Comparison in purity and antitumor effect of brand and generic paclitaxel against human ovarian cancer cells by an in vitro experimental model

Context: The purity and the therapeutic effectiveness of the generic paclitaxel have not yet been examined and compared to the original brand form. Objective: This study aimed to compare the in vitro purity and biological effects of original brand form (Taxol) and a generic drug of paclitaxel. Materials and Methods: Purity was determined by high-performance liquid chromatography analysis, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, cell proliferation by clonogenic assay, morphology by Liu's staining, and cell cycle distribution by DNA histogram. Results: Taxol and generic paclitaxel shared similar high-performance liquid chromatography profiles with a major peak at the same retention time and ultraviolet spectrum. Generic paclitaxel inhibited the cell viability to an extent greater than Taxol. By assessing the IC₅₀, generic paclitaxel also exhibited a greater inhibitory activity on clonogenicity of human ovarian adenocarcinoma SKOV-3 cells. Although both generic paclitaxel and Taxol arrested SKOV-3 and ES-2 cells at G2/M phase with concurrent development of hypoploid and polyploid cells, Taxol treatment exhibited markedly less extent of these changes. Observation of cellular morphology revealed a greater amount of mitotic catastrophe-like and apoptotic cells in generic paclitaxel-treated cells than Taxol-treated cells. Discussion and Conclusion: The results suggest that generic paclitaxel may possess a greater cell death inducing capacity and clonogenicity inhibitory activity against ovarian cancer cells than the original brand Taxol of the same purity. We conclude that this experimental model for assessing the difference between generic and brand name drugs might be considered as a reference while determining their interchangeability and could be easily established in a hospital-based laboratory.     

Preparation of injectable paclitaxel sustained release microspheres by spray drying for inhibition of glioma in vitro

The major aim of this work was to prepare injectable paclitaxel‐loaded poly(D ,L ‐lactide) microspheres for the inhibition of brain glioma. Paclitaxel‐loaded PLA microspheres were prepared by spray drying method employing ethyl acetate as solvent. And the microspheres were characterized by scanning electron microscopy (SEM) for the morphology and differential scanning calorimetry for thermal analysis. The encapsulation efficiency (EE) and in vitro release profiles of paclitaxel‐loaded microspheres were determined by using ultraviolet spectrophotometer. The results showed that the microspheres possess a narrow size distribution with the average diameter of 4.6 μm. The surface of the microspheres was smooth, and the paclitaxel dispersed in microspheres in amorphous state. The solvent residue was 0.03%, and the EE reaches ～ 90%. The microspheres exhibited a sustained release behavior, and the release period last for at least three months, depending on the EE of the microspheres. The γ irradiation sterilization had little effect on the EE and drug release in vitro. Compared with the commercial formulation, the sustained release microsphere showed a stronger inhibition on the tumor cells, suggesting the potential application of long‐term delivery of paclitaxel‐loaded PLA microspheres in clinic tumor therapy. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug‐based nanoplatform self‐assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox‐responsive prodrug‐nanosystem demonstrates multiple therapeutic advantages, including one‐step facile fabrication, high drug‐loading efficiency (56%, w/w), on‐demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug‐nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.     

A Novel Self‐Assembled Mitochondria‐Targeting Protein Nanoparticle Acting as Theranostic Platform for Cancer

Self‐assembled protein nanoparticles have attracted much attention in biomedicine because of their biocompatibility and biodegradability. Protein nanoparticles have become widely utilized as diagnostic or therapeutic agents for various cancers. However, there are no reports that protein nanoparticles can specifically target mitochondria. This targeting is desirable, since mitochondria are critical in the development of cancer cells. In this study, the discovery of a novel self‐assembled metal protein nanoparticle, designated GST‐MT‐3, is reported, which targets the mitochondria of cancer cells within 30 min in vitro and rapidly accumulates in tumors within 1 h in vivo. The nanoparticles chelate cobalt ions [GST‐MT‐3(Co²⁺)], which induces reactive oxygen species (ROS) production and reduces the mitochondrial membrane potential. These effects lead to antitumor activity in vivo. GST‐MT‐3(Co²⁺) with covalently conjugated paclitaxel synergistically suppress tumors and prolong survival. Importantly, the effective dosage of paclitaxel is 50‐fold lower than that utilized in standard chemotherapy (0.2 vs 10 mg kg^?1). To the best of the authors' knowledge, GST‐MT‐3 is the first reported protein nanoparticle that targets mitochondria. It has the potential to be an excellent platform for combination therapies.     

Developing combination of artesunate with paclitaxel loaded into poly-d,l-lactic-co-glycolic acid nanoparticle for systemic delivery to exhibit synergic chemotherapeutic response

Objectives: Paclitaxel (PTX) has been indicated for the treatment of a variety of solid tumors, whereas artesunate (ART) has been reported to have the potential for use in combination chemotherapy. In this study, the combination of ART and PTX was prepared in nanoparticle to induce the synergic effect and improve therapeutic efficiency in treatment of breast cancer.

Methods: Dual anticancer agents (PTX and ART) were loaded into Poly-D,L-lactic-co-glycolic acid (PLGA) nanoparticle (NP) by solvent evaporation technique from oil-in-water emulsion, stabilized with Tween 80. Physicochemical properties of obtained nanoparticles (PTX-ART-NPs) were characterized including particle size (Z), polydispersity index (PDI), zeta potentials (ZP), encapsulation efficiency (EE), and in-vitro drug release. Combination index (CI) was calculated to determine the synergic effect of the combination and select the best ratio of ART and PTX. The final NPs analyzed intracellular uptake, cytotoxicity assay, and apoptosis study.

Results: The final NP had a small size (around 120?nm) with a narrow size distribution (PDI <0.3). EE values for each drug were 87.8?±?1.1% and 99.5?±?0.1% for ART and PTX, respectively, and drugs were released from NPs in a controlled release pattern. All combinations of PTX and ART had CI values under 1, which confirmed the synergic effects. Meanwhile, NP preparation increased cytotoxicity on three breast cancer cell-lines comparable to free drugs.

Conclusions: Combination of ART- and PTX-loaded PLGA NP showed promising results for anticancer therapy, especially for breast cancer treatment.     

伪三元相图在紫杉醇自乳化制剂筛选中的应用

分别以油酸正丁酯、十四酸异丙酯为油相，吐温85、Cremophor-EL为表面活性剂，无水乙醇、异丙醇、1，2-丙二醇、正丁醇为助表面活性剂，在37℃水浴中，用水滴定上述三组分不同配比的混合物，绘制伪三元相图，并对自乳化系统进行研究。结果表明十四酸异丙酯为油相、聚氧乙烯蓖麻油为表面活性剂、正丁醇为助表面活性剂，SA／CoSA=4：1紫杉醇有较好的稳定的乳化体系。     

Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties

The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties.     

与医药保健品有关的几种林产化学品研究现状

综述了植物甾醇、紫杉醇、桦木酸、桧木醇等几种与医药保健品有关的林产化学品的研究开发现状。     

从红豆杉中提取紫杉醇的工艺研究

紫杉醇(Taxol)是从红豆杉树皮中分离得到的一种二萜化合物,具有独特疗效的抗癌物,现已被多个国家批准应用于临床治疗卵巢癌和乳腺癌等疾病。由于红豆杉中的紫杉醇含量非常低(仅为0.010%~0.013%),而且大量结构类似的紫杉烷类物质存在,使得紫杉醇的分离纯化非常困难。本文通过对比5种不同提取方法 (液液萃取、固相萃取、硅胶层析、氧化铝层析、薄层层析),提出一种新的以氧化铝层析结合固相萃取工艺,具有紫杉醇高回收率的特点。