查找使用阿拉丁产品的科研文献

Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: Preparation, in vitro and in vivo evaluation

Fatima Zohra Dahmani,Hui Yang,Jianping Zhou,Jing Yao,Ting Zhang,Qiang Zhang

In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92   ±   2.08% and 25.82   ±   1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140   nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells ( p   <   0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C max level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system .

Paclitaxel-loaded redox-sensitive nanoparticles based on hyaluronic acid-vitamin E succinate conjugates for improved lung cancer treatment

Yu Song,Han Cai,Tingjie Yin,Meirong Huo,Ping Ma,Jianping Zhou,Wenfang Lai

Simultaneous determination of paclitaxel and dasatinib in rat plasma and pharmacokinetic study on liquid chromatography-tandem mass spectrometry

Yuan Liang,Jun Yin,Yu Yang,Ruiyan Huang,Penghui Hu,Chang Shu

For most cancers, drugs in combination with chemotherapy is a promising way. Dasatinib in combination with paclitaxel can potentially be used to overcome triple-negative breast cancer. In this work, we established an liquid chromatography-tandem mass spectrometry method for the simultaneous determination of dasatinib and paclitaxel. T ert -Butyl methyl ether was used to extract paclitaxel, dasatinib, and docetaxel (Internal standard). The study used multiple reaction monitoring mode with electrospray ionization . Monitoring ion pairs for paclitaxel and dasatinib was m/z 876.2→308.2 and m/z 488.3→401.1, respectively. The chromatographic separation was performed on a Hedera ODS-2 column (150 × 2.1 mm, 5 μm; Hanbon Science and Technology, China) maintained at 40°C. The mobile phase was acetonitrile containing 0.3% formic acid (B) and water (A). The gradient elution procedure was used: 0–1 min, 70% B; 1.1–4 min, 90% B; 4.1–7 min, 70% B. The results satisfied the requirements of biological sample determination. The liquid chromatography-tandem mass spectrometry method was successfully applied to the pharmacokinetic study of rats. The rats were simultaneously injected with dasatinib and paclitaxel by tail vein. What is more, this presented method could provide technical support for the clinical combination of these two drugs.

Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer

Xidong Tian,Hriday Bera,Xiong Guo,Ruizhao Xu,Jin Sun,Zhonggui He,Dongmei Cun,Mingshi Yang

Chemotherapeutics often failed to elicit optimal antitumor responses against lung cancer due to their limited exposure and accumulation in tumors. To achieve an effective therapeutic outcome of paclitaxel (PTX) against metastatic lung cancer with attenuated systemic and local toxicities, pulmonary delivery of redox-responsive PTX dimeric nanoparticles (NPs) was introduced. PTX dimers conjugated through variable lengths of diacid linkers containing disulfide bonds (−SS−) (i.e., α–PTX–SS–PTX, β–PTX–SS–PTX, and γ–PTX–SS–PTX) were initially synthesized and were subsequently self-assembled into uniform nanosized particles in the presence of vitamin E TPGS with high drug loading capacity (DE > 97%). Among various redox-sensitive scaffolds, β–PTX–SS–PTX NPs exhibited an optimal reactive oxygen species/glutathione-responsive drug release behavior, causing a lower local toxicity profile of PTX in the lungs. The scaffolds also demonstrated excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. Further, they depicted an improved lung retention as compared to the control nanovesicles (β–PTX–CC–PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered β–PTX–SS–PTX NPs exhibited a stronger anticancer potential with reduced systemic toxicity as compared to Taxol intravenous injection containing an equivalent PTX dose. The PTX dimeric NPs could also dramatically reduce the local toxicity relative to Taxol following their pulmonary delivery. Thus, this study presents redox-responsive PTX dimeric NPs as a promising nanomedicine for improved therapeutic efficacy against metastatic lung cancer.

Tumor-penetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes

Tinghui Yin,Ping Wang,Jingguo Li,Yiru Wang,Bowen Zheng,Rongqin Zheng,Du Cheng,Xintao Shuai

Drug resistance is a big problem in systemic chemotherapy of hepatocellular carcinoma (HCC), and nanomedicines loaded with both chemotherapeutic agents (e.g. paclitaxel, PTX) and siRNA's targeting antiapoptosis genes (e.g. BCL-2) possess the advantages to simultaneously overcome the efflux pump-mediated drug resistance and antiapoptosis-related drug resistance. However, tumor-penetrating drug delivery with this type of nanomedicines is extremely difficult due to their relatively big size compared to the single drug-loaded nanomedicines. Aiming at address this problem, US-responsive nanobubbles encapsulating both anti-cancer drug paclitaxel (PTX) and siRNA (PTX–NBs/siRNA) for HCC treatment were developed by hetero-assembly of polymeric micelles and liposomes in the present study. Utilizing an external low-frequency US force imposed to the tumor site, effective tumor-penetrating codelivery of siRNA and PTX was achieved via tail vein injection of PTX–NBs/siRNA into nude mice bearing human HepG2 xerografts. Consequently, the PTX treatment-inducible antiapoptosis in HepG2 cells was effectively suppressed by the codelivered siRNA targeting an antiapoptosis gene (BCL-2 siRNA) during chemotherapy. Owing to the synergistic anti-cancer effect of two therapeutic agents, tumor growth was completely inhibited using low-dose PTX in animal study. Our results highlight the great potential of this type of US-responsive hetero-assemblies carrying both anti-cancer drug and siRNA as an effective nanomedicinal system for HCC therapy.

Delivery of paclitaxel by carboxymethyl chitosan-functionalized dendritic fibrous nano-silica: Fabrication, characterization, controlled release performance and pharmacokinetics

Yameng Zhu,Mengxuan Wu,Xinxin Miao,Boyao Wang,Jun He,Xilong Qiu

In this study, carboxymethyl chitosan (CMCS) with excellent biocompatibility was used as the “gatekeeper” to design and fabricate a pH-responsive drug delivery system (CMCS-DFNS) as paclitaxel carriers. Characterization results showed that CMCS-DFNS was successfully prepared and the nanocarriers displayed excellent drug loading efficiency of 19.8 %, and the results of the adsorption mechanism revealed that the adsorption of PTX was consistent with the Freundlich isotherm and pseudo-second-order kinetic model. Furthermore, the pH-responsive controlled release behavior at different pH (pH = 7.4, 6.5, and 5.0) was evaluated, and the results demonstrated that the cumulative release at pH 5.0 was 58.8 %, which was 2.7 times higher than that at pH 7.4, suggesting that the carrier exhibited a good pH sensitivity. The results of in vitro cellular experiments further indicated that CMCS-DFNS significantly improved the drug uptake efficiency in breast cancer MCF-7 cells. Importantly, the results of in vivo and cellular pharmacokinetic revealed that CMCS-DFNS can improve the circulation time and enhance the relative bioavailability of paclitaxel. Therefore, the fabricated pH-responsive drug delivery system has potential applications in the delivery of anti-tumor drugs, and provides a new delivery pathway for other compounds with low bioavailability.

AIE-active polymeric micelles based on modified chitosan for bioimaging-guided targeted delivery and controlled release of paclitaxel

Haohui Shi,Na Liang,Jiyang Liu,Siyi Li,Xianfeng Gong,Pengfei Yan,Shaoping Sun

In this study, a novel polymer based on aggregation-induced emission (AIE) fluorogen , biotin and disulfide bonds modified chitosan (TPE-bi(SS-CS-Bio)) was designed and synthesized. The polymer could self-assemble into micelles in aqueous media and encapsulate paclitaxel (PTX) into the core with high drug loading. Fluorescence study indicated that the micelles exhibited excellent AIE feature with intense blue fluorescence emitted. In vitro drug release study indicated that the micelles could disassemble rapidly in the presence of high level of glutathione . The modification by biotin could enhance the cellular uptake of the micelles. The drug-loaded micelles possessed remarkable cytotoxicity against MCF-7 cells, and their distribution in the cells could be traced due to the excellent AIE feature. In vivo antitumor efficacy study demonstrated the superior antitumor activity of the PTX-loaded TPE-bi(SS-CS-Bio) micelles. These results indicated that TPE-bi(SS-CS-Bio) has the ability of biological imaging and can be used as a potential carrier for PTX.

A novel luminescence sensor based on porous molecularly imprinted polymer-ZnS quantum dots for selective recognition of paclitaxel

Jianwei Bai,Longqi Chen,Yawei Zhu,Xiqing Wang,Xiaodan Wu,Yujie Fu

In this study, a molecularly imprinted fluorescent sensor was constructed successfully for selective recognition of PTX by introducing methacryl polyhedral oligomeric silsesquioxane (M-POSS) to add porous structure. The obtained fluorescent sensors were prepared by grafting MIP shell on the surface of silane functionalized Mn: ZnS Quantum Dots (QDs) by a free radical polymerization process. The binding properties and selectivity of the MIP-QDs were demonstrated by adsorption capacity obtained based on fluorescence spectroscopy. These MIP-based fluorescent sensors showed good dispersibility and high stability in solution. Under the optimized conditions, the binding experiment demonstrated the fluorescent intensity of the porous fluorescent sensors was obviously decreased with the increase of PTX in the concentration range 0.1–2.0 μM and the detection limit was 0.043 μM. These results demonstrated a new type of molecularly imprinted fluorescent porous nanoparticles with potential applications for selective recognition of PTX biological samples.

Selective separation and inexpensive purification of paclitaxel based on molecularly imprinted polymers modified with ternary deep eutectic solvents

Ling Tan,Lian-Di Zhou,Zhuang-Fei Jiang,Rong-Rong Ma,Jia-Yuan He,Zhi-Ning Xia,Qi-Hui Zhang,Chong-Zhi Wang,Chun-Su Yuan

Paclitaxel (PTX) is a powerful anticancer natural product, with its separation and purification having been widely studied. In this work, new molecular imprinted polymers (MIPs) using deep eutectic solvents (DESs) with different molar ratios were prepared as functional monomers. These were then used as adsorbents in solid phase extraction (SPE) for the separation of PTX from its structural analogs. The polymers were characterized by energy disperive X-rays (EDX), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and fourier transform infrared spectroscopy (FT-IR). The results suggested that the formative regular DES-MIPs had an even pore-size distribution and a large specific surface area. The dynamic adsorption and static adsorption showed that the DES-MIPs had excellent adsorption performance, with a maximum adsorption capacity and optimum adsorption time of 87.08 mg/g and 180 min, respectively. The selective adsorption experiments showed that the material had outstanding selectivity, and the maximum selectivity factor was 6.20. For stability, after six consecutive adsorption and desorption cycles, the DES-MIPs maintained the perfect stability and reusability. Furthermore, the fabricated SPE column was successfully utilized for extracting and eluting PTX. This study provides a reliable protocol for the separation and purification PTX from its structural analogs and the DES-MIPs materials have excellent potential application value in pharmaceutical industry.

End-Chain Fluorescent Highly Branched Poly(l-lactide)s: Synthesis, Architecture-Dependence, and Fluorescent Visible Paclitaxel-Loaded Microspheres

Yufei Bian,Xuefei Leng,Zhiyong Wei,Zefeng Wang,Zhu Tu,Yanshai Wang,Yang Li

A facile method in combination of “grafting from” and “end-functionalization” was developed for the synthesis of fluorescent highly branched poly(l-lactide)s (PLLA-COU) via ring opening polymerization (ROP) and esterification end-capping. These resulting PLLA-COU with four kinds of architectures, including linear, star, linear-comb, and star-comb structures, were subjected to characterization and application as fluorescent visible paclitaxel-loaded microspheres. The mutual effects of architecture and end-groups on thermal and fluorescence properties, enzymatic degradation, and drug release behaviors were focused. Contrast to linear and star PLLA-COU, two comb-shaped analogues demonstrated higher fluorescence quantum yield, faster drug release, and lower enzymatic degradation rate. All the fluorescent microspheres could maintain fluorescence traceability. The fluorescent PLLA-COU displayed negligible toxicity and good biocompatibility. This work highlights that the fluorescent highly branched poly(l-lactide)s are properties-tailored and used as fluorescent visible drug delivery systems (DDS) for potential theranostic applications.

Tenacigenin B ester derivatives from Marsdenia tenacissima actively inhibited CYP3A4 and enhanced in vivo antitumor activity of paclitaxel

Bin Xie,Yuan-Yuan Lu,Zhuo-Hui Luo,Zhao Qu,Chun-Ge Zheng,Xin-An Huang,Hong-Yan Zhou,Ying-Jie Hu,Xiao-Ling Shen

Ethnopharmacological relevance Marsdenia tenacissima (Roxb.) Wight et Arn is a vine distributed in southwest area of China and used in folk medicine for treatment of tumors. Recent decades of studies on this plant reveal its synergistic effects with certain anticancer drugs in cancer therapy. In our previous study, an extract ETA which contains total aglycones made from M. tenacissima significantly enhanced antitumor activity of paclitaxel in tumor-bearing mice. However, the effective constituents in ETA and the underlying mechanisms remain unclear. Aim of the study Reveal the active components in ETA as well as the molecular mechanism in enhancing antitumor efficacy of paclitaxel. Material and methods Main constituents in ETA were purified by chemical methods. Effects of the purified constituents on metabolic activity of CYP450 enzymes were evaluated in human liver microsomes. Ability of the constituents to enhance antitumor activity of paclitaxel were investigated in nude mice bearing HeLa tumors. Pharmacokinetic study was performed in SD rats . Molecular docking was carried out for investigation of drug-protein interactions. Results Three main C 21 steroidal aglycones, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B ( MT1 ), 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B ( MT2 ) and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B ( MT3 ), together with tenacigenin B ( MT4 ) was prepared from ETA. Among them, MT1 , MT2 and MT3 strongly inhibit the metabolic activity of CYP3A4 . MT2 also showed inhibitory effects on CYP2C8 , CYP2B6 and CYP2C19 . In HeLa tumor xenografts, MT1 , MT2 and MT3 (30 mg/kg) did not affect tumor growth themselves, but significantly enhanced paclitaxel-induced growth inhibition. In addition, coadministration of MT2 with paclitaxel resulted in significant reduction of liver CYP2C8. In pharmacokinetic study, MT2 significantly increased the blood concentration of paclitaxel with increased AUC value by 2.2–5.3 folds. Molecular docking analysis suggested hydrophobic interaction modes of tenacigenin B derivatives with CYP3A4, and also the essential roles of the C-11 and C-12 ester groups for effective interaction with CYP3A4. Conclusion Our study proves that, 11α- O -tigloyl-12β- O -acetyl-tenacigenin B, 11α- O -2-methylbutanoyl-12β- O -tigloyl-tenacigenin B and 11α- O -2-methylbutanoyl-12β- O -acetyl-tenacigenin B, which are the main constituents of ETA, are active inhibitors of CYP3A4 with potential to increase therapeutic efficacy of anticancer drugs that are substrates of CYP3A4. Tenacigenin B derivatives with C-11 and C-12 ester group substitutions, or at least a large part of them, are active components in ETA and M. tenacissima to enhance in vivo antitumor efficacies of paclitaxel.

Preparation and evaluation of carboxymethyl chitosan-rhein polymeric micelles with synergistic antitumor effect for oral delivery of paclitaxel

Xiaoying Wang,Yangli Guo,Liangzhen Qiu,Xiaying Wang,Tonglei Li,Lifeng Han,Huizhi Ouyang,Wei Xu,Kedan Chu

An amphiphilic carboxymethyl chitosan-rhein (CR) conjugate was prepared, characterized, and evaluated as a potential carrier material for oral delivery of paclitaxel (PTX). CR conjugate self-assembled in aqueous environment into CR polymeric micelles (CR PMs). The drug loading capacity and entrapment efficiency of PTX-loaded CR PMs were 35.24 ± 1.58% and 86.99 ± 12.26%, respectively. Pharmacokinetic results indicate that PTX-loaded CR PMs could significantly enhance the oral bioavailability of PTX. Confocal imaging of intestinal sections verified many of CR PMs were absorbed as whole through the intestinal membrane. The cytotoxicity assays in Caco-2 cells and in vivo antitumor efficacy showed that PTX-loaded CR PMs had a stronger antitumor efficacy. A synergistic antitumor effect between CR conjugate and PTX was proven in MCF-7 cells and antitumor efficacy studies. The investigation of CR conjugate developed in this study showed that CR PMs are promising for oral delivery of water-insoluble antitumor drugs.