聚己内酯-紫杉醇高分子前药的合成及性能研究

利用侧链带有羧基的官能化两亲性聚己内酯基共聚物Pluronic-b-poly(ε-caprolactone-co-6-carboxylic-ε- caprolactone) [Pluronic-b-P(CL-co-CCL), FC]为底物, 与紫杉醇(PTX)反应得到了一系列PTX的聚合物前药FCPTX. 通过核磁共振(¹H NMR)和高效液相色谱(HPLC)表征了聚合物前药结构并分析了前药中的PTX接枝率. 通过聚合物前药胶束进一步物理包载PTX, 得到载有PTX的聚合物前药胶束PTX/FCPTX, 其载药量和包封率随着前药FCPTX中的PTX接枝率的增加而提高. 利用荧光光谱(FS)、透射电镜(TEM)和粒径分析仪(DLS)表征了胶束的临界胶束浓度(CMC), 形态和粒径. 体外细胞评价表明, 聚合物前药FCPTX具有较高的胞内累积量和良好的血液相容性、能有效降低紫杉醇的药物毒性. 作为一种优秀的药物载体, 聚合物前药FCPTX在联合化疗领域有着较大的应用潜力.     

Properties of a Water-Soluble Paclitaxel Conjugate in Aqueous Solution and its Interaction with Serum Albumin

A summary of the most recent investigations of conformation and solution properties of a polymer conjugate of the anti-cancer drug paclitaxel is given. First results of spectroscopic studies of interaction with model proteins in the solid state and in solution are discussed.     

Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye‐Labeled Cargo

We report a new approach to monitor drug release from nanocarriers via a paclitaxel–methylene blue conjugate (PTX‐MB) with redox activity. This construct is in a photoacoustically silent reduced state inside poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (PTX‐MB@PLGA NPs). During release, PTX‐MB is spontaneously oxidized to produce a concentration‐dependent photoacoustic signal. An in vitro drug‐release study showed an initial burst release (25 %) between 0–24 h and a sustained release between 24–120 h with a cumulative release of 40.6 % and a 670‐fold increase in photoacoustic signal. An in vivo murine drug release showed a photoacoustic signal enhancement of up to 649 % after 10 hours. PTX‐MB@PLGA NPs showed an IC₅₀ of 78 μg mL^?1 and 44.7±4.8 % decrease of tumor burden in an orthotopic model of colon cancer via luciferase‐positive CT26 cells.     

Determination of paclitaxel in human and rat blood samples after administration of low dose paclitaxel by HPLC-UV detection

A simple and sensitive HPLC-UV method was developed for the determination of paclitaxel (TXL) in human and rat blood samples. 4-Hydroxybenzoic acid n-hexyl ester was used as an internal standard. TXL was extracted by a liquid-liquid extraction with tert-butylmethyl ether. The disturbing peaks in the case of serum sample were removed by pre-extraction with hexane. The separation of TXL was achieved within 25 min using an ODS column with 50% acetonitrile aqueous solution as a mobile phase at a flow rate of 1.0 mL/min. The eluent was monitored at 230 nm, and the resulted retention times of TXL and IS were 11.2 and 20.4 min. The detection limits of TXL for human plasma, serum and rat plasma samples at a signal-to-noise ratio of 3 were 10, 9.5 and 7.5 ng/mL, respectively. The proposed methods were applicable to the determination of TXL in human patients' plasma ranging from 15 to 27 ng/mL. Furthermore, monitoring of the time course of TXL after its single administration to rat could be demonstrated.     

Cu(II)-triggered release of paclitaxel from a supramolecular complex

The research on the stimuli-responsive property of biological or synthetic macromolecules in a wide range of scientific fields is a crucial subject for the achievements of the targeted drug release and the precise control of the functions of the supramolecules at a molecular level. We used an anthraquinone-functioned cyclodextrin (1) bridged by an aza-arm to solubilise paclitaxel (PTX) by forming a supramolecular complex (1/PTX). The possible inclusion mode was given based on the experimental results of ultraviolet–visible spectroscopy, Fourier transform infrared, X-ray diffraction, fluorescence spectra, nuclear magnetic resonance, transmission electron microscope, scanning electron microscope and dynamic light scattering characterisations. The controlled release of PTX can be achieved by adding Cu²⁺ to the solution. This study provides useful references in developing stimuli-responsive drug-carrying and drug-releasing materials.     

Methoxy poly(ethylene glycol)‐b‐poly(octadecanoic anhydride)‐b‐methoxy poly(ethylene glycol) amphiphilic triblock copolymer nanoparticles as delivery vehicles for paclitaxel

A series of amphiphilic triblock copolymers, methoxy poly(ethylene glycol)‐b‐poly(octadecanoic anhydride)‐b‐methoxy poly(ethylene glycol) (mPEG‐b‐POA‐b‐mPEG), were prepared via melt polycondensation of methoxy poly(ethylene glycol) (mPEG) and poly(octadecanoic anhydride) (POA). mPEG‐b‐POA‐b‐mPEG were characterized by FTIR, ¹H‐NMR, GPC, DSC, and XRD. Drug‐loaded mPEG‐b‐POA‐b‐mPEG nanoparticles (NPs) with spherical morphology and narrow size polydispersity index were prepared by nanoprecipitation technique with paclitaxel as the model drug. In vitro release behaviors of drug‐loaded NPs present that the biphasic process and the release mechanism of each phase are zero order drug releases. According to this study, mPEG‐b‐POA‐b‐mPEG NPs could serve as suitable delivery agents for paclitaxel and other hydrophobic drugs. Copyright © 2009 John Wiley & Sons, Ltd.     

FTIR结合HPLC研究不同施肥措施对曼地亚红豆杉紫杉醇含量的影响

本文通过高效液相色谱技术(HPLC)测定紫杉醇含量并与其药材的傅里叶红外光谱(FTIR)进行相关分析,研究不同肥料处理下曼地亚红豆杉药材紫杉醇含量相关的特征峰,并比较分析不同浓度复合肥对曼地亚红豆杉紫杉醇含量的影响。结果显示:不同处理间红外吸收光谱的峰形和峰位置均比较接近,但各谱峰的峰强有一定差异;为进一步研究与紫杉醇含量相关的吸收峰,对3369、1732、1616、1445、1373、1245、1147、1104、1056 cm-1等处的峰强与实测紫杉醇含量的关系进行多元对数相关回归分析,结果显示:在1445、1373、1317、1245、1147、1104、1056 cm-1等处附近的吸收强度与实际测定紫杉醇含量均密切相关,R(复相关系数)=0.98,P(概率)=0.002;两种方法均一致显示,在春梢抽梢前施少量的复合肥对紫杉醇含量积累有一定促进作用,但复合肥20 g/株时反而不利于紫杉醇的积累;四个物候期比较,以春梢抽梢前期施用复合肥对紫杉醇的累积影响最大。本研究结果对曼地亚红豆杉良种选育和规范化栽培技术研究均具有重要的指导意义。     

Taxanes Hybrid Nanovectors: From Design to Physico‐Chemical Evaluation of Docetaxel and Paclitaxel Gold (III)‐PEGylated Complex Nanocarriers

This study gives an original methodology to synthetize novel metallo‐drugs nanoparticles relevant for medicinal chemistry. Gold (HAuCl₄) are complexes with antitumor compounds (paclitaxel (PTX); docetaxel (DTX)) and dicarboxylic acid‐terminated polyethylene‐glycol (PEG) that plays a role of surfactants. The proposed synthesis is fast and leads to hybrid‐metal nanoparticles (AuNPs) in which drug solubility is improved. The interactions between drugs (DTX, PTX), PEG diacid (PEG), and Au (III) ions to form hybrid nanocarriers called DTX IN PEG‐AuNPs and PTX IN PEG‐AuNPs, are characterized by various analytical techniques (Raman and UV–vis spectroscopies) and transmission electron microscopy. The efficient drugs release under pH conditions is also achieved and characterized showing an amazing reversible equilibrium between Au (III)‐complex‐drug and Au⁰NPs. For therapeutic purposes, such AuNPs are then decorated with the anti‐EGFR polyclonal antibodies, which specifically recognizes the hERG1 channel aberrantly expressed on the membrane of human lung cancer cells. This paper, through an original chemical approach, will occupy an important position in the field of nanomedicine, and hope that novel perspectives will be proposed for the development of high drug‐loading nanomedicines.     

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly impairs their effectiveness, thereby decreasing overall survival (OS) and progression-free survival (PFS) rates, especially for the patients with metastatic, recurrent, and unresectable forms of the disease. Therefore, the development of novel effective drugs interfering with the microtubules’ dynamic state remains a big challenge in current oncology. We report here about the novel ethyl 2-amino-1-(furan-2-carboxamido)-5-(2-aryl/tert-butyl-2-oxoethylidene)-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates (EAPCs) exhibiting potent anti-cancer activities against the breast and lung cancer cell lines in vitro. This was due to their ability to inhibit tubulin polymerization and induce cell cycle arrest in M-phase. As an outcome, the EAPC-treated cancer cells exhibited a significant increase in apoptosis, which was evidenced by the expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin-V-positive cells. By using the in silico molecular modeling methods (e.g., induced-fit docking, binding metadynamics, and unbiased molecular dynamics), we found that EAPC-67 and -70 preferentially bind to the colchicine-binding site of tubulin. Lastly, we have shown that the EAPCs indicated above and colchicine utilizes a similar molecular mechanism to inhibit tubulin polymerization via targeting the T7 loop in the β-chain of tubulin, thereby preventing the conformational changes in the tubulin dimers required for their polymerization. Collectively, we identified the novel and potent TBAs that bind to the colchicine-binding site and disrupt the microtubule network. As a result of these events, the compounds induced a robust cell cycle arrest in M-phase and exhibited potent pro-apoptotic activities against the epithelial cancer cell lines in vitro.     

In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.