查找使用阿拉丁产品的科研文献

Preparation and evaluation of SN-38-loaded MMP-2-responsive polymer micelles

Xiuting He,Zhongcheng Cao,Nuannuan Li,Liuxiang Chu,Jiazhen Wang,Chunyan Zhang,Xiaoyan He,Xiaoyan Lu,Kaoxiang Sun,Qingguo Meng

7-Ethyl-10-hydroxycamptothecin (SN-38)-loaded polyethylene glycol-GPLGVRG-poly β-benzyl- l -aspartic acid (PEG-GPLGVRG-PBLA) self-assemblies were successfully prepared using a classical nanoprecipitation method to give an enzyme-responsive nano-drug delivery system. The PEG-GPLGVRG-PBLA/SN-38 self-assemblies were characterized by transmission electron microscopy , dynamic light scattering , and high-performance liquid chromatography. The encapsulation efficiency was 91.7 ± 1.21% and the drug loading was 16.6 ± 0.93%. The 12 h in vitro release of SN-38 from PEG-GPLGVRG-PBLA/SN-38 treated with MMP-2 was 73.2 ± 2.05%, which was significantly higher than that for the group without MMP-2, demonstrating the enzyme-responsiveness of the nano-drug delivery system. In addition, the cellular uptake and tumor accumulation of PEG-GPLGVRG-PBLA were better than those of PEG-PBLA, and the blank PEG-GPLGVRG-PBLA showed high biocompatibility . These findings indicate that the enzyme-responsive nano SN-38 delivery system could provide new opportunities in tumor therapy.

Chitosan nanomedicines-engineered bifidobacteria complexes for effective colorectal tumor-targeted delivery of SN-38

Danjun Wu,Kaili Fu,Wangyang Zhang,Yazhen Li,Yaning Ji,Yiwei Dai,Gensheng Yang

The clinical application of 7-ethyl hydroxy-camptothecin (SN-38) maintains challenges not only due to its poor solubility and stability but also the lack of effective carriers to actively deliver SN-38 to deep tumor sites. Although SN-38-based nanomedicines could improve the solubility and stability from different aspects, the tumor targeting efficiency remains very low. Leveraging the hypoxic taxis of bifidobacteria bifidum ( B. bifi ) to the deep tumor area, we report SN-38-based nanomedicines-engineered bifidobacterial complexes for effective tumor-targeted delivery. Firstly, SN-38 was covalently coupled with poly-L-glutamic acid (L-PGA) and obtained soluble polymeric prodrug L-PGA-SN38 to improve its solubility and stability. To prolong the drug release, L-PGA-SN38 was mildly complexed with chitosan to form nanomedicines, and nanomedicines engineered B. bifi were further elaborated via electrostatic interaction of the excess of cationic chitosan shell from nanomedicines and anionic teichoic acid from B. bifi . The engineered B. bifi complexes inherited the bioactivity of native B. bifi and exhibited distinctly enhanced accumulation at the tumor site. More importantly, significantly elevated anti-tumor efficacy was achieved after the treatment of CS-L-PGA-SN38 NPs/ B. bifi complexes, with favorable tumor suppression up to 80%. Such a B. bifi -mediated delivery system offers a promising platform for effective drug delivery and enhanced drug accumulation in the hypoxia deep tumor with superior anti-tumor efficacy.

Anti-Neoplastic Cytotoxicity of SN-38-Loaded PCL/Gelatin Electrospun Composite Nanofiber Scaffolds against Human Glioblastoma Cells In Vitro

Xiaodong Zhu,Shilei Ni,Tongliang Xia,Qingyu Yao,Haoyuan Li,Benlin Wang,Jiangang Wang,Xingang Li,Wandong Su

ABSTRACT: Electrospun poly(ε-caprolactone) (PCL)/gelatin (GT) scaffolds were developed to provide controlled release of 7-ethyl-10-hydroxy camptothecin (SN-38). Acetic acid was introduced to improve the miscibility of PCL and GT to produce a homogeneous nanofiber membrane mixture. The effect of SN-38 content in binary mixtures on processability, fiber morphology, water sorption, swelling, and drug release was investigated. Electrospun PCL/GT blend nonwoven fibers showed fiber surface roughness, decreased PCL crystallinity, and increased swelling with increasing drug content of 1, 2, and 4 wt %. Additionally, increasing the SN-38 concentration reduced the degradation rate of the GT. Furthermore, we hypothesize the existence of a drug content saturation point in the monoaxial fiber to explain the different drug release patterns of PG2 compared with those of PG1 and PG4. The matrix also showed good biodegradation and anti-tumor function. Our results demonstrate that SN-38-loaded PCL/GT fibers can be obtained by electrospinning. The SN-38-loaded fibers merit further evaluation as a means to potentially prevent locoregional recurrence following surgical tumor resection.

Facile synthesis of plasmonic BP@Au nanomatrix for sensitive detection of irinotecan and its active SN-38 metabolite via laser desorption/ionization mass spectrometry

Mandal Govinda,Umar Muhammad,Lv Rui,Guo Ruochen,Ge Tianjin,Awais Muhammad,Yang Shunli,Hasan Muhammad Sajjad Ul,Liu Jian

A new methodology is presented for the rapid, specific, and sensitive detection of irinotecan (CPT-11), a chemotherapeutic agent utilized in the treatment of cancer, along with its metabolically active derivative, SN-38, via laser desorption/ionization mass spectrometry (LDI MS). The method includes the detection of camptothecin (CPT), which can be utilized as an internal standard for the quantitative assessment of both CPT-11 and SN-38 in mouse serum. The approach utilizes a plasmonic two-dimensional (2D) black phosphorus nanosheet (BPN)-gold nanomatrix (BP@Au) in LDI MS. The experimental results demonstrated that the BP@Au nanomatrix outperformed the standard organic matrices (SA, CHCA, and DHB) in detecting irinotecan and its active metabolite with improved specificity and sensitivity, crucial factors for applications in personalized medicine. Mass spectra obtained using organic matrices revealed interference from matrix peaks overlapping with analyte peaks. The coefficient of determination ( R 2 ) was 0.9806 for CPT-11 and 0.9932 for SN-38, indicating strong linearity suitable for quantification. Moreover, the method achieved a lower limit of detection (LOD) of 62.76 ng/mL for CPT-11 and 189.87 ng/mL for SN-38, significantly enhancing the detection sensitivity by approximately 2–8 times compared with previous matrix-assisted laser desorption/ionization (MALDI) methodologies. This method was subsequently applied to the quantitative determination of analytes in mouse serum. The analyte recoveries for CPT-11 and SN-38 were 95.40% and 92.95%, respectively. Overall, this study offers potential insights and opens avenues for developing new nanomaterials as a MALDI nanomatrix, demonstrating enhanced capabilities for the rapid, specific, and sensitive detection of small biomolecules within the realms of analytical chemistry and personalized medicine. Graphical

Fabrication of Bioconjugates Clacked Chitosan-Coated SN-38 Liposomal Nanoparticles: Improved Precise Chemotherapy Efficacy in Lung Cancer Cells and Its Apoptosis

Xiaojun Zhang,Wei Sun,Changting Liu

Employing an active targeting method with monoclonal antibodies for chemotherapeutics-loaded nanocarriers represents a promising option to enhance the specific drug delivery and alleviate the detrimental effects of chemotherapeutic agents. Targeted delivery to the human epidermal growth factor receptor-2 (HER2), which is overexpressed in HER2+ lung cancerous cells, can be accomplished by conjugating nanoparticles with a monoclonal antibody (anti-HER2). We developed trastuzumab (TZ)-conjugated chitosan iodoacetamide (CsIA)-coated liposomal nanoparticles carrying SN-38 (TZ-SN-CsIA LNPs) as a lung-targeted delivery. CsIA was used to develop trastuzumab-clacked nanoparticles (TZ LNPs). The structure, physicochemical characteristics, SN-38 encapsulation, SN-38 release, and anticancer properties of the LNPs were established. The TZ LNPs were spherical, measuring around 77 nm in diameter, and exhibited a positive zeta potential; upon drug incorporation, the diameter of the TZ LNPs enlarged. A sustained, 24-h SN-38 release from the nanocarriers was accomplished. TZ LNPs demonstrated substantial cellular accumulation and markedly enhanced anticancer efficacy against HER2+ Calu-3 lung adenocarcinoma cancer cells compared to the drug solution and unconjugated LNPs. Consequently, TZ-SN-CsIA LNPs may be a potential nanocarrier for HER2+ lung cancer.

Biomimetic modification of macrophage membrane-coated prussian blue nanoparticles loaded with SN-38 to treat colorectal cancer by photothermal-chemotherapy

Hou Xuyang,Wei Zuxing,Qi Xiaoyan,Liu Dekun,Sun Yin,Jiang Yuhong,Liu Chao,Zhou Weihan,Yang Leping,Liu Kuijie

SN-38 is the active metabolite of irinotecan and acts as an effective topoisomerase I inhibitor with therapeutic effects on many malignant tumors, including some drug-resistant cancers. However, the poor solubility, low bioavailability, and severe dose-dependent toxicity limits the clinical application of SN-38. Currently, emerging macrophage membrane-coated nanoparticles provide an efficient biomimetic approach to develop novel SN-38 formulations for the reduction of its side effects. Photothermal therapy (PTT) is a promising methods in tumor treatment to thermally ablate tumors using various materials such Prussian blue nanoparticles (NPs) and can combined with chemotherapy to synergistically work. There is no report that combined SN38 and photothermal therapy for the treatment of colorectal cancer (CRC). SN38-PB@CM NPs were constructed by loading SN-38 into macrophage cell membrane-coated hollow mesoporous Prussian blue (PB) NPs. The morphology, size and zeta potential were evaluated by transmission microscopy and dynamic light scatter (DLS). Coomassie bright blue staining was performed to assess total protein profile. The photothermal properties of it were also investigated via near-infrared imaging. CCK8 and calcein-AM/PI staining were used to evaluate cell viability. Flow cytometry was performed to assess cell apoptosis. The fluorescent microscopy was used to observe cellular uptake of SN38-PB@CM NPs to assess its internalization in vitro. The biodistribution, tumor-targeting efficacy, antitumor efficacy and safety of SN38-PB@CM NPs in vivo were assessed in CT26 tumor-bearing mice via In Vivo Imaging System. SN38-PB@CM NPs were successfully constructed and exhibited a uniform size distribution (140.5 ± 4.3 nm) and an excellent drug-loading capacity (5.61 ± 0.64%). SN38-PB@CM NPs showed stable release properties within 72 h. It can also enhance the selective intracellular delivery of SN38 in vitro and showed good near-infrared (NIR) photothermal properties. And the NPs showed excellent tumor targeting, effective photothermal therapy, improved biosafety and antitumor efficacy on CT26-bearing mice. Multifunctional SN38-PB@CM NPs could achieve improved biosafety, great tumor-targeting, high-efficiency PTT and excellent antitumor efficacy, which provided a promising and attractive combination therapy for the treatment of CRC. Graphic Abstract

Prediction of Drug–Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation

Wang Zhe,Wang Xiaoyu,Wang Zhen,Fan Xiaoyu,Yan Mingrui,Jiang Lili,Xia Yangliu,Cao Jun,Liu Yong

Background Dabrafenib and irinotecan are two drugs that can be utilized to treat melanoma. A previous in vivo study has shown that dabrafenib enhances the antitumor activity of irinotecan in a xenograft model with unclear mechanism. Objectives This study aims to investigate the inhibition of dabrafenib on SN-38 (the active metabolite of irinotecan) glucuronidation, trying to elucidate the possible mechanism underlying the synergistic effect and to provide a basis for further development and optimization of this combination in clinical research. Methods Recombinant human uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and human liver microsomes (HLMs) were employed to catalyze the glucuronidation of SN-38 in vitro. Inhibition kinetic analysis and quantitative prediction study were combined to predict drug–drug interaction (DDI) potential in vivo. Results Dabrafenib noncompetitively inhibited SN-38 glucuronidation in pooled HLMs and recombinant UGT1A1 with unbound inhibitor constant ( K i,u ) values of 12.43 ± 0.28 and 3.89 ± 0.40 μM, respectively. Based on the in vitro K i,u value and estimation of kinetic parameters, dabrafenib administered at 150 mg twice daily may result in about a 1−2% increase in the area under the curve (AUC) of SN-38 in vivo. However, the ratios of intra-enterocyte concentration of dabrafenib to K i,u ([ I ] gut / K i,u ) are 2.73 and 8.72 in HLMs and recombinant UGT1A1, respectively, indicating a high risk of intestinal DDI when dabrafenib was used in combination with irinotecan. Conclusion Dabrafenib is a potent noncompetitive inhibitor of UGT1A1 and may bring potential risk of DDI when combined with irinotecan.

Downregulation of MACC1 facilitates the reversal effect of verapamil on the chemoresistance to active metabolite of irinotecan in human colon cancer cells

Xiaotao Qian,Yongxin Zhao,Tengyue Zhang,Pingsheng Fan

The aim of this study is to investigate the reversal effect of verapamil (VER) on chemoresistance to irinotecan (CPT-11) in human colon cancer cells and relevant mechanisms. Cell counting kit-8 (CCK-8) test and colony-forming unit (CFU) experiment results show that VER strengthens the sensitivity of human colon cancer cell line HT29 to CPT-11 but has a small effect on SW480 cells. High-throughput transcriptome sequencing, RT-PCR, and Western blot results show that the inhibition of metastasis-associated in colon cancer-1 (MACC1) expression by VER is the key factor for reversal effect on chemoresistance to CPT-11. Transfection experiments further show that VER can reverse the resistance of human colon cancer cells to SN-38, the active metabolite of CPT-11, when MACC1 is overexpressed. The nude mouse transplantation tumor experiment provides an in vivo proof that VER can strengthen sensitivity to CPT-11 in drug-resistant human colon cancer cells, and the effect might be related to the inhibited expression of MACC1. In summary, VER might strengthen the reversal effect of VER on chemoresistance to CPT-11 in human colon cancer cells and facilitate the apoptosis of human colon cancer cells by downregulating MACC1 expression.

LBA and LC-MS/MS based comprehensive bioanalytical methods for FDA018, a Trop-2 targeted antibody-drug conjugate

Minlu Cheng,Xianjing Li,Ya Li,Yiya Wang,Wenjia Li,Shuai Wang,Chang Shu,Qinxin Song,Li Ding

Recently, the approval of Trop-2 targeted antibody drug conjugate (ADC) has changed the dilemma of patients with advanced triple-negative breast cancer who rely on chemotherapeutics to improve their survival. FDA018, an ADC consisting of an anti-Trop-2 antibody conjugated with a topoisomerase inhibitor SN-38 via an acid-cleavable linker, is currently being investigated in clinical trials. Based on the urgent demand to evaluate the clinical pharmacokinetics of FDA018, ligand binding assays (LBAs) for the determination of SN-38-conjugated antibody and total antibody and LC-MS/MS methods for the determination of the free SN-38, its metabolite SN-38G and total SN-38 were developed. The comparability and DAR sensitivity evaluation of the ELISA strategies for SN-38-conjugated antibody and total antibody were emphasized. The sensitivity of the LC-MS/MS method for the simultaneous determination of SN-38 and SN-38G reached 0.500 ng/mL and 0.250 ng/mL, respectively. An effective solution has been proposed for the optical instability of the cleavable linker of FDA018 during the pretreatment process of biological samples. The established bioanalytical methods were comprehensively validated and the results satisfied the acceptable criteria of ICH M10. The validated bioanalytical methods have been applied to the single-dose pharmacokinetic study of FDA018 in patients with Trop-2-positive malignant tumors successfully, and the pharmacokinetic profiles of FDA018 and its constituent components were investigated.

Fabrication of biodegradable micelles with sheddable poly(ethylene glycol) shells as the carrier of 7-ethyl-10-hydroxy-camptothecin

Qian Guo,Ping Luo,Yu Luo,Fang Du,Wei Lu,Shiyuan Liu,Jin Huang,Jiahui Yu

Biodegradable micelles with sheddable poly(ethylene glycol) shells were fabricated based on poly(ethylene glycol)- block -poly(γ-benzyl l -glutamate) (mPEG-SS-PBLG) diblock copolymer and applied as the carrier of 7-ethyl-10-hydroxy-camptothecin (SN-38) in order to enhance its solubility and stability in aqueous media. The diblock polymer was designed to have the hydrophilic PEG moiety and hydrophobic PBLG moiety linked by biodegradable disulfide bond, so in reducing environment the PEG shells can be detached. The polymer was able to form the micelles of nano-scale in aqueous media, suggesting their passive targeting potential to tumor tissue. Water-insoluble antitumor drug, SN-38, was easily encapsulated into mPEG-SS-PBLG nanomicelles by lyophilization method. When setting theoretical drug loading content at 10   wt%, the drug encapsulation efficiency (EE) was assayed as 73.5%. Owing to the disulfide bond in mPEG-SS-PBLG, intense release of SN-38 occurred in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition, however, micelles showed gradual release of SN-38 in the absence of DTT. Also, the mPEG-SS-PBLG micelles effectively protected the active lactone ring of SN-38 from hydrolysis under physiological condition. Compared with free SN-38, SN-38-loaded nanomicelles showed essentially decreased cytotoxicity against L929 cell line in 24   h, bare mPEG-SS-PBLG nanomicelles showed almost non-toxicity.

Synthesis and evaluation of highly releasable and structurally stable antibody-SN-38-conjugates

Lianqi Liu,Fei Xie,Dian Xiao,Xin Xu,Zheng Su,Yanming Wang,Shiyong Fan,Xinbo Zhou,Song Li

Inhibition of UGT1A1*1 and UGT1A1*6 catalyzed glucuronidation of SN-38 by silybins

Wei Li,Yin-Nan Chen,Yue-Yue Chen,Zhe Wang,Zhen Wang,Li-Li Jiang,Hong-Can Shi,Yong Liu

UGT1A1 is the main enzyme that catalyzes the metabolic elimination and detoxification of SN-38, the active form of the drug irinotecan . Milk thistle products have been used widely to protect the liver from injury associated with the use of chemotherapeutic agents. To evaluate whether SN-38 metabolism can be affected by milk thistle products, the inhibitory effects of silybins on UGT1A1*1 and UGT1A1*6 were evaluated in the present investigation. Both silybin A and silybin B potently inhibited SN-38 glucuronidation catalyzed by UGT1A1*1 or UGT1A1*6. It was noteworthy that silybin A and silybin B showed synergistic effect in UGT1A1*1 microsomes at concentration around IC 50 , while additive effect in UGT1A1*6. According to the predicted AUC i /AUC ratios (the ratio of the area under the plasma concentration–time curve of SN-38 in the presence and absence of silybins), the coadministration of irinotecan and several milk thistle products, including silybin-phosphatidylcholine complex, two Legalon capsules , four Silymarin tablets or four Liverman capsules, may lead to clinically significant herb-drug interactions (HDI) via UGT1A1 inhibition. Meanwhile, R gut values were much higher than 11 in all the groups, indicating potential HDI due to intestinal UGT1A1 inhibition.