细胞摄取和细胞杀伤效果。活体成像结果显示,由EPR效应引起的被动靶向和主动同源靶向,纳米药物在肿瘤部位的荧光强度高于其他组织,说明HG@TA具有良好的肿瘤靶向能力。结论制备的纳米药物HG@TA创新性地融合类囊体膜与食管癌细胞膜形成仿生杂交膜包载的白蛋白藤黄酸纳米颗粒,改善肿瘤乏氧的同时降低GSH水平,进步提高光动力治疗联合化疗的抗肿瘤效果,且能在近红外窗口产生荧光,实时非侵入性地指导体内治疗,为肿瘤的治疗提供了新策略。     

紫杉醇Pluronic P105聚合物胶束的制备、表征与逆转肿瘤多药耐药性的体外研究

药物递送系统是克服肿瘤多药耐药性(MDR)的一种新策略。本文以聚合物胶束系统和难溶性药物紫杉醇(PTX)为研究对象，旨在制备一种新型的PTX给药系统，既能增溶难溶性药物，又具有克服肿瘤MDR的能力。以Pluronic P105为载体，采用固体分散-水化法制备PTX聚合物胶束，并以星点设计-效应面优化法进行处方优化。对其粒径、体外释放等性质进行表征后，以人耐药卵巢癌细胞SKOV-3/PTX为细胞模型，体外评价PTX聚合物胶束的细胞摄取及其逆转肿瘤细胞耐药性的作用。结果显示，聚合物胶束制剂的载药量约为1.1%、药物浓度约为700 μg·mL^-1、平均粒径约为24 nm。胶束制剂与普通制剂(Taxol)在6 h内的累积释放分别为45.4%和95.2%，前者具有较强的缓释作用；胶束制剂与Taxol对SKOV-3/PTX的IC₅₀值分别为1.14和5.11 μg·mL^-1，二者的耐药逆转指数(RRI)分别为9.65和2.15。胶束制剂可促进耐药细胞对P-糖蛋白(P-gp)底物(PTX或Rhodamine-123)的摄取。结果表明，Pluronic P105可有效增溶难溶性药物PTX，并形成具有较强缓释作用的纳米级聚合物胶束制剂，该制剂可显著提高PTX对人卵巢癌耐药细胞的细胞毒性，能逆转其耐药性。     

NGR配体修饰的紫杉醇PEG-PLGA胶束抗肿瘤作用的体外体内研究(英文)

本研究制备了NGR(asparagine-glycine-arginine)配体修饰的紫杉醇PEG-PLGA胶束(NGR-PM-PTX),并对其靶向肿瘤新生血管内皮细胞及肿瘤细胞所表达的氨肽酶N进行了研究。采用薄膜法制备NGR-PM-PTX胶束。通过针对人脐静脉内皮细胞(HUVEC),人纤维肉瘤细胞(HT1080)和人乳腺癌细胞(MCF-7)的流式细胞试验和激光共聚焦实验,在体外细胞水平上研究并证实了NGR配体修饰的聚合物胶束对于上述细胞的靶向效果。HT1080荷瘤裸鼠的体内药效学研究结果进一步证实NGR-PM-PTX的抗肿瘤药效。     

脂质胶束介导VEGF基因对称和不对称siRNA的抑瘤效果

目的:探讨脂质胶束递送靶向VEGF基因的对称siRNA和不对称siRNA(asiRNA)的抑瘤效果。方法:通过RNA电泳等方法,筛选不同组分比例的脂质胶束,用Western blot、细胞板计数法、CCK-8实验检测对乳腺癌MCF-7细胞活力的影响。构建H22肝癌荷瘤小鼠模型,随机分为不同实验组,连续14天尾静脉注射给药,计算抑瘤率和小鼠生存率。结果:在4组不同RNA干扰片段中,asiRNA21/23组抑制VEGF蛋白表达效果最好。在H22荷瘤小鼠实验中,asiRNA21/23组显示了明显的抑瘤效果,且延长了荷瘤小鼠的生存期。结论:脂质胶束递送VEGF-asiRNA21/23降低了MCF-7细胞中VEGF基因的表达,且具有明显的肿瘤抑制效果。     

7-乙基-10-羟基喜树碱聚合物胶束的肿瘤靶向性研究

目的研究7-乙基-10-羟基喜树碱/聚乙二醇-聚天冬氨酸聚合物胶束(7-ethyl-10-hydroxycamptothecin/polyethylene glycol-polyaspartic acid polymer micelles,SN-38/PEG-pasp)在荷瘤小鼠体内的组织分布特点。方法采用LC-MS法测定荷瘤小鼠血浆和组织中7-乙基-10-羟基喜树碱(7-ethyl-10-hydroxycamptothecin,SN-38)的质量浓度,并用SPSS13.0统计学软件对测定的数据进行分析。结果药物在肿瘤组织中相对摄取率(r_e)达到10,远远高于其他组织,除去肝其余组织作为非靶向组织时,肿瘤的靶向效率(t_e)均大于1,呈现出明显的肿瘤靶向特征,胶束组药物在体内质量浓度排布顺序:肿瘤>肝>肺>脾>肾>心>血。结论 SN-38/PEG-pasp在肿瘤组织中药物浓度明显高于除肝脏外的其他各组织,具有明确的肿瘤靶向性。     

In vivo pharmacokinetics,biodistribution and antitumor effect of paclitaxel-loaded micelles based on α-tocopherol succinate-modified chitosan

In our previous study, α-tocopherol succinate modified chitosan (CS-TOS) was synthesized and encapsulated paclitaxel (PTX) to form micelles. Preliminary study revealed that the CS-TOS was a potential micellar carrier for PTX. In this study, some further researches were done using Taxol formulation as the control to evaluate the micelle system deeply. In vitro cell experiments demonstrated that the cytotoxic effect of PTX-loaded CS-TOS micelles against MCF-7 cells was comparable with that of Taxol formulation, and the PTX-loaded micelles had excellent cellular uptake ability, which was in a time-dependent manner. The in vivo pharmacokinetic study in rats showed that the micelles prolonged the half-life and increased AUC of PTX than Taxol formulation. From biodistribution study, it was clear that for micelles, the drug concentrations in the liver and spleen were significantly higher than those of Taxol formulation, but much lower in the heart and kidney. Furthermore, the PTX-loaded micelles showed superior antitumor effect, but yielded less toxicity as indicated by the results of antitumor efficacy study and survival study in U14 tumor-bearing mice. These results suggested that CS-TOS micelles could be a potentially useful drug delivery system to improve the performance and safety of PTX.     

消癌平注射液联合紫杉醇对人卵巢癌SK-OV-3细胞增殖及裸鼠异位移植瘤生长的作用

目的 研究消癌平（XAP）注射液和紫杉醇（PTX）联合应用对人卵巢癌SK-OV-3细胞增殖及裸鼠异位移植瘤的抑制作用。方法 将生长至对数期的人卵巢癌SK-OV-3细胞分为6组：对照组、紫杉醇组（10 nmol/L）、消癌平注射液低、高剂量组（20、80 μl/ml）、消癌平注射液低、高剂量联合组（PTX 10 nmol/L+XAP 20 μl/ml、PTX 10 nmol/L+XAP 80 μl/ml）,各组分别加入药物干预24 h或48 h后,MTT法测定并计算细胞存活率。将36只雌性荷人卵巢癌细胞SK-OV-3的异位移植瘤裸鼠随机分为6组,包括对照组（G1：生理盐水）、紫杉醇组（G2：PTX 10 mg/kg）、消癌平注射液低、高剂量组（G3：XAP 20 ml/kg、G4：XAP 50 ml/kg）、低剂量联合组（G5：PTX 10 mg/kg+XAP 20 ml/kg）以及高剂量联合组（G6：PTX 10 mg/kg+XAP 50 ml/kg）,每组6只。各治疗组予相应药物治疗18 d,观察记录小鼠一般情况、体重、肿瘤体积,并计算抑瘤率。结果 SK-OV-3细胞体外实验结果显示,与对照组相比,消癌平注射液、低剂量联合组和高剂量联合组的SK-OV-3细胞存活率均显著降低（P<0.05或P<0.01）,且联合用药组与紫杉醇组相比,也有显著差异（P<0.05）,并呈现剂量和时间依赖性。裸鼠异位移植瘤实验结果显示,高剂量联合组的抑瘤率明显高于对照组和紫杉醇组,差异有统计学意义（P<0.05）。结论 消癌平注射液和紫杉醇联用对人卵巢癌细胞SK-OV-3裸鼠异位移植瘤的抑制具有协同作用（P<0.05）。     

Cytotoxic enhancement of hexapeptide-conjugated micelles in EGFR high-expressed cancer cells

Objectives: The aim of this study was to develop the hexapeptide-conjugated active targeting micelles for delivery of doxorubicin (DOX) and paclitaxel (PTX) to EGFR high-expressed cancer cells.

Methods: A hexapeptide, which mimicked the EGFR, was applied as a targeting ligand. The active targeting micelles were prepared using the synthesized poly(D,L-lactide-co-glycolide)–PEG copolymer conjugated with the hexapeptide. The micelles were used for encapsulating DOX and/or PTX, and the cellular uptake, in vitro drug release and cellular viability of drug-loaded peptide-conjugated and peptide-free micelles were investigated.

Results: The particle size of drug-loaded peptide-conjugated and peptide-free micelles was < 150 nm with narrow size distribution. The uptake of peptide-conjugated micelles was more efficient in EGFR high-expressed MDA-MB-468 and SKOV3 cells than in EGFR low-expressed HepG2 cells. The in vitro release of DOX and PTX was faster in pH 4.0 (500 U lipase) than in pH 7.4 release medium. The cytotoxicity in terms of IC₅₀ of DOX/PTX-loaded peptide-conjugated micelles was 4.8-folds lower than that of peptide-free micelles and 18.2-folds lower than DOX/PTX drug solution in SOKV3 cells.

Conclusion: The peptide-conjugated micelles acted as a nanocarrier to increase intracellular accumulation of anticancer drugs in EGFR high-expressed SKOV3 cancer cells to enhance cell cytotoxicity.     

Difunctional Pluronic copolymer micelles for paclitaxel delivery: synergistic effect of folate-mediated targeting and Pluronic-mediated overcoming multidrug resistance in tumor cell lines

A significant obstacle for successful chemotherapy with paclitaxel (PTX) is multidrug resistance (MDR) in tumor cells. Micelles and mixed micelles were prepared from Pluronic block copolymer P105 or L101 as PTX delivery systems for overcoming MDR. Both micelle systems were covalently modified with the targeting agent folic acid to recognize and bind a variety of tumor cells via their surface-overexpressed folate receptor. There was an increased level of uptake of folate-conjugated micellar PTX (i.e. FOL-P105/PTX, FOL-PL/PTX) compared to plain micellar PTX (i.e. P105/PTX, PL/PTX) in human breast cancer MDR cell sublines, MCF-7/ADR, and the uptake of folate-conjugated micellar PTX could be inhibited by free folic acid, which suggested that the level of uptake could be mediated by the folate receptor. The cytotoxicity of folate-conjugated micellar PTX in the MDR cell culture model was much higher compared with plain micellar PTX or free PTX, and the plain micellar PTX also has higher cytotoxicity than free PTX. Overall, the MDR cells are more susceptible to the cytotoxic effects of Pluronic micellar PTX than their parental cells. The introduction of folic acid into P105 or PL mixed micelles enhanced the cell-killing effect by active internalization. Increased internalization explained the improved cytotoxicity of the FOL-micellar PTX to tumor cells. We suggest that the combined mechanisms of folate-mediated active internalization and Pluronic-mediated overcoming MDR be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into the tumor cells where folate receptor is frequently overexpressed, reducing accumulation of micellar PTX in other tissues or organs and further reducing side effects and toxicities of the drug.     

Development of redox-responsive theranostic nanoparticles for near-infrared fluorescence imaging-guided photodynamic/chemotherapy of tumor

The development of imaging-guided smart drug delivery systems for combinational photodynamic/chemotherapy of the tumor has become highly demanded in oncology. Herein, redox-responsive theranostic polymeric nanoparticles (NPs) were fabricated innovatively using low molecular weight heparin (LWMH) as the backbone. Chlorin e6 (Ce6) and alpha-tocopherol succinate (TOS) were conjugated to LMWH via cystamine as the redox-sensitive linker, forming amphiphilic Ce6-LMWH-TOS (CHT) polymer, which could self-assemble into NPs in water and encapsulate paclitaxel (PTX) inside the inner core (PTX/CHT NPs). The enhanced near-infrared (NIR) fluorescence intensity and reactive oxygen species (ROS) generation of Ce6 were observed in a reductive environment, suggesting the cystamine-switched “ON/OFF” of Ce6. Also, the in vitro release of PTX exhibited a redox-triggered profile. MCF-7 cells showed a dramatically higher uptake of Ce6 delivered by CHT NPs compared with free Ce6. The improved therapeutic effect of PTX/CHT NPs compared with mono-photodynamic or mono-chemotherapy was observed in vitro via MTT and apoptosis assays. Also, the PTX/CHT NPs exhibited a significantly better in anti-tumor efficiency upon NIR irradiation according to the results of in vivo combination therapy conducted on 4T1-tumor-bearing mice. The in vivo NIR fluorescence capacity of CHT NPs was also evaluated in tumor-bearing nude mice, implying that the CHT NPs could enhance the accumulation and retention of Ce6 in tumor foci compared with free Ce6. Interestingly, the anti-metastasis activity of CHT NPs was observed against MCF-7 cells by a wound healing assay, which was comparable to LMWH, suggesting LMWH was promising for construction of nanocarriers for cancer management.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles

A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t _1/2β and AUC of the micelle formulation were 4.9 and 5.3-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

In vivo pharmacokinetics,biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle

Abstract

A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC₅₀ value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93?µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the V_d, T_1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX.     

The efficacy of WGA modified daunorubicin anti-resistant liposomes in treatment of drug-resistant MCF-7 breast cancer

Background: Breast cancer is the most common malignancy and remains a leading cause of cancer-related deaths in female. Chemotherapy failure of breast cancer is mainly associated with multidrug resistance of cancer cells.

Purpose: The WGA modified daunorubicin anti-resistant liposomes were developed for circumventing the multidrug resistance and eliminating cancer cells.

Methods: WGA was modified on liposomal surface for increasing the intracellular uptake. Tetrandrine was inserted into the phospholipid bilayer for reversing cancer drug-resistance, and daunorubicin was encapsulated in liposomal aqueous core as an anticancer agent. Evaluations were performed on MCF-7 cells, MCF-7/ADR cells and xenografts of MCF-7/ADR cells.

Results: In vitro results showed that WGA modified daunorubicin anti-resistant liposomes exhibited suitable physicochemical properties, significantly increased intracellular uptake in both MCF-7 cells and MCF-7/ADR cells, and circumvented the multidrug resistance via inhibiting P-gp. In vivo results demonstrated that the targeting liposomes showed a long-circulatory effect in blood system, and could remarkably accumulate at the tumor location. The involved action mechanisms for the enhanced anticancer efficacy were activation of pro-apoptotic proteins (Bax and Bok), apoptotic enzymes (caspase 8, caspase 9 and caspase 3).

Conclusion: The established WGA modified daunorubicin anti-resistant liposomes could provide a potential strategy for treating resistant MCF-7 breast cancer.