查找使用阿拉丁产品的科研文献

Co-delivery of doxorubicin and P-glycoprotein siRNA by multifunctional triblock copolymers for enhanced anticancer efficacy in breast cancer cells

Minghui Xu,Junmin Qian,Aili Suo,Ning Cui,Yu Yao,Weijun Xu,Ting Liu,Hongjie Wang

Combined treatment of chemotherapeutics and small interfering RNAs (siRNAs) is a promising therapy strategy for breast carcinoma via their synergetic effects. In this study, to improve the therapeutic effect of doxorubicin (DOX), novel triblock copolymers, folate/methoxy-poly(ethylene glycol)-block-poly(L-glutamate-hydrazide)-block-poly(N,N-dimethylaminopropyl methacrylamide) (FA/m-PEG-b-P(LG-Hyd)-b-PDMAPMA), were synthesized and used as a vehicle for the co-delivery of DOX and P-glycoprotein (P-gp) siRNA into breast cancer cells. The triblock copolymers were synthesized by a combination of ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxyanhydride using cystamine-terminated heterotelechelic PEG derivatives possessing folate or methoxy end groups (FA/m-PEG-Cys) as initiators and reversible addition–fragmentation chain transfer polymerization of N,N-dimethylaminopropyl methacrylamide followed by hydrazinolysis. The successful synthesis of the copolymers was confirmed by 1H NMR and gel permeation chromatography. DOX was covalently conjugated onto the poly(L-glutamate-hydrazide) blocks via a pH-labile hydrazone linkage, and the DOX-conjugated triblock copolymers could self-assemble into nanoparticles in aqueous solutions. P-glycoprotein (P-gp) siRNA was then bound to the cationic poly(N,N-dimethylaminopropyl methacrylamide) (PDMAPMA) blocks through an electrostatic interaction, resulting in the formation of spherical nanocomplexes with an average diameter of 196.8 nm and a zeta potential of +28.3 mV. The in vitro release behaviors of DOX and siRNA from the nanocomplexes were pH- and reduction-dependent, and the release rates were much faster under a reductive acidic condition (pH 5.0, glutathione: 10 mM) simulating the intracellular endo-lysosomal environment of cancer cells compared to physiological conditions. The fast payload release rates were closely related to both the glutathione-triggered detachment of PEG blocks from the nanocomplex surface and the pH-sensitive cleavage of hydrazone linkages. FA-decorated nanocomplexes showed higher cellular uptake efficiency and cytotoxicity against MCF-7 cells than FA-free nanocomplexes, as confirmed by confocal laser scanning microscopy, transmission electron microscopy, MTT and flow cytometry analyses. Our results demonstrated that the multifunctional triblock copolymer-mediated co-delivery of DOX and P-gp siRNA might be a new promising therapeutic strategy for breast cancer treatment.

Selective electrochemical determination of glutathione from the leakage of intracellular GSH contents in HeLa cells following doxorubicin-induced cell apoptosis

Lingzhi Zhao,Liu Zhao,Yanqing Miao,Chengxiao Zhang

A highly selective method for the electrochemical detection of reduced glutathione (GSH) has been developed on the basis of the product of a reaction between GSH and catechol as the electron mediator on single-walled carbon nanotubes modified glassy carbon electrode. A polymerization-adduct ECE mechanism at SWNTs/GCE was proposed. The oxidation peak potential was −0.160   V (vs. Ag/AgCl, sat. KCl) and the oxidation peak current showed a dependence relationship with GSH concentration in the range of 1.0 ∼500.0   μM with a detection limit of 0.5   μM GSH. The developed method can discriminate GSH from other thiol species such as L-cysteine (Cys) and cysteamine hydrochloride (Cym) within their certain concentration ranges. The as-established electrochemical method has been successfully applied for the determination of GSH from the leakage of intracellular GSH contents in HeLa cells following doxorubicin-induced cell apoptosis.

pH-responsive poly(ethylene glycol)-poly(ϵ-caprolactone)-poly(glutamic acid) polymersome as an efficient doxorubicin carrier for cancer therapy

Lanxia Zhao,Xia Zhang,Xin Liu,Juan Li,Yuxia Luan

The synthesis, characterization and potential application in the doxorubicin (Dox) delivery system of a biodegradable polypeptide-based block copolymer, poly(ethylene glycol) 2000 -poly(ϵ-caprolactone) 6000 -poly(glutamic acid) 1000 (PEG 2000 -PCL 6000 -PGA 1000 ), was investigated. The copolymer was synthesized via ring-opening polymerization and characterized by 1 H NMR and Fourier transform IR. The synthesized copolymer could self-assemble into aggregates and the critical aggregation concentration was 0.23 mg mL −1 . Transmission electron microscopy indicated that spherical polymersomes formed with a desirable size about 180 nm. Therefore Dox was encapsulated into these polymersomes, and then we investigated its applications in a drug delivery system. These Dox-loaded polymersomes (PolyDox) were characterized by dynamic light scattering, zeta potential and pH responsiveness measurements. In vitro drug release indicated that the release rate of drug from PolyDox was pH-responsive and significantly decreased. The drug pharmacokinetic parameters were improved in comparison to the group treated with free Dox, which proved the prolonged Dox release from PolyDox. A WST-1 assay indicated a low toxicity and good compatibility of copolymer to cells within 48 h. The results also showed that PolyDox appeared to induce a higher anti-tumor effect. Cell uptake results indicated that PolyDox displayed higher cellular uptake in A549 cells. Endocytosis inhibition results demonstrated that the internalization of PolyDox was mostly mediated by the fluid-phase endocytosis pathway. © 2017 Society of Chemical Industry

In vitro and in vivo evaluation of stimuli-responsive vesicle from PEGylated hyperbranched PAMAM-doxorubicin conjugate for gastric cancer therapy

Jinshan Nie,Yang Wang,Wei Wang

Gastric Cancer is one of the major leading causes of death by cancer worldwide, but the chemotherapeutics, one of the preferred approaches, bring about extensive side effects when systemically injected. In our work, doxorubicin-loaded pH and redox responsive hyperbranched poly(amidoamine)( h- PAMAM)-based vesicle was prepared to enhance anti-tumor efficacy of chemotherapeutic compounds. The doxorubicin (DOX) molecules were attached to PEGylated h- PAMAM by acid sensitive cis -aconityl linkage to form pH sensitive conjugate (PPCD), which self-assembled in THF into micelles . The resulted micelles were then crosslinked by disulfide bonds and transferred from THF into water to form vesicles, which could be disassembled into small-sized conjugates under the redox condition. The drug release profiles showed that the PPCD vesicle presented stimuli-triggered drug release in acidic and reducing environment, and lower DOX leakage under neutral condition. The in vitro cell assay reflected the rapid DOX release and significant tumor-cytotoxic effect of the PPCD vesicle. The in vivo anticancer activity and systematic toxicity studies showed that the PPCD vesicles had lower tissue toxicity with good antitumor effect. In brief, h- PAMAM-based PPCD vesicle provides a safe and effective drug delivery system for the therapy of gastric cancer.

Carrier-Free, Hyaluronic Acid-Modified Self-Assembled Doxorubicin, and Chlorin e6 Nanoparticles Enhance Combined Chemo- and Photodynamic Therapy in vivo

BeiBei Lin,Peizhen Lin,Xiaobi Zhang,Yingyi Liao,Yinfei Yu,Xuegu Xu,Xiaoling Wang

Background Developing carrier-free nanomedicines via self-assembly of two antitumor drug molecules is a potential strategy for enhancing the combination treatment of tumors. Similarly, conventional chemotherapy combined with photodynamic therapy may synergistically improve the antitumor effect while minimizing the adverse reactions associated with antitumor treatment. Hyaluronic acid (HA) can bind to overexpressed HA receptors on the tumor cell surface, increasing cell internalization and resulting in good tumor-targeting properties.Methods Herein, we propose an easy and environmentally friendly approach for fabricating a novel formulation of carrier-free pure nanodrugs through self-assembly of the antitumor drug doxorubicin (DOX) and the photosensitizer chlorin e6 (Ce6), followed by sequential modification with HA to achieve simultaneous and targeted photodynamic therapy and chemotherapy.Results The fabricated HA-DOX-Ce6 nanoparticles (NPs) exhibited enhanced drug loading and stability while possessing the properties of near-infrared fluorescence imaging, self-targeting drug delivery, and combined photodynamic therapy and chemotherapy.Conclusions HA-DOX-Ce6 NPs, along with laser irradiation, effectively suppressed tumor development both in vitro and in vivo with minimal side effects. Overall, this biomaterial-based, carrier-free drug delivery system, in combination with cotargeted therapies, has shown potential for considerable improvements in treatment outcomes and patient prognosis.

Camptothecin prodrug nanomicelle based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake

Ya Gao,Yi Xiao,Shiyuan Liu,Jiahui Yu

Hyaluronic acid/dextran-based polymeric micelles co-delivering ursolic acid and doxorubicin to mitochondria for potentiating chemotherapy in MDR cancer

Yufan Guo,Xiuru Yang,Yihong Zhang,Fazhen Luo,Juan Yang,Xupeng Zhang,Jinxia Mi,Yan Xie

Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA : 9.06 %). After hyaluronic acid (HA)-mediated endocytosis , the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles . Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc. ; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.

Hyaluronic acid-modified biomimetic liposomes co-loaded with doxorubicin and melatonin for targeted inhibition of breast cancer proliferation and metastasis

Yu Xiu,Hao Luo,Qian Xu,Wentong Li,Jingliang Wu,Ruohan Sun,Dandan Sun,Keda Yan,Hongying Liu,Qing Wang

The tumor microenvironment (TME) plays an important role in tumor development. In TME, cancer-associated fibroblasts (CAFs) and neutrophil extracellular traps (NETs) facilitate tumor proliferation, drug resistance, and metastasis. Anti-tumor strategies targeting CAFs and NETs might be effective therapeutic modalities to inhibit tumor growth, drug resistance, and metastasis. In this study, a platelet membrane-encapsulated hyaluronic acid (HA)-acid-modified biomimetic nano-delivery system co-loaded with doxorubicin (DOX) and melatonin (MT) was prepared. MCF-7 + MRC-5 co-culture cell model and 4 T1 + NIH-3 T3 co-implanted in situ breast cancer model were used to simulate the real breast cancer microenvironment. As expected, the HA-PLIP-based nano-delivery system enhanced drug internalization and inhibited drug efflux. The growth and proliferation of breast cancer cells were significantly inhibited. Histological analysis showed that DM/HA-PLIP significantly inhibited tumor growth, suppressed extracellular matrix (ECM) deposition reduced tumor neovascularization and α-SMA protein expression, and significantly reduced the number of metastatic nodules and NETs. In summary, DM/HA-PLIP is expected to substantially improve the therapeutic efficacy of breast cancer by inhibiting the crosstalk of CAFs and NETs with tumor cells, which has a broad clinical application prospect.

In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1

Qing Yang,Xiaosheng Jin,Yuansen Zhang,Xiaoqiu Wu,Haiying Lin,Tingting Ji,Rongzhou Li

The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.

Molecularly imprinted polymer coupled with zinc-doped carbon quantum dots as a fluorescent probe for the determination of doxorubicin hydrochloride

Han Zhang,Fang Fang,Jiangle Yi,Yuanling Sun,Xueying Wang

As an effective chemotherapy drug, doxorubicin hydrochloride (DOX) plays an important role in treating cancer. However, its serious side effects and chemoresistance limit its wide use. Therefore, the accurate determination of doxorubicin is particularly important for controlled dosage. In this work, blue fluorescent carbon quantum dots (HCQDs) doped with Zn were synthesized by hydrothermal method using hair as the carbon source. Then, a fluorescent molecularly imprinted polymer (HCQDs@MIP) for the determination of DOX was synthesized by sol–gel method with HCQDs, APTES, TEOS and DOX as the fluorescence source, functional monomer, crosslinker and template, respectively. DOX showed good linear quenching ability for the blue fluorescence of HCQDs@MIP with a detection limit of 1.72 nM in the concentration range of 0.431 to 216 μM. The results proved that the fluorescence quenching of DOX to HCQDs was caused by static quenching and internal filtering effects. The fluorescent probe was successfully applied to the detection of DOX in injections, and the recovery rate was 94.9–102%.

A fully biodegradable spherical nucleic acid nanoplatform for self-codelivery of doxorubicin and miR122 for innate and adaptive immunity activation

Ming-Chao Jiang,Zhou-Long Fang,Jin-Yan Zhang,Wei Ma,Luan-Feng Liao,Cui-Yun Yu,Hua Wei

Facile construction of a fully biodegradable spherical nucleic acid (SNA) nanoplatform is highly desirable for clinical translations but remains rarely explored. We developed herein the first polycarbonate-based biodegradable SNA nanoplatform for self-codelivery of a chemotherapeutic drug, doxorubicin (DOX), and a human liver-specific miR122 for synergistic chemo-gene therapy of hepatocellular carcinoma (HCC). Ring-opening polymerization (ROP) of a carbonate monomer leads to a well-defined polycarbonate backbone for subsequent DOX conjugation to the pendant side chains via acidic pH-cleavage Schiff base links and miR122 incorporation to the chain termini via click coupling, affording an amphiphilic polycarbonate-DOX-miR122 conjugate, PBis-Mpa 30 -DOX-miR122 that can self-assemble into stabilized SNA. Besides the desired biodegradability, another notable merit of this nanoplatform is the use of miR122 not only for gene therapy but also for enhanced innate immune response. Together with the ICD-triggering effect of DOX, PBis-Mpa 30 -DOX-miR122 SNA-mediated DOX and miR122 codelivery leads to synergistic immunogenicity enhancement, resulting in tumor growth inhibition value (TGI) of 98.1 % significantly higher than those of the groups treated with only drug or gene in a Hepa1-6-tumor-bearing mice model. Overall, this study develops a useful strategy toward biodegradable SNA construction, and presents a drug and gene-based self-codelivery SNA with synergistic immunogenicity enhancement for efficient HCC therapy. Statement of significance Facile construction of a fully biodegradable SNA nanoplatform is useful for in vivo applications but remains relatively unexplored likely due to the synthetic challenge. We report herein construction of a polycarbonate-based SNA nanoplatform for co-delivering a chemotherapeutic drug, DOX, and a human liver-specific miR-122 for synergistic HCC treatment. In addition to the desired biodegradability properties, this SNA nanoplatform integrates DOX-triggered ICD and miR-122-enhanced innate immunity for simultaneously activating adaptive and innate immunities, which leads to potent antitumor efficiency with a TGI value of 98.1 % in a Hepa1-6-tumor-bearing mice model.

Novel water-soluble and pH-responsive anticancer drug nanocarriers: Doxorubicin–PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs)

Yulei Chang,Xinlei Meng,Yili Zhao,Kun Li,Bao Zhao,Ming Zhu,Yapeng Li,Xuesi Chen,Jingyuan Wang

PH-responsive drug release system based on the conjugates of PAMAM dendrimers–doxorubicin (PAMAM–DOX) and superparamagnetic iron oxide (Fe 3 O 4 ) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH-responsive drug release system. The drug release profiles of DOX–PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH   =   5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer–DOX-coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo.