1. Liquisolid system of paclitaxel using modified polysaccharides: In vitro cytotoxicity, apoptosis study, cell cycle analysis, in vitro mitochondrial membrane potential assessment, and pharmacokinetics.
期刊:International journal of biological macromolecules
日期:2019-06-25
DOI :10.1016/j.ijbiomac.2019.06.188
The research was aimed to develop a liquisolid formulation of paclitaxel using novel, highly porous liquisolid carriers (modified polysaccharides) to enhance bioavailability of orally administered paclitaxel. Modified polysaccharides namely co-grinded treated guar gum (C-TGG), co-grinded treated tamarind kernel powder (C-TTKP) and co-grinded treated locust bean gum (C-TLBG) were developed by sequentially subjecting the corresponding polysaccharides to wetting, drying and co-grinding with mannitol (1:1). A total of 12 liquisolid systems of paclitaxel (LSP-1 to LSP-12) were formulated using non-volatile solvent (polysorbate 80/Solutol HS 15®), carrier material (C-TGG/C-TTKP/C-TLBG), and Aerosil® 200 as coating material, and evaluated for pre-compression parameters. The liquisolid systems were directly compressed to produce liquisolid tablets (LTP-1 to LTP-12) and assessed for post compression parameters, cytotoxic/cellular analysis and pharmacokinetics. The modified polysaccharides exhibited narrow symmetrical particle size distribution, high liquid absorption potential, diminutive swelling index, favorable in vitro biodegradability and compression amenability. Among the directly compressed liquisolid tabs, LTP-10 exhibited highest CDR of 98.70 ± 2.68% and permeability of 61.59%. The IC of <20 mmol/L indicated remarkable cytotoxic potential on human gastro-enteric tumor cancerous cell lines (NCI-N87). Additionally, LTP-10 exhibited significantly high values for cell death 37.92 and 54.17% (P < 0.01) in early and late apoptosis and mitochondrial membrane potential regain (33%) in comparison to paclitaxel (P < 0.05) and 5-fluorouracil (P < 0.01). Pharmacokinetics revealed C of 536.48 ± 4.63 μg/L at 1.64 ± 0.44 h for LTP-10 indicating enhancement in bioavailability (5.43 fold) of paclitaxel on oral administration.
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4区Q2影响因子: 3
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2. Recent Development of Copolymeric Nano-Drug Delivery System for Paclitaxel.
2. 紫杉醇共聚纳米药物递送系统的最新发展。
作者:Chen Shiyu , Song Zhimei , Feng Runliang
期刊:Anti-cancer agents in medicinal chemistry
日期:2020-01-01
DOI :10.2174/1871520620666200719001038
BACKGROUND:Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high cytotoxicity to normal tissue and worse pharmacokinetic property limit its clinical application. OBJECTIVE:To review the recent progress on the PTX delivery systems. METHODS:In recent years, the copolymeric nano-drug delivery systems for PTX are broadly studied. It mainly includes micelles, nanoparticles, liposomes, complexes, prodrugs and hydrogels, etc. They were developed or further modified with target molecules to investigate the release behavior, targeting to tissues, pharmacokinetic property, anticancer activities and bio-safety of PTX. In the review, we will describe and discuss the recent progress on the nano-drug delivery system for PTX since 2011. RESULTS:The water-solubility, selective delivery to cancers, tissue toxicity, controlled release and pharmacokinetic property of PTX are improved by its encapsulation into the nano-drug delivery systems. In addition, its activities against cancer are also comparable or high when compared with the commercial formulation. CONCLUSION:Encapsulating PTX into nano-drug carriers should be helpful to reduce its toxicity to human, keeping or enhancing its activity and improving its pharmacokinetic property.
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1区Q1影响因子: 15.6
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3. Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin.
3. 1,18-十八碳二酸-紫杉醇与人血清白蛋白复合的抗肿瘤活性。
作者:Callmann Cassandra E , LeGuyader Clare L M , Burton Spencer T , Thompson Matthew P , Hennis Robert , Barback Christopher , Henriksen Niel M , Chan Warren C , Jaremko Matt J , Yang Jin , Garcia Arnold , Burkart Michael D , Gilson Michael K , Momper Jeremiah D , Bertin Paul A , Gianneschi Nathan C
期刊:Journal of the American Chemical Society
日期:2019-07-18
DOI :10.1021/jacs.9b04272
We describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX () prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).
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1区Q1影响因子: 6.9
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4. Cellular Interactome Dynamics during Paclitaxel Treatment.
4. 紫杉醇治疗期间的细胞相互作用动力学。
期刊:Cell reports
日期:2019-11-19
DOI :10.1016/j.celrep.2019.10.063
Cell-cycle inhibitors, including paclitaxel, are among the most widely used and effective cancer therapies. However, several challenges limit the success of paclitaxel, including drug resistance and toxic side effects. Paclitaxel is thought to act primarily by stabilizing microtubules, locking cells in a mitotic state. However, the resulting cytotoxicity and tumor shrinkage rates observed cannot be fully explained by this mechanism alone. Here we apply quantitative chemical cross-linking with mass spectrometry analysis to paclitaxel-treated cells. Our results provide large-scale measurements of relative protein levels and, perhaps more importantly, changes to protein conformations and interactions that occur upon paclitaxel treatment. Drug concentration-dependent changes are revealed in known drug targets including tubulins, as well as many other proteins and protein complexes involved in apoptotic signaling and cellular homeostasis. As such, this study provides insight into systems-level changes to protein structures and interactions that occur with paclitaxel treatment.
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2区Q1影响因子: 6.5
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5. Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells.
PURPOSE:The aim of this study was to show enhanced anticancer activity of paclitaxel (Ptx) incorporated into solid lipid nanoparticles (SLNs) and reveal reversal of multidrug resistance (MDR) by SLNs mediated by increased uptake through different entry mechanisms from that in drug-sensitive cells. METHODS:Anticancer activity of Ptx incorporated in SLNs (Ptx-SLNs) was measured in the drug-sensitive human breast cancer cell line MCF7 and its MDR variant MCF7/ADR. Cellular uptake of cargo molecules in SLNs was compared using Ptx-SLNs and rhodamine 123-loaded SLNs (Rho-SLNs) in both cell lines. In addition, endocytic uptake was evaluated using genistein (Gen) and chlorpromazine (Cpz) as inhibitors of clathrin- and caveola-mediated endocytosis, respectively. RESULTS:Ptx-SLNs showed remarkably enhanced anticancer activity in MCF7/ADR compared to Ptx delivered in dimethyl sulfoxide (DMSO) and Cremophor EL-based vehicles. SLNs significantly increased intracellular uptake of Ptx and Rho in MCF7/ADR. Western blotting demonstrated that clathrin was expressed in both cell lines, while caveolin 1 was expressed only in MCF7/ADR. In MCF7/ADR, uptake of Ptx-SLNs and Rho-SLNs was reduced by Gen, while there was no change by Cpz, suggesting the involvement of caveola-mediated endocytosis. Size reduction of Rho-SLNs through high-pressure homogenization (Rho-SLNs) appeared to cause a shift of the endocytosis mechanism from a clathrin-independent pathway to a clathrin-dependent one. In contrast to MCF7/ADR, the uptake of SLNs into MCF7 was not changed by Gen or Cpz, suggesting involvement of clathrin- and caveola-independent mechanism for the entry of SLNs. CONCLUSION:MDR was reversed by incorporating drug into SLNs, and the reversal was mediated by increased uptake of SLNs evading efflux pumps in MDR cells. The enhanced uptake could also be due to the use of different endocytosis pathways by SLNs in MDR cells from drug-sensitive cancer cells.
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2区Q1影响因子: 5.5
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6. Transgelin 2 Promotes Paclitaxel Resistance, Migration, and Invasion of Breast Cancer by Directly Interacting with PTEN and Activating PI3K/Akt/GSK-3β Pathway.
作者:Liu Leichao , Meng Ti , Zheng Xiaowei , Liu Yang , Hao Ruifang , Yan Yan , Chen Siying , You Haisheng , Xing Jianfeng , Dong Yalin
期刊:Molecular cancer therapeutics
日期:2019-09-05
DOI :10.1158/1535-7163.MCT-19-0261
MDR and tumor migration and invasion are still the main obstacles to effective breast cancer chemotherapies. Transgelin 2 has recently been shown to induce drug resistance, tumor migration, and invasion. The aim of this study was to determine the biological functions of Transgelin 2 and the mechanism underlying how Transgelin 2 induces paclitaxel (PTX) resistance and the migration and invasion of breast cancer. We detected that the protein level of Transgelin 2 was significantly upregulated in breast cancer tissues compared with adjacent nontumor tissues. A bioinformatics analysis indicated that Transgelin 2 was significantly related to clinicopathologic parameters and patient prognosis. Overexpression of Transgelin 2 enhanced the migration and invasion of human breast cancer cells and decreased the sensitivity of breast cancer cells to paclitaxel. Meanwhile, the tumorigenesis and metastasis of breast cancer cells were also enhanced by Transgelin 2 overexpression Moreover, Transgelin 2 overexpression activated the PI3K/Akt/GSK-3β pathway by increasing the phosphorylation levels of Akt and GSK-3β and decreasing the expression of PTEN. We also found that Transgelin 2 could directly interact with PTEN and was located upstream of PTEN. Furthermore, the PI3K/Akt pathway inhibitor MK-2206 reversed the resistance to paclitaxel and inhibited the migration and invasion of breast cancer cells. These findings indicate that Transgelin 2 promotes paclitaxel resistance and the migration and invasion of breast cancer by directly interacting with PTEN and activating the PI3K/Akt/GSK-3β pathway. Transgelin 2 may therefore be useful as a novel biomarker and therapeutic target for breast cancer.
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1区Q1影响因子: 9.1
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7. Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy.
7. 通过增加非整倍性来提高乳腺癌对紫杉醇的敏感性。
作者:Rodrigues-Ferreira Sylvie , Nehlig Anne , Moindjie Hadia , Monchecourt Clarisse , Seiler Cynthia , Marangoni Elisabetta , Chateau-Joubert Sophie , Dujaric Marie-Eglantine , Servant Nicolas , Asselain Bernard , de Cremoux Patricia , Lacroix-Triki Magali , Arnedos Monica , Pierga Jean-Yves , André Fabrice , Nahmias Clara
期刊:Proceedings of the National Academy of Sciences of the United States of America
日期:2019-11-04
DOI :10.1073/pnas.1910824116
Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.
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1区Q1影响因子: 16.6
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8. Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner.
8. 紫杉醇通过在TLR4依赖性地重新编程肿瘤相关巨噬细胞向M1档案降低肿瘤的生长。
作者:Wanderley Carlos W , Colón David F , Luiz João Paulo M , Oliveira Francisco F , Viacava Paula R , Leite Caio A , Pereira Janaina A , Silva Camila M , Silva Cassia R , Silva Rangel L , Speck-Hernandez Cesar A , Mota José M , Alves-Filho José C , Lima-Junior Roberto C , Cunha Thiago M , Cunha Fernando Q
期刊:Cancer research
日期:2018-08-13
DOI :10.1158/0008-5472.CAN-17-3480
Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. , paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre/TLR4), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment. This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype. http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg .
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1区Q1影响因子: 9.1
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9. AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.
9. 控制氧化还原体内平衡气道高反应性和形状BRCA1-associated乳腺癌的肿瘤微环境。
期刊:Proceedings of the National Academy of Sciences of the United States of America
日期:2019-02-07
DOI :10.1073/pnas.1815126116
Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.
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1区Q1影响因子: 9.1
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10. Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy.
作者:Luo Cong , Sun Jin , Liu Dan , Sun Bingjun , Miao Lei , Musetti Sara , Li Jing , Han Xiaopeng , Du Yuqian , Li Lin , Huang Leaf , He Zhonggui
期刊:Nano letters
日期:2016-08-08
DOI :10.1021/acs.nanolett.6b01632
Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.
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1区Q1影响因子: 9.7
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11. Tannic acid-inspired paclitaxel nanoparticles for enhanced anticancer effects in breast cancer cells.
11. 单宁酸启发紫杉醇纳米颗粒用于增强的乳腺癌细胞中的抗癌作用。
期刊:Journal of colloid and interface science
日期:2018-09-22
DOI :10.1016/j.jcis.2018.09.072
Paclitaxel (PTX) is a gold standard chemotherapeutic agent for breast, ovarian, pancreatic and non-small cell lung carcinoma. However, in clinical use PTX can have adverse side effects or inadequate pharmacodynamic parameters, limiting its use. Nanotechnology is often employed to reduce the therapeutic dosage required for effective therapy, while also minimizing the systemic side effects of chemotherapy drugs. However, there is no nanoformulation of paclitaxel with chemosensitization motifs built in. With this objective, we screened eleven pharmaceutical excipients to develop an alternative paclitaxel nanoformulation using a self-assembly method. Based on the screening results, we observed tannic acid possesses unique properties to produce a paclitaxel nanoparticle formulation, i.e., tannic acid-paclitaxel nanoparticles. This stable TAP nanoformulation, referred to as TAP nanoparticles (TAP NPs), showed a spherical shape of ~ 102 nm and negative zeta potential of ~ -8.85. The presence of PTX in TAP NPs was confirmed by Fourier Transform Infrared (FTIR) spectra, thermogravimetric analyzer (TGA), and X-ray diffraction (XRD). Encapsulation efficiency of PTX in TAP NPs was determined to be ≥96%. Intracellular drug uptake of plain drug PTX on breast cancer cells (MDA-MB-231) shows more or less constant drug levels in 2 to 6 h, suggesting drug efflux by the P-gp transporters, over TAP NPs, in which PTX uptake was more than 95.52 ± 11.01% in 6 h, as analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Various biological assays such as proliferation, clonogenic formation, invasion, and migration confirm superior anticancer effects of TAP NPs over plain PTX at all tested concentrations. P-gp expression, beta-tubulin stabilization, Western blot, and microarray analysis further confirm the improved therapeutic potential of TAP NPs. These results suggest that the TAP nanoformulation provides an important reference for developing a therapeutic nanoformulation affording pronounced, enhanced effects in breast cancer therapy.