查找使用阿拉丁产品的科研文献

Boric acid-crosslinked polyvinyl alcohol concave round cake-like microspheres for enhanced doxorubicin delivery in chemoembolization therapy

Rongkang Yu,Shuyue Wu,Ruibo Zhao,Han Zhang,Yao Li,Xiangdong Kong

Transcatheter arterial chemoembolization (TACE) is considered a critical treatment for hepatocellular carcinoma, but conventional embolic agents remain challenging in drug release profiles and embolization precision. Herein, we fabricated polyvinyl alcohol (PVA) concave round cake-like microspheres crosslinked with boric acid (H 3 BO 3 ) for enhanced drug delivery and embolization. PVA microspheres loaded with doxorubicin (DOX) were constructed using a crosslinking-assisted solvent evaporation method, with size control through calibrated needles. The microspheres were characterized for morphology, drug loading, release kinetics, and mechanical properties using techniques such as SEM, FTIR, TGA, XRD, and compression tests. The microspheres demonstrated over 85 % drug encapsulation efficiency and a maximum drug loading of 66.8 % w/w. In vitro cytotoxicity assays showed significant dose-dependent anticancer activity against HepG2 cells. Furthermore, the concave round cake-like microspheres exhibited excellent biocompatibility with human umbilical vein endothelial cells (HUVECs) and minimal hemolytic activity. Embolization simulations confirmed effective vascular occlusion. These results suggest that DOX-loaded PVA microspheres, with controlled drug release and robust embolic efficacy, represent a promising dual-function agent for TACE.

Tetramethylpyrazine attenuates the cancer stem cell like-properties and doxorubicin resistance by targeting HMGCR in breast cancer

Xuan Jiang,Manli Wang,Guoliang Cui,Yuanyuan Wu,Zhonghong Wei,Suyun Yu,Aiyun Wang,Wei Zou,Yanhong Pan,Xiaoman Li,Yin Lu

Background Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat , has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood. Purpose Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics. Methods Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo , extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7 ADR ) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed. Results TMP was found to inhibit BCSC-like properties both in vitro and in vivo , evidenced by a reduction in the CD44 + /CD24 - population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR. Conclusion These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.

Reactive oxygen species-sensitive chondroitin sulfate A-cholesteryl hemisuccinate micelles for targeted doxorubicin delivery in tumor therapy

Jingmou Yu,Qinglan Yuan,Chuan Li,Sile Hong,Yuting Li,Yafen Li,Jing Ren,Dengzhao Jiang,Pu Chen,Lei Zhang

The efficient drug release triggered by the tumor microenvironment is challenging in the development of stimuli-sensitive nanomedicine. In this study, we developed novel polymeric micelles sensitive to reactive oxygen species (ROS) for targeted delivery of doxorubicin (DOX) in tumor therapy. Hydrophilic chondroitin sulfate A (CSA) was conjugated with cholesteryl hemisuccinate (CHS) via a ROS-cleavable thioketal (TK) bond. The resulting CSA-TK-CHS could form self-assembled micelles, and DOX-loaded CSA-TK-CHS (CSA-TK-CHS/DOX) micelles displayed a nearly spherical shape with an average hydrodynamic diameter of 324 nm. The bioresponsive DOX release of CSA-TK-CHS/DOX micelles was evaluated in an H 2 O 2 -containing phosphate buffer solution (PBS). CSA-TK-CHS/DOX micelles showed higher cellular uptake than free DOX in 4T1 cells by confocal laser scanning microscopy (CLSM) observation. And CSA-TK-CHS/DOX improved DOX cytotoxicity against CD44-overexpressed 4T1 and CT26 tumor cells. Notably, CSA-TK-CHS/DOX micelles displayed significantly stronger potency ( P  < 0.01) in antitumor activity than DOX·HCl in orthotropic 4T1-bearing Balb/c mice. Overall, these findings indicate that amphiphilic CSA-TK-CHS micelles are a promising targeted and intelligent drug carrier for tumor therapy.

Synthesis and Characterization of Doxorubicin Loaded pH-Sensitive Magnetic Core–Shell Nanocomposites for Targeted Drug Delivery Applications

Wei Jiang,Juan Wu,Yewen Shen,Renbing Tian,Shuai Zhou,Wei Jiang

In order to improve the effects of medical therapy for cancer, we prepared magnetic nanocomposites (Fe 3 O 4 @SiO 2 –NH–NH 2 ) as doxorubicin (DOX) carriers via two different schemes. Scheme (I): the carriers were synthesized from magnetic silica nanoparticles (Fe 3 O 4 @SiO 2 ) via layer by layer modification, scheme (II): the carriers were obtained from amino-modified magnetic silica nanoparticles (Fe 3 O 4 @SiO 2 –NH 2 ) synthesized by one-step, and followed by surface modification. In order to load DOX effectively, the surface of the carriers were further modified to make the surface with a large number of hydrazine bonds which can form a pH-sensitive bond (hydrazone bond) with DOX. The two kinds of carriers both exhibited a size around 80 nm, high stability and superparamagnetic behavior. However, DOX-loaded carriers (Fe 3 O 4 @SiO 2 –DOX(2)) performed relatively poorer performance in terms of drug loading and releasing (the loading efficiency of DOX decreased from 67.33% to 42.15%, while the releasing efficiency of DOX decreased from 66.16% to 62.23% within 72 h at pH 4.0). Water-soluble tetrazolium salts (WST-1) assays in cancer cells (Hela) demonstrated that the Fe 3 O 4 @SiO 2 –DOX presented high anti-tumor activity, while the carriers were nearly nontoxic. Thus, the results suggested that the magnetic nanocomposites synthesized by the two different methods both can be employed to deliver DOX, while the carriers obtained via the first method may perform better and would be applied in the field of cancer therapy in the future.

Fabrication of doxorubicin-loaded ellipsoid micelle based on diblock copolymer with a linkage of enzyme-cleavable peptide

Haitao Huang,Jianqi Geng,Jafar Golzarian,Jin Huang,Jiahui Yu

In this study, a novel micellar drug carrier was fabricated from an amphiphilic diblock copolymer containing poly (ethylene glycol) monomethyl ether (mPEG) and stearic moiety (C 18 ) with a linkage of valine-citrulline (VC), which can be cleaved by cathepsin B (C B ) enriched in lysosome of tumor cell. Moreover, the self-assembled micelles were observed as ellipsoid shape with major and minor axis of ca. 169 and 103   nm, respectively. Such drug carrier was used to encapsulate anti-cancer drug doxorubicin (DOX), and hence showed a faster drug release behavior in a mimic lysosome condition containing cathepsin B. It was ascribed to the lysosome-sensitivity of the valine-citrulline linkage, which was verified by the size distribution curve shifted to greater size under the same mimic lysosome condition. Furthermore, in comparison with pristine doxorubicin, the encapsulation strategy of as-fabricated micellar carrier resulted in a predominant decrease of cytotoxicity. On the whole, a micellar drug carrier, which can be disassembled by cathepsin B, has been emerging as a potential of specific drug release in lysosome. Additionally, the controlled nanoscale together with elongated structure of such assembled ellipsoid micelles might contribute passive targeting function to tumor tissue and faster cellular uptake behavior (Zhou et al. [33] ).

Stimuli-responsive polymeric prodrug-based nanomedicine delivering nifuroxazide and doxorubicin against primary breast cancer and pulmonary metastasis

Lei Luo,Fanshu Xu,Huilan Peng,Yonghuang Luo,Xiaohe Tian,Giuseppe Battaglia,Hu Zhang,Qiyong Gong,Zhongwei Gu,Kui Luo

Functionalized drug delivery systems against malignant lung metastasis of breast cancer have been extensively studied, while metastasis remains a challenging issue. We propose a new strategy to achieve eradication of primary breast cancer cells and inhibition of pulmonary metastasis. A cathepsin B/pH dual-sensitive block copolymer with a molecular weight of 92 kDa was synthesized to conjugate with doxorubicin (DOX). The copolymer-DOX was further loaded with nifuroxazide (NFX) to self-assemble co-prodrug-loaded micelles (CLM). CLM displayed a drug release pattern in response to pH/enzyme dual stimuli and was enzymatically biodegradable. CLM was demonstrated to reduce viability and inhibit migration and invasion of 4T1 murine breast cancer cells in vitro. After i.v. injection of CLM, its nanoscale size and stimuli-responsiveness facilitated delivery of drugs to the tumor site in mice. Enhanced anti-tumor efficacy and great anti-metastatic effects were found in both orthotropic and lung metastasis 4T1 breast cancer mice models. Meanwhile, histological immunofluorescence and immunohistochemical analyses revealed a high level of apoptosis, suppressed expression of matrix metalloproteinases and reduction in MDSCs infiltration , and all these contributed to inhibit pulmonary metastasis. CLM may be explored as a potential nanomedicine against breast cancer metastasis.

Co-Delivery of paclitaxel and doxorubicin in folate-Targeted pluronic/ploy (D,L-lactide-b-glycolide) polymersomes

Tian Yi Wu,Wen Jie Cao,Zi Ling Li,Yan Chun Gong,Xiang Yuan Xiong

Drugs with different solubility can be selectively embedded into polymersomes with the hydrophilic core and hydrophobic bilayer. Novel folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes were constructed and used for the co-delivery of paclitaxel (PTX) and doxorubicin (DOX) to improve their inhibitory effect over cancer cells. The particle size of blank polymersomes was mainly distributed below 125 nm. The release of PTX and DOX from polymersomes showed an initial burst release followed by a sustained and slow release. The in vitro cytotoxicity data showed that the targeted co-loaded polymersomes (PTX&DOX FA-Ps) exhibited better inhibitory effect than single-loaded polymersomes and free drugs did. Furthermore, PTX&DOX FA-Ps showed the synergistic therapeutic effect over OVCAR-3 cancer cells. The cellular uptake results also showed that folate modified polymersomes had excellent targeting performance. Therefore, the folate-targeted Pluronic/poly (D,L-lactide-b-glycolide) polymersomes have potential application value as novel drug carriers to co-deliver PTX and DOX.

A doxorubicin and siRNA coloaded nanolamellar hydroxyapatite/PLGA electrospun scaffold as a safe antitumor drug delivery system

Xiangbo Zhu,Zhiwei Yang,Deqiang Gan,Teng Cui,Honglin Luo,Yizao Wan,Quanchao Zhang

To circumvent the severe cytotoxicity and drug resistance of chemotherapeutics in cancer chemotherapy, we rationally designed an electrospun nanofibrous delivery system for the codelivery of the doxorubicin (DOX) and small interfering ribonucleic acid (siRNA) to improve antitumor activity and mitigate DOX drug resistance. DOX was intercalated into nanolamellar hydroxyapatite (LHAp), which was incorporated into electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers, and finally, the DOX-intercalated LHAp/PLGA scaffold was coated with polydopamine (PDA) followed by immobilization with siRNA/polyethyleneimine (PEI) complexes. Benefiting from its intrinsic degradability, the scaffold demonstrated pH-responsive release behavior, leading to the simultaneous delivery of DOX and siRNA. Consequently, the codelivery scaffold demonstrated enhanced therapeutic efficiency in vitro and in vivo compared with the scaffold loaded with single drug due to the combined effects of DOX and siRNA and did not show toxicity or side effects in mice. Therefore, it is a safe and effective strategy for preventing postsurgical tumor recurrence.

Erythrocyte-membrane camouflaged manganese dioxide-polydopamine nanocarriers for doxorubicin delivery and MRI-visualized chemo-photothermal cancer therapy

Xiaoming Wang,Zhiwei Duan,Xiaopo Wu,Yao Zhang,Longda Feng,Cui Wei,Shaofeng Chen,Qilei Chen,Xiaowen Zhou,Yi Zhou,Linghao Qin

Doxorubicin (DOX) chemotherapy is limited by systemic toxicity, poor tumor accumulation, and the acidic, hypoxic tumor microenvironment (TME). We developed MnO 2 -PDA-DOX@RBC/FA/PEG nanoparticles by coating manganese dioxide (MnO 2 ) cores with polydopamine (PDA) for DOX loading and cloaking the particles with folic acid (FA)- and polyethylene glycol (PEG)-modified erythrocyte membranes. The nanosystem combined colloidal stability, erythrocyte-membrane-associated long circulation, FA-mediated tumor targeting, near-infrared photothermal conversion, and TME-responsive drug release. MnO 2 catalyzed hydrogen peroxide decomposition to generate oxygen and consumed protons under acidic conditions, while acid-triggered MnO 2 degradation produced Mn 2 ⁺ for T 1 -weighted magnetic resonance imaging (MRI). In HepG2 cells, the nanoparticles enhanced DOX uptake, promoted lysosomal escape and mitochondrial accumulation, disrupted redox homeostasis, and strengthened apoptosis under 808 nm irradiation. In H22 tumor-bearing mice, MnO 2 -PDA-DOX@RBC/FA/PEG prolonged DOX circulation, reduced cardiac exposure, increased tumor accumulation, and achieved superior chemo-photothermal antitumor efficacy with reduced systemic inflammation. This biomimetic theranostic platform enables MRI- visualized, TME-responsive chemo-photothermal cancer therapy. Download: Download high-res image (195KB) Download: Download full-size image

Reversal of P-glycoprotein-mediated multidrug resistance by doxorubicin and quinine co-loaded liposomes in tumor cells

Qiying Shen,Liyan Qiu

Preparation and evaluation of highly biocompatible nanogels with pH-sensitive charge-convertible capability based on doxorubicin prodrug

Yixin Zhu,Yakun Ma,Yanli Zhao,Min Yang,Lingbing Li

In this paper, to achieve the targeted ability of anti-tumor drug doxorubicin (DOX), enhance the treatment effect and reduce the side effect, a novel pH-sensitive and charge-convertible prodrug nanogel was prepared. Firstly, cis -aconitic anhydride-doxorubicin prodrug (CAD) and Pluronic F127-chitosan-CAD (F127-CS-CAD) conjugates were synthesized. Then the DOX loaded polyion complex micelles (F127-CS-CAD/CAD) were prepared by self-assembling, thus CAD was incorporated into micelles via electrostatic interactions between electronegative CAD and positively charged F127-CS-CAD and hydrophobic interactions. Finally a pH-responsive charge-convertible copolymer, folic acid modified gelatin (Gel-FA) was shielded on the surface of micelles and the Gel-FA/F127-CS-CAD/CAD nanogel was formed, the charge-convertible capability was evaluated through changes of the morphology and Zeta potential under different pH value environment by transmission electron microscopy (TEM) and Zeta potential analyzer. And in vitro pH-dependent and two-phase drug release from nanogel was also evaluated. In vitro anti-tumor activity of Gel-FA/F127-CS-CAD/CAD nanogel was performed on HeLa cells and HepG2 cells to prove the strong cell toxicity of nanogels. Finally, the in vivo safety experiments showed that the nanogel achieved the reducing the toxic side effects of DOX significantly.

Polymer–Doxorubicin Prodrug with Biocompatibility, pH Response, and Main Chain Breakability Prepared by Catalyst-Free Click Reaction

Dian Li,Yue Song,Jinlin He,Mingzu Zhang,Peihong Ni

Click chemistry has increasing applications of the development of polymer materials and modification of drug carriers. The amino–yne click polymerization reacts quickly at room temperature without catalyst, and the enamine bond (-ena-) gained from the reaction is sensitive to acid and can be used to prepare stimulus-responsive polymeric prodrugs. Herein, we report an alkynyl-terminated polymer containing alternately distributed low molecular weight polyethylene glycol (PEG) and hexamethylenediamino (HMDA) linked by enamine bonds, abbreviated as A-P(PEG-alt-HMDA)-A, which was synthesized within 3 h at 35 °C without catalyst. The polymer was verified to have good water solubility, biocompatibility, and acid-sensitive fracturing. Then, a pH-responsive polymeric prodrug (DOX-ena-PPEG-ena-DOX) was further prepared through the amino–yne click reaction between the alkynyl groups of A-P(PEG-alt-HMDA)-A and the amino group of doxorubicin hydrochloride (DOX·HCl). The resulting prodrug can self-assemble into nanoparticles (NPs) in aqueous solution. The pH responsiveness of the prodrug NPs was demonstrated by a stability experiment of NPs and in vitro drug release behavior measurement. The accumulative release of doxorubicin (DOX) was tested with different pH media, which confirmed that the prodrug NPs could effectively dissociate and release drug under a weak acid microenvironment of lysosome/endosome. Subsequently, we investigated cell cytotoxicity and intracellular uptake of the prodrug. It turned out that the prodrug nanoparticles could be internalized into HeLa cells, release original DOX, and efficiently inhibit the proliferation of cancer cells. These results show that the pH-responsive DOX-ena-PPEG-ena-DOX has the potential for use in cancer therapy.