查找使用阿拉丁产品的科研文献

Acid-triggered drug release from micelles based on amphiphilic oligo(ethylene glycol)–doxorubicin alternative copolymers

Ying Wang,Qiaojie Luo,Rui Sun,Guangyu Zha,Xiaodong Li,Zhiquan Shen,Weipu Zhu

We report a facile strategy to synthesize pH-sensitive amphiphilic oligo(ethylene glycol) (OEG)–doxorubicin (DOX) alternative conjugates. Poly[oligo(ethylene glycol) malicate] (POEGM) with numerous pendent hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with malic acid under mild conditions. Then, benzaldehyde groups were introduced into the POEGM backbone via esterification between the pendant hydroxyl groups and 4-formylbenzoic acid. DOX moieties were finally attached to the polymeric backbone via benzoic imine linkages to obtain the OEG–DOX conjugates. Because of the high molecular weight and alternate architecture, this type of amphiphilic OEG–DOX alternative conjugates can form stable micelles in aqueous solution with a high DOX loading content (38.2 wt%) and low critical micelle concentrations (0.021 mg mL−1). Due to the pH-sensitive benzoic imine linkages between the DOX moieties and polymeric backbone, DOX could be rapidly released from the micelles at pH 5.8, whereas only a minimal amount of DOX was released at pH 7.4 under the same conditions. The cytotoxicity assay indicates that the OEG–DOX conjugates show cytotoxic effects to MCF-7 tumor cells, while the corresponding polymer material POEGM–CHO exhibits a great biocompatibility for MCF-7 tumor cells. These pH-sensitive and high drug loading nano-carriers based on the OEG–DOX alternative conjugates provide a promising platform for targeted cancer therapy.

Trastuzumab modified silica nanoparticles loaded with doxorubicin for targeted and synergic therapy of breast cancer

Ling-xin Meng,Qiang Ren,Qin Meng,Yu-xiu Zheng,Mao-lei He,Shu-yan Sun,Zhao-jun Ding,Bing-cheng Li,Hui-yun Wang

Untargeted delivery as well as low efficacy are two main obstacles for effective breast cancer therapy. Here in this study, we surface modified silica nanoparticles (SLN) with Trastuzumab (Tra) to construct a tumor-targeting carrier (Tra-SLN) for specific drug delivery to human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cells. In addition, Tra-SLN could also loaded with broad-spectrum anticancer drug doxorubicin (DOX) to finally construct a drug delivery system (DDS) capable of co-delivering Tra and DOX (Tra-SLN/DOX). Our results demonstrated that the as-prepared Tra-SLN/DOX was nanoscale particles with spheroid appearance which showed preferable stability in physiological environments. In addition, the Tra-SLN/DOX could specifically target to HER2 overexpressed MCF-7 cells. Both in vitro and in vivo experiments revealed that the Tra-SLN/DOX exerted enhanced anticancer efficacy when compared with Tra or DOX alone. It was suggested that Tra-SLN/DOX might be a promising platform for enhanced therapy of breast cancer.

pH Responsiveness of Hexosomes and Cubosomes for Combined Delivery of Brucea javanica Oil and Doxorubicin

Yawen Li,Angelina Angelova,Fangzhou Hu,Vasil M. Garamus,Changjun Peng,Na Li,Jianwen Liu,Dan Liu,Aihua Zou

We report pH-responsive liquid crystalline lipid nanoparticles, which are dual-loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH = 7.4) to cubic (pH = 6.8) to emulsified microemulsion (pH = 5.3) phase transition with a therapeutic application in cancer inhibition. BJO is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an antitumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need for safe delivery carriers. Here, pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein–oleic acid–BJO–DOX) systems are determined by synchrotron small-angle X-ray scattering and the Langmuir film balance technique. The nanocarrier assemblies display good physical stability in the studied pH range and adequate particle sizes and ζ-potentials. Their interaction with model lipid membrane interfaces is enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO–DOX dual-loaded pH-switchable liquid crystalline nanoparticles are performed on the human breast cancer Michigan Cancer Foundation-7 (MCF-7) cell line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines exhibit enhanced antitumor efficacy. The performed preliminary studies suggest a potential reversal of the resistance of the MCF-7/DOX cells to DOX. These results highlight the necessity for further understanding the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, and emulsified microemulsion inner organizations for therapeutic outcomes.

Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy

Yongju He,Zhigui Su,Lingjing Xue,Hui Xu,Can Zhang

Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG 2 C 18 -L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl- l -glutamyl2-histidyl-hexahydrobenzoic acid, HHG 2 C 18 ) was used to construct a pH-sensitive lipid bilayer (HHG 2 C 18 -L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH 2 ). Erlotinib and DOX were separately incorporated into HHG 2 C 18 -L and MSN-NH 2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG 2 C 18 -L(E   +   D)). We confirmed that M-HHG 2 C 18 -L(E   +   D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH 2 , erlotinib released faster than DOX during the cellular transport. Additionally, HHG 2 C 18 -L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH 2 , leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E   +   D)) and simultaneous DRUG coadministration. M-HHG 2 C 18 -L(E   +   D) with sequential staggered drug release and pH-sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG 2 C 18 -L(E   +   D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG 2 C 18 -L(E   +   D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG 2 C 18 -L(E   +   D) had great potential application in cancer treatment.

Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy

Rui Han,Yuan Sun,Chen Kang,Huijing Sun,Wenguang Wei

Preparation of Doxorubicin- and Psoralen-Loaded Nanostructured Lipid Carrier and Its Multidrug Resistance Reversal Study

Cai Tiange,Huang Yinghong,Du Chuling,Xia Xi,Zhang Ronghua,Yang Li,Han Li,Cai Yu

Multidrug resistance (MDR) is the major cause of tumor chemotherapy failure. This study aimed to combine doxorubicin with the MDR-reversal agent psoralen (PSO) by loading them into a nanostructured lipid carrier (NLC) to enhance the reversal activity of PSO and DOX. PSO-DOX-NLC was prepared based on the method of emulsification evaporation–low-temperature solidification. A central composite design and response-surface-optimization methodology were adopted to generate the optimal formulation of PSO-DOX-NLC. The encapsulation efficiency, morphology, zeta potential, particle size, in vitro release, differential scanning calorimetry (DSC), and infrared-spectroscopy properties, and reversal effect of PSO-DOX-NLC were also studied. The NLC prepared for this process was round and uniform in size and zeta potential; it's optimal formulation was 130 mg of lipid, 1.83:1 lecithin-to-lipid ratio, and 2.6% emulsifier. In vitro release data indicated that PSO-DOX-NLC had an apparent slow-release effect. Infrared spectra and DSC data showed that PSO-DOX-NLC may have formed a noncrystalline structure in the NLC system. The IC50 values of PSO/DOX, DOX-NLC, and PSO/DOX-NLC were 2.448, 0.965, and 0.379 μg/mL respectively, proving that PSO-DOX-NLC can improve the reversal activity.

High-sensitivity and high-specificity optical fiber SPR doxorubicin sensor enabled by Ti3C2 MXene sensitization

Like Li,Yi Li,Guohong Zou,Lu Cai,Maoqing Chen,Xiaoming Chen,Bo Han,Ya-nan Zhang,Yong Zhao

Doxorubicin, as an anthracycline antibiotic, is a commonly used and effective chemotherapeutic agent for treating various malignancies. However, it has a narrow therapeutic window. Therefore, real-time monitoring of doxorubicin concentration in chemotherapy patients is essential for enhancing treatment efficacy, minimizing side effects, and ensuring patient safety. In this paper, we proposed a Ti 3 C 2 MXene-sensitized fiber surface plasmon resonance (SPR) doxorubicin sensor. By covalently functionalizing the reflective SPR sensing structure with Ti 3 C 2 MXene, the refractive index sensitivity increased by 60.0 %. Furthermore, by covalently modifying the doxorubicin-specific aptamer, the sensor achieves high sensitivity and high specificity in the detection of doxorubicin. Within the linear range of 10–100 μM, it demonstrates a sensitivity of 0.24 nm/μM and a limit of detection of 2.79 μM. Furthermore, experiments confirmed that the doxorubicin sensor exhibits excellent specificity and can be applied for the detection of doxorubicin in real serum samples. The proposed doxorubicin sensor offers benefits such as high sensitivity, high specificity, fast response, and small size, and has the potential to meet the clinical requirements for monitoring doxorubicin concentration in chemotherapy patients.

TRIP13 Activates Glycolysis to Promote Cell Stemness and Strengthen Doxorubicin Resistance of Colorectal Cancer Cells

Liu Guangyi,Wang Huan,Ran Rui,Wang Yicheng,Li Yang

Background: Chemotherapy resistance is one of the main causes of clinical chemotherapy failure. Current cancer research explores the drug resistance mechanism and new therapeutic targets. This work aims to elucidate the mechanism of thyroid hormone receptor interactor 13 (TRIP13) affecting doxorubicin (DOX) resistance in colorectal cancer (CRC). Methods: Bioinformatics analyses were employed to clarify TRIP13 expression in CRC tissues and predict the correlation of the TRIP13 enrichment pathway with glycolysis-related genes and stemness index mRNAsi. Quantitative real-time polymerase chain reaction and western blot were adopted to analyze the expression of TRIP13 and glycolysis- related genes. Cell Counting Kit-8 was utilized to determine the cell viability and IC50 value. Western blot was employed to measure the expression of stemness-related factors. Cell function assays were performed to detect cells' sphere-forming ability and glycolysis level. Animal models were constructed to determine the effects of TRIP13 expression on CRC tumor growth. Results: TRIP13 was significantly overexpressed in CRC, concentrated in the glycolysis signaling pathway, and positively correlated with stemness index mRNAsi. High expression of TRIP13 facilitated DOX resistance in CRC. Further mechanistic studies revealed that overexpression of TRIP13 could promote cell stemness through glycolysis, which was also confirmed in animal experiments. Conclusion: TRIP13 was highly expressed in CRC, which enhanced the DOX resistance of CRC cells by activating glycolysis to promote cell stemness. These findings offer new insights into the pathogenesis of DOX resistance in CRC and suggest that TRIP13 may be a new target for reversing DOX resistance in CRC.

Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy

Caiying Zhu,Jingjing Xiao,Ming Tang,Hua Feng,Wulian Chen,Ming Du

The preparation of polymer therapeutics capable of controlled release of multiple chemotherapeutic drugs has remained a tough problem in synergistic combination cancer therapy. Herein, a novel dual-drug co-delivery system carrying doxorubicin (DOX) and platinum(IV) (Pt[IV]) was developed. An amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-AzPMA), was synthesized and used as a nanoscale drug carrier in which DOX and Pt(IV) could be packaged together. The copolymers were shell cross-linked by Pt(IV) prodrug via a click reaction. Studies on the in vitro drug release and cellular uptake of the dual-drug co-delivery system showed that the micelles were effectively taken up by the cells and simultaneously released drugs in the cells. Futhermore, the co-delivery polymer nanoparticles caused much higher cell death in HeLa and A357 tumor cells than either the free drugs or single-drug-loaded micelles at the same dosage, exhibiting a synergistic combination of DOX and Pt(IV). The results obtained with the shell cross-linked micelles based on an anticancer drug used as a cross-linking linkage suggested a promising application of the micelles for multidrug delivery in combination cancer therapy.

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

Li Zong,Guorong Cheng,Jingwu Zhao,Xiaoyu Zhuang,Zhong Zheng,Zhiqiang Liu,Fengrui Song

The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.Keywords:ursolic acid;metastasis;multidrug resistance;polyamine metabolism;ornithine decarboxylase

Targeted delivery of celastrol and siRNA via macrophage biomimetic nanoparticles for doxorubicin-induced cardiomyopathy therapy

Qiyu Zhang,Tianyu Guo,Xuna Xue,Zhibo Zhang,Xinyan Liu,Qing Cai,Ning Wang,Bo Zhang,Jinyong Peng

Macrophage membrane biomimetic nanoparticles M@HCDA can target damaged myocardium and co-deliver siADAM17 and Celastrol. • Treatment of M@HCDA in vitro and in vivo suppressed doxorubicin-induced mitochondrial injury and rescued cardiac function. • M@HCDA improves doxorubicin-induced ferroptosis by targeting and delivering Celastrol to regulate GPX4 and SLC7A11. • M@HCDA alleviates doxorubicin-induced inflammation by inhibiting the MAPK signaling through targeted delivery of siADAM17. Doxorubicin-induced cardiomyopathy (DIC) is a severe complication following anthracycline chemotherapy, and its main pathogenesis is inflammatory responses and ferroptosis. This study constructed hyaluronic acid-based macrophage biomimetic nanoparticles (M@HCDA) to co-delivery of Celastrol (Cel) and siADAM17 for the treatment of DIC. This research revealed that Cel exerted an anti-ferroptosis effect by regulating GPX4 and SLC7A11, while siADAM17 inhibited TAK1-MAPK pathway activation by silencing ADAM17. Meanwhile, the synergistic effect of Cel and siADAM17 significantly alleviated oxidative stress, myocardial fibrosis, apoptosis, and mitochondrial dysfunction, thereby relieving myocardial injury caused by DOX-induced cardiotoxicity and providing effective early cardioprotection. In vitro and in vivo experiments indicated that M@HCDA exhibited good stability, biocompatibility, and targeting capability, showing the clinical application potential. The design and development of M@HCDA provide new experimental evidence and candidate strategy for treating DIC. Download: Download high-res image (610KB) Download: Download full-size image

An injectable thermo-responsive hydrogel based cellulose-brush derivative for the sustained release of doxorubicin

Liu Xiaohong,Li Ming,Zhang Haichuan,Chen Liheng,Fu Shiyu

A cellulose- grafted -poly( N -isopropylacrylamide) (cellulose- g -PNIPAAm) copolymer with thermo-responsivity was synthesized using homogeneous activators regenerated by electron transfer for atom transfer radical polymerization (ARGET-ATRP). The prepared copolymer dispersed at low concentration in water or phosphate-buffered saline (PBS) at 25 °C could self-assembly into micelles at 37 °C. The size and morphology of these micelles were determined by dynamic light scattering and transmission electron microscopy. The copolymer at a concentration over 4.2% by weight in water formed an injectable thermo-responsive hydrogel that was composed of micelles when the temperature increased to 37 °C. This hydrogel was used to load the anticancer drug doxorubicin (DOX). In vitro release studies demonstrated that this hydrogel released DOX in a sustained manner. Furthermore, this cellulose-based injectable thermo-responsive hydrogel was used in cytotoxicity tests, revealing that it was very biocompatible. Based on the above results, this cellulose- g -PNIPAAm injectable thermo-responsive hydrogel has strong potential for application in smart drug delivery systems.