Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation

An improved PEGylated liposomal formulation of paclitaxel has been developed with the purpose of improving the solubility of paclitaxel as well as the physicochemical stability of liposome in comparison to the current Taxol formulation. The use of 3% (v/v) Tween 80 in the hydration media was able to increase the solubility of drug. The addition of sucrose as a lyoprotectant in the freeze-drying process increased the stability of the liposome particles. There was no significant difference in the entrapment efficiency of paclitaxel between the conventional non-PEGylated liposomes and our PEGylated liposomes. Cytotoxicity in human breast cancer cell lines (MDA-MB-231 and SK-BR-3) of our paclitaxel formulation was less potent compared to Taxol after 24h incubation, but was equipotent after 72 h due to the slower release of drug from the liposome. Our PEGylated liposomes increased the biological half-life of paclitaxel from 5.05 (+/-1.52)h to 17.8 (+/-2.35)h compared to the conventional liposomes in rats. Biodistribution studies in breast cancer xenografted nude mouse model showed that our liposomes significantly decreased the uptake in reticuloendothelial system (RES)-containing organs (liver, spleen and lung) while increasing the uptake in tumor tissues after injection compared to Taxol or the conventional liposomal formulation. Moreover, the PEGylated liposome showed greater tumor growth inhibition effect in in vivo studies. Therefore, our PEGylated liposomal formulation of paclitaxel could serve as a better alternative for the passive targeting of human breast tumors.     

Additive effects of trastuzumab and genistein on human breast cancer cells

Soy isoflavone genistein, a tyrosine kinase inhibitor and agonist of estrogen receptor-β (ERβ), is known to have antitumoral properties. Given that ERβ often is coexpressed with HER2 in breast cancer, both functions of genistein might be able to enhance the antitumoral action of trastuzumab. In this in-vitro study, we tested whether combined treatment with genistein and trastuzumab exerts additive effects on breast cancer cells. HER2-overexpressing breast cancer cell lines were treated with genistein alone and in combination with trastuzumab. The effects of this treatment on proliferation and gene expression were analyzed. Treatment with high-dose genistein (10 μmol/l) significantly increased the growth-inhibitory effect of trastuzumab on HER2-overexpressing, ERα/β-positive BT-474 breast cancer cells. Combinatory treatment using lower doses of trastuzumab exerted similar effects as a single treatment with standard doses of this drug. In contrast, this effect was absent in ERα-negative SK-BR-3 cells. Similar results were obtained after cotreatment with the ERβ agonist, 2,3-bis(4-hydroxyphenyl)propionitrile. The growth-inhibitory effect of both drugs was accompanied by an increased expression of the putative tumor suppressor ERβ variant, cx, and their combination further elevated mRNA levels of this receptor. In conclusion, genistein significantly enhanced the antitumoral effect of trastuzumab on BT-474 breast cancer cells in vitro. The relevance of these data particularly for women with HER2-overexpressing and ERα/β-positive breast cancer has to be verified in animal or clinical studies.     

表没食子儿茶素没食子酸酯联合曲妥珠单抗对HER2过表达乳腺癌细胞增殖的影响及其机制

目的 研究表没食子儿茶素没食子酸酯（EGCG）联合曲妥珠单抗对人表皮生长因子受体2(HER2)过表达乳腺癌细胞增殖的影响及其作用机制。方法 表达纯化曲妥珠单抗;用CCK-8细胞增殖检测试剂盒（CCK8）检测不同浓度EGCG、曲妥珠单抗及两药联用对HER2过表达乳腺癌细胞BT474、SK-BR-3的增殖抑制作用;用Western blot法检测EGCG、曲妥珠单抗及两药联用对BT474乳腺癌细胞中HER2,表皮生长因子受体（EGFR）,丝裂原激活的蛋白激酶（MAPK）和蛋白激酶B(Akt)及它们的磷酸化蛋白的表达水平的影响。结果 细胞增殖试验结果显示,EGCG、曲妥珠单抗以及二者联用均能有效抑制BT474和SK-BR-3细胞的增殖,且在一定浓度范围内,EGCG与曲妥珠单抗联用显示出协同增殖抑制作用。Western blot结果显示EGCG、曲妥珠单抗以及二者联合均能抑制BT474细胞中Akt,MAPK,EGFR,HER2的磷酸化蛋白表达,与单药相比,二者联合抑制作用显著增强,其差异具有统计学意义(P<0.05)。结论 EGCG联合曲妥珠单抗能协同抑制HER2过表达乳腺癌细胞的增殖,...     

Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ 相似文献   

Relation of cell proliferation to expression of peripheral benzodiazepine receptors in human breast cancer cell lines

Peripheral benzodiazepine receptor (PBR) agonist [(3)H]Ro5-4864 has been shown to bind with high affinity to the human breast cancer cell line BT-20. Therefore, we investigated different human breast cancer cell lines with regard to binding to [(3)H]Ro5-4864 and staining with the PBR-specific monoclonal antibody 8D7. Results were correlated with cell proliferation characteristics. In flow cytometric analysis, the estrogen receptor (ER)-negative breast cancer cell lines BT-20, MDA-MB-435-S, and SK-BR-3 showed significantly higher PBR expression (relative fluorescence intensity) than the ER-positive cells T47-D, MCF-7 and BT-474 (P<0.05). Accordingly, BT-20 and MDA-MB-435-S had the highest capacity for binding [(3)H]-Ro5-4864, while the ER-positive cells exhibited only low binding of the benzodiazepine. PBR expression correlated inversely with cell doubling time (r = 0.78) and positively with Ki-67 expression (r = 0.77). The amount of mitochondria was significantly higher in cells with high PBR expression. As PBR could be demonstrated only after permeabilization of cells, PBR is suggested to be localized within the cytoplasm. Moreover, colocalization of PBR and mitochondria was shown by confocal microscopy analysis. The highest amounts of both PBR and mitochondria were found in cell lines with high mitotic activity. Therefore, it is concluded that the level of PBR is dependent on the number of mitochondria. PBR and its putative endogenous ligand diazepam-binding inhibitor are possibly involved in the regulation of cell proliferation of human breast cancer cell lines.     

Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules

Purpose The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded lipid nanocapsules (LNC) in rats to assess the intrinsic effect of the dosage form on the improvement of paclitaxel oral exposure. Methods Paclitaxel-loaded LNC were prepared and characterized in terms of size distribution, drug payload, and the kinetics of paclitaxel crystallization. Taxol?, Taxol? with verapamil, or paclitaxel-loaded LNC were administered orally to rats. The plasma concentration of paclitaxel was determined using liquid chromatography mass spectrometry. Results The average size of LNC was 60.9 ± 1.5 nm. The drug payload of paclitaxel was 1.91 ± 0.01 mg/g of aqueous dispersion. The encapsulation efficiency was 99.9 ± 1.0%, and 1.7 ± 0.1% of paclitaxel was crystallized after 24 h. The oral bioavailability of Taxol? alone was 6.5%. After oral administration of paclitaxel-loaded LNC or paclitaxel associated with verapamil, the area under the plasma concentration–time curve was significantly increased (about 3-fold) in comparison to the control group (p < 0.05). Conclusions The results indicated that LNC provided a promising new formulation to enhance the oral bioavailability of paclitaxel while avoiding the use of pharmacologically active P-gp inhibitors, such as verapamil.     

Lapatinib-incorporated lipoprotein-like nanoparticles： preparation and a proposed breast cancer-targeting mechanism

Aim： Lapatinib is a dual inhibitor of EGFR and human epidermal growth factor receptor 2 （HER2）, and used to treat advanced breast cancer. To overcome its poor water solubility, we constructed lapatinib-incorporated lipoprotein-like nanoparticles （LTNPs）, and evaluated the particle characteristics and possible anti-breast cancer mechanisms.
Methods： LTNPs （lapatinib bound to albumin as a core, and egg yolk lecithin forming a lipid corona） were prepared. The particle characteristics were investigated using transmission electron microscopy （TEM） and atomic force microscopy （AFM）. The uptake and subcellular localization of LTNPs, as well as the effects of LTNPs on cell cycle were examined in BT-474 human breast cancer cells in vitro. Mice bearing BT-474 subcutaneous xenograft were intravenously injected with coumarin-6 loaded LTNPs （30 mg/kg） to study the targeting mechanisms in vivo.
Results： The LTNPs particles were generally spherical but flexible under TEM and AFM, and approximately 62.1 nm in size with a zeta potential of 22.80 mV. In BT-474 cells, uptake of LTNPs was mediated by endosomes through energy-dependent endocytosis involving clathrin-dependent pinocytosis and macropinocytosis, and they could effectively escape from endosomes to the cytoplasm. Treatment of BT-474 cells with LTNPs （20 μg/mL） induced a significant cell arrest at G0/G1 phase compared with the same concentration of lapatinib suspension. In mice bearing BT-474 xenograft, intravenously injected LTNPs was found to target and accumulate in tumors, and colocalized with HER2 and SPRAC （secreted protein, acidic and rich in cysteine）.
Conclusion： LTNPs can be taken up into breast cancer cells through specific pathways in vitro, and targeted to breast cancer xenograft in vivo via enhanced permeability and retention effect and SPARC.     

Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with <Superscript>177</Superscript>Lu

Purpose

To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with ¹⁷⁷Lu (trastuzumab-AuNP-¹⁷⁷Lu) targeted to HER2 with non-targeted AuNP-¹⁷⁷Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection.

Methods

AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex ¹⁷⁷Lu. The binding and internalization of trastuzumab-AuNP-¹⁷⁷Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-¹⁷⁷Lu or AuNP-¹⁷⁷Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-¹⁷⁷Lu, AuNP-¹⁷⁷Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.

Results

Trastuzumab-AuNP-¹⁷⁷Lu was bound and internalized by HER2 positive BC cells (K_D?=?7.6?±?2.0 nM). Trastuzumab-AuNP-¹⁷⁷Lu was 42.9 and 2.6-fold more effective than AuNP-¹⁷⁷Lu at decreasing the clonogenic survival of SK-BR-3 (1.3?×?10⁶ HER2/cell) and MDA-MB-361 (5.1?×?10⁵ HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-¹⁷⁷Lu than AuNP-¹⁷⁷Lu. Trastuzumab-AuNP-¹⁷⁷Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-¹⁷⁷Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-¹⁷⁷Lu or AuNP-¹⁷⁷Lu treatments.

Conclusion

Trastuzumab-AuNP-¹⁷⁷Lu enables an efficient local radiation treatment of HER2-positive BC.

     

STI571 sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner

Previously, we demonstrated that Abl kinases are highly active in invasive breast cancer cell lines, and contribute to survival in response to nutrient deprivation, invasion and proliferation. To determine whether an Abl kinase inhibitor, STI571 (Gleevec; imatinib mesylate) sensitizes breast cancer cells to chemotherapeutic agents, we treated three breast cancer cell lines (BT-549, MDA-MB-231, and MDA-MB-468) that have active Abl kinases, with STI571 in combination with several conventional chemotherapeutic drugs frequently used to treat breast cancer, and assessed the effect on cell viability, proliferation, and apoptosis. We found that STI571 had synergistic effects with cisplatin in BT-549 and to some extent in MDA-MB-468 cells; synergized with camptothecin using an alternate dosing regimen in MDA-MB-231 cells; and STI571 synergistically sensitized MDA-MB-468 cells to paclitaxel and to high doses of 5-fluorouracil. Significantly, STI571 increased the ability of cisplatin to inhibit constitutive activation of PI3K/Akt in BT-549 cells, synergized with camptothecin to increase the stability of IκB in MDA-MB-231 cells, and in MDA-MB-468 cells, camptothecin and 5-fluorouracil inhibited STI571-dependent activation of STAT3. In other cell line/drug combinations, STI571 had additive or antagonistic effects, indicating that the ability of STI571 to sensitize breast cancer cells to chemotherapeutic agents is cell type-dependent. Significantly, unlike cisplatin, paclitaxel, and camptothecin, mechloroethamine was strongly antagonistic to STI571, and the effect was not cell line-dependent. Taken together, these data indicate that the cellular milieu governs the response of breast cancer cells to STI571/chemotherapeutic combination regimens, which suggests that treatment with these combinations requires individualization.     

Intravenous Hydrophobic Drug Delivery: A Porous Particle Formulation of Paclitaxel (AI-850)

No HeadingPurpose. To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.Methods. A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.Results. The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).Conclusions. The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.     

Trials of new combinations of Herceptin in metastatic breast cancer

Herceptin extends survival in human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer patients when administered with paclitaxel or anthracycline/cyclophosphamide (AC), and the combination with 3-weekly paclitaxel is the current standard first-line therapy. However, other combinations may be equally effective. This review provides information on recent and ongoing trials of new Herceptin combinations. Preliminary results indicate that Herceptin plus epirubicin/cyclophosphamide may be effective without the cardiotoxicity of the AC combination. Weekly paclitaxel plus Herceptin has produced responses in 83% of HER2-positive patients treated. Co-administering Herceptin with other cytotoxic agents has also been investigated, with combination partners being chosen based on in vitro synergy with Herceptin, known efficacy as monotherapy and convenience of weekly administration (e.g. docetaxel, vinorelbine). High response rates have been observed in these clinical trials, e.g. up to 80% in combination with vinorelbine. Furthermore, Herceptin in combination with weekly paclitaxel, docetaxel or vinorelbine was well tolerated: there was no significant cardiotoxicity or unexpected toxicity and the combination showed an adverse event profile similar to that seen with monotherapy with the cytotoxic agent. Thus, Herceptin produces additional clinical benefit when added to all the cytotoxic agents with which it has been examined, further demonstrating its potential for use in HER2-positive breast cancer patients.     

ErbB2高表达的人乳腺癌原位移植瘤裸鼠模型的建立

目的采用人乳腺癌细胞株BT-474建立稳定高表达ErbB2的人乳腺癌裸鼠移植瘤模型,选择合适的模型制作方法。方法实验前1d在36只裸鼠颈部皮下埋植0.5mg17β雌二醇缓释片,并随机分为3组:原位组将5×106个BT-474细胞接种于裸鼠左侧第二乳房垫内,胁部皮下组将同样数量的BT-474细胞接种于裸鼠左侧胁部皮下,腋窝组则接种于裸鼠左侧腋窝内;观察3组裸鼠荷瘤情况及移植瘤病理组织学特点,并采用免疫组化方法动态监测移植瘤的ErbB2表达情况。结果 3组裸鼠的荷瘤率均为100%,都保持了原发肿瘤高表达ErbB2的特点;和两组对照相比,原位组肿瘤形状、生长速度及细胞增殖与血管生成等生物学特征一致性更强;此外,原位组的肿瘤对治疗药物处理也有良好反应。结论 BT-474细胞接种于乳房垫内比胁部皮下及腋窝建立的裸鼠移植瘤模型更适于进行抗ErbB2抗体等药物的药理学研究。     

From HER2 to herceptin

HER2 overexpression occurs in 25% of breast cancers and seems to correlate with poor prognosis. HER2 overexpression may predict tamoxifen failure and different response rates to chemotherapeutic agents such as the taxanes and anthracyclines. The detection of HER2 and its overexpression is performed using fluorescent in situ hybridisation (FISH) and/or immunohistochemistry (IHC). Trastuzumab [Herceptin (H)] is a humanised IgG monoclonal antibody specific for the growth factor receptor HER2. Pre-clinical trials using monoclonal antibodies have shown inhibition of breast tumour growth in athymic nude mice. Phase II and III clinical trials have evaluated the efficacy and safety of Herceptin in women with metastatic breast cancer in combination with other agents and as a single agent. Currently, Trastuzumab and paclitaxel is the only combination indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2. It is also indicated as a single agent in women with HER2-overexpressing metastatic breast cancer that has progressed after previous chemotherapy. Herceptin is a well-tolerated drug and the side-effects that are commonly seen with chemotherapy, such as neutropenia, alopecia and mucositis, are rarely observed. The main risk factors for cardiotoxicity are concurrent or previous anthracycline exposure. The potential role of Herceptin in the adjuvant setting is currently being evaluated.     

Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

Overexpression of HER-2 in breast cancer is frequently associated with expression of EGFR, and EGFR expression influences response to HER-2 inhibition. The aim of this study was to examine the effects of combining dual inhibition of EGFR and HER-2, using trastuzumab, gefitinib and lapatinib, in HER-2 overexpressing breast cancer cells. Combination proliferation assays were performed in two HER-2 positive breast cancer cell lines, SKBR-3 and BT-474. Trastuzumab combined with lapatinib was also tested in BT-474 xenografts. In proliferation assays, dual targeting with trastuzumab and gefitinib or lapatinib showed synergy or additivity in both SKBR-3 and BT-474 cells. Trastuzumab (10 nM) or gefitinib (5 μM) alone did not induce significant apoptosis, whereas lapatinib (0.75 μM) induced significant apoptosis in SKBR-3 cells. Trastuzumab combined with lapatinib further enhanced apoptosis induction. Trastuzumab (10 nM) and gefitinib (5 μM) induced apoptosis comparable to lapatinib alone (0.75 μM), suggesting that inhibition of both EGFR and HER-2 may be required to induce apoptosis in these cells. Pre-treatment with trastuzumab and gefitinib or lapatinib enhanced response to chemotherapy in vitro. The combination of trastuzumab and lapatinib also effectively blocked tumour growth in vivo. Dual targeting of EGFR and HER-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.     

Maximizing the response to Herceptin therapy through optimal use and patient selection

The aggressiveness of human epidermal growth factor receptor-2 (HER2)-positive breast cancer and the poor prognosis of women with this disease demand the availability of accurate and reliable tests for HER2 status and the optimization of HER2-targeted therapy. The distinctive clinical pattern of HER2-positive breast cancer underlines the importance of testing for HER2 status and efforts are ongoing to validate the two major methods in use-immunohistochemistry (IHC), which measures cell membrane HER2 expression, and fluorescence in situ hybridization (FISH), which measures gene copy number. Clinical trial results demonstrate that there is an association between strong HER2 overexpression (IHC 3+) and optimal response to therapy with the novel recombinant HER2 antibody Herceptin. High levels of concordance between IHC 3+ and FISH-positive status have been observed, and response to treatment with Herceptin is similar for patients whose breast cancers are IHC 3+ and those who are FISH-positive. Observations to date have led to the formulation of an algorithm for HER2 status determination and Herceptin use which recommends that: (i) the HER2 status of all women with breast cancer be determined at presentation, (ii) all IHC 3+ and FISH-positive patients with metastatic disease should receive Herceptin, (iii) Herceptin should be used early in the course of metastatic breast cancer and preferably first line, and (iv) Herceptin therapy should be continued until disease progression.     

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.     

~(131)I-herceptin对乳腺癌细胞株的放射免疫治疗

目的探索131I-herceptin对高表达Her-2基因的乳腺癌细胞株的生物学作用。方法 MTT比色法检测131I-herceptin对表达不同水平Her-2基因的三株乳腺癌细胞株SK-BR-3、MDA-MB-231、MCF-7的抑制作用,流式细胞术测量各干预组的DNA倍体和凋亡率。结果 131I-herceptin对SK-BR-3细胞的抑制作用明显强于对MDA-MB-231、MCF-7细胞的抑制作用(P<0.05、P<0.01),并且明显强于131I组、herceptin组以及131I+herceptin组(P<0.05);131I-herceptin组的凋亡率(37.71%)明显高于131I+herceptin组(14.61%)(P<0.05)、herceptin组(3.37%)和131I组(0.93%)(P<0.01)。各干预组都出现细胞周期的阻滞,131I-herceptin组最明显(73.19%)。结论 131I-herceptin对高表达Her-2基因的人乳腺癌细胞株SK-BR-3有明显的抑制和杀伤作用。     

Investigation of the release behavior of DEHP from infusion sets by paclitaxel-loaded polymeric micelles

The current clinical formulation of paclitaxel (Taxol) contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. Cremophor EL and dehydrated ethanol are well known to leach di-(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and PVC administration sets. DEHP is a possible hepatotoxin, carcinogen, teratogen and mutagen. Long-term exposure to DEHP may cause health risks. As an alternative formulation for paclitaxel, paclitaxel-loaded polymeric micelles (PLPM), made of monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) diblock copolymer, has demonstrated clear advantages over Taxol in pharmacokinetics and therapeutic index. Paclitaxel in either PLPM or Taxol formulations, diluted in 0.9% sodium chloride injection, was stable in the PVC infusion bags. The PLPM formulation significantly reduced the amount of DEHP extracted from PVC infusion bags and PVC administration sets. For PLPM diluted in 0.9% sodium chloride injection, the total amount of DEHP delivered over the simulated infusion period was 0.7 mg for 3h and 2.0 mg for 24 h, which was less than 2.9% of the DEHP extracted by Taxol. These results confirmed that there is negligible risk of DEHP exposure from diluted PLPM i.v. infusion using PVC infusion bags and PVC administration sets.     

Polylactide-Based Paclitaxel-Loaded Nanoparticles Fabricated by Dispersion Polymerization: Characterization,Evaluation in Cancer Cell Lines,and Preliminary Biodistribution Studies

The macromonomer method was used to prepare cross-linked, paclitaxel-loaded polylactide (PLA)–polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton nuclear magnetic resonance and Fourier transform infrared spectra confirm the synthesis of PLA macromonomer and cross-linking agent. The formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared with medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared with paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within 1 h. Preliminary biodistribution studies also show nanoparticle accumulation in tumor xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2546–2555, 2014