查找使用阿拉丁产品的科研文献

Phosphatidylserine targeting peptide-functionalized pH sensitive mixed micelles for enhanced anti-tumor drug delivery

Siyu Guan,Qianqian Zhang,Jianwei Bao,Tijie Duan,Rongfeng Hu,Tori Czech,Jihui Tang

In recent decades, targeted drug delivery systems (TDDS) have been widely used as an ideal method of improving therapeutic effects and reducing systemic side effects of chemotherapeutic agents. Historically, a handful of methods have been developed to further improve the targeting ability of delivery systems. Thus, in this study, two methods, taking advantage of tumor characteristics, were used for the creation of a multi-targeted delivery system. The first was the fabrication of pH-sensitive micelles , lending the ability to increase drug release by exploiting the acidic tumor environment. The second method was through utilization of the surface-exposed phosphatidylserine (PS) of tumors, which is normally found in the inner leaflet in healthy cells. Using PS as a target site, PS binding peptide (PSBP-6) was conjugated to pH-sensitive mixed micelles, (consisting of poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PDLLA) and poly (ethylene glycol)-b-poly (L-histidine) (PEG-PHIS)). After successful preparation of micelles, paclitaxel (PTX), a common chemotherapeutic agent, was selected to measure drug loading capacity and encapsulation efficiency, showing 7.9% and 83.5%, respectively. The in vitro release of PTX from mixed micelles at pH 5.0, 6.5, and 7.4 was 78.1, 56.8, and 51.4%, respectively, indicating acid-triggered drug release. The PSBP-6-modified, mixed micelles exhibited significantly enhanced in vitro cytotoxicity and demonstrated more efficient cellular uptake compared to unmodified mixed micelles in the HeLa cell line. Moreover, pharmacokinetic , in vivo biodistribution , and fluorescence imaging studies showed that PSBP-6-PEG-PDLLA/PEG-PHIS mixed micelles provide prolonged time in blood circulation and enhanced tumor accumulation. These results suggest that the use of PS as a novel targeting site is advantageous, and that these new multi-targeted mixed micelles show great potential for realization of broad prospects in the targeted treatment of tumors for chemotherapeutic delivery.

Redox-sensitive micelles based on retinoic acid modified chitosan conjugate for intracellular drug delivery and smart drug release in cancer therapy

Tingting Luo,Jingtian Han,Feng Zhao,Xiaohong Pan,Baocheng Tian,Xiujuan Ding,Jing Zhang

Novel chitosan-cystamine-retinoic acid conjugate (CS-SS-RA) was synthesized and could self-assemble into redox-sensitive micelles in aqueous environment with low critical micelle concentration value. CS-SS-RA micelles were characterized with spherical shape, desirable particle size, negative zeta potential, high paclitaxel (PTX) loading and encapsulation efficiency and redox-sensitivity. Hemolysis and cytotoxicity studies proved the safety of CS-SS-RA micelles for intravenous administration. Cytotoxicity study against HepG2 cells and the growth inhibition study on three-dimensional multicellular tumor spheroids (MCTSs) revealed that PTX-loaded CS-SS-RA micelles exhibited higher antitumor activity than free PTX. The in vitro cellular uptake profiles of FITC-labeled CS-SS-RA micelles evaluated via confocal laser scanning microscopy and flow cytometry indicated that CS-SS-RA micelles could enhance cellular uptake efficiency of PTX, and their internalization by HepG2 cells were mediated by clathrin-mediated endocytosis and macropinocytosis. These results demonstrated that CS-SS-RA micelles could be developed as a promising platform for intracellular delivery of hydrophobic antitumor agents.

Elucidation of cellular uptake and intracellular trafficking of heparosan polysaccharide-based micelles in various cancer cells

Lipeng Qiu,Xiaotian Shan,Miaomiao Long,Kamel S. Ahmed,Li Zhao,Jing Mao,Huijie Zhang,Changling Sun,Chongzhao You,Guozhong Lv,Jinghua Chen

Heparosan polysaccharide , known as a heparin precursor, can be used in drug delivery systems due to its good biocompatibility and anti-cancer effect. But few studies on the cellular uptake mechanism of heparosan polysaccharide-based nanocarrier have been investigated. Therefore, the intracellular trafficking and the uptake mechanism of heparosan-based micelles by different tumor cells were investigated in this study. Heparosan-cholesterol amphipathic conjugates (KC) were constructed and doxorubicin (DOX) was loaded to prepare DOX/KC micelles. Different cancer cells were selected to find out the influence on DOX/KC uptake. There was an obvious difference in cytotoxicity and cellular uptake of DOX/KC in various cancer cells. Interestingly, DOX/KC micelles exhibited the strongest cytotoxicity against MGC80-3 cells and displayed highly cellular uptake by B16 cells. The results of the uptake mechanism showed that the internalization of DOX/KC micelles into MGC80-3 cells and A549 cells was mainly through clathrin-mediated endocytosis and macropinocytosis , while micropinocytosis , clathrin-mediated endocytosis and clathrin/caveolae -independent multi-pathways all contributed to the uptake of micelles in B16 cells. Furthermore, after being internalized by MGC80-3 cells, DOX/KC could escape from the lysosome and simultaneously be transported into the nucleus and mitochondria resulting in the greatest cytotoxicity. These results indicate that heparosan-based drug delivery systems may have different uptake and subcellular distribution behavior in tumor cells, and they will achieve the maximum efficacy only in specific kind of cancers.

Ratiometric co-encapsulation and co-delivery of doxorubicin and paclitaxel by tumor-targeted lipodisks for combination therapy of breast cancer

Chunlai Feng,Haisheng Zhang,Jiaming Chen,Siqi Wang,Yuanrong Xin,Yang Qu,Qi Zhang,Wei Ji,Fumiyoshi Yamashita,Mengjie Rui,Ximing Xu

Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro , combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) incorporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained co-loaded lipodisks were approximately 30  nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro , as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues. Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo , potentially enhancing the clinical outcome of synergistic therapy.

Biomineralization-inspired Crystallization of Manganese Oxide on Silk Fibroin Nanoparticles for in vivo MR/fluorescence Imaging-assisted Tri-modal Therapy of Cancer

Ruihao Yang,Mengmeng Hou,Ya Gao,Shiyu Lu,Lei Zhang,Zhigang Xu,Chang Ming Li,Yuejun Kang,Peng Xue

Regenerated silk fibroin (SF) is a type of natural biomacromolecules with outstanding biocompatibility and biodegradability. However, stimulus-responsive SF-based nanocomplex has seldom been reported for application in tumor diagnosis and therapy. Methods : As a proof-of-concept study, a multifunctional SF@MnO 2 nanoparticle-based platform was strategically synthesized using SF as a reductant and a template via a biomineralization-inspired crystallization process in an extremely facile way. Because of their mesoporous structure and abundant amino and carboxyl terminal residues, SF@MnO 2 nanoparticles were co-loaded with a photodynamic agent indocyanine green (ICG) and a chemotherapeutic drug doxorubicin (DOX) to form a SF@MnO 2 /ICG/DOX (SMID) nanocomplex. Results : The obtained product was highly reactive with endogenous hydrogen peroxide (H 2 O 2 ) in tumor microenvironment, which was decomposed into O 2 to enhance tumor-specific photodynamic therapy (PDT). Moreover, SMID nanocomplex produced a strong and stable photothermal effect upon near-infrared (NIR) irradiation for photothermal therapy (PTT) owing to the distinct photothermal response of SF@MnO 2 and stably conjugated ICG . The concurrent NIR fluorescence and magnetic resonance (MR) imaging in vivo both indicated effective tumor-specific enrichment of SMID nanoparticles via enhanced permeability and retention (EPR) effect. Animal studies further verified that SMID nanoparticles remarkably improved tumor inhibitive efficacy through combination PTT/PDT/chemotherapy with minimal systemic toxicity or adverse effect. Conclusion : This study demonstrated the promising potential of SF-based nanomaterial to address some of the key challenges in cancer therapy due to unfavorable tumor microenvironment for drug delivery.

Dual-Functionalized Janus Mesoporous Silica Nanoparticles with Active Targeting and Charge Reversal for Synergistic Tumor-Targeting Therapy

Yajun Liu,Rui Dai,Qiuyu Wei,Wenzhe Li,Guang Zhu,Hao Chi,Zhaoming Guo,Li Wang,Changhao Cui,Jianqiang Xu,Kun Ma

Janus nanoparticles with an anisotropic feature concentrated multiple properties on a single carrier, providing synergistic effects. In this study, dual-functionalized Janus nanoparticles (HA-JMSN/DOX-DMMA) were constructed with a tumor-targeting ligand (hyaluronic acid, HA) modified on the one side and a charge reversal group (2,3-dimethylmaleic anhydride, DMMA) on the other side. The drug release of HA-JMSN/DOX-DMMA was positively correlated with the acidity of the environment. The cytotoxicity and cell uptake of HA-JMSN/DOX-DMMA were superior to the isotropous nanoparticles. The endocytosis pathway of HA-JMSN/DOX-DMMA involved the clathrin-mediated endocytosis (HA) and the micropinocytosis (DMMA) at the same time, which indicated that they both participated in the interaction between nanoparticles and tumor cells. After being injected intravenously in mice, the distribution of HA-JMSN/DOX-DMMA in tumor was enhanced significantly. The antitumor therapy study in vivo showed that HA-JMSN/DOX-DMMA inhibited tumor growth and improved the survival rate of tumor-bearing mice effectively. In general, HA-JMSN/DOX-DMMA could take the synergistic effect of active targeting and charge reversal to deliver drug in tumor cells and kill them efficiently, which was a promising antitumor nanodrug.

Targeted imaging of the lysosome and endoplasmic reticulum and their pH monitoring with surface regulated carbon dots

Shuang E,Quan-Xing Mao,Xiao-Li Yuan,Xiao-Lei Kong,Xu-Wei Chen,Jian-Hua Wang

Organelles play crucial roles in cellular activities and the functions of organelles are related greatly to the pH values, therefore, the bio-imaging of targeted organelles and their related pH sensing is of great importance in biological assays. Herein we report the fluorescence imaging of specific organelles, i.e., lysosomes and endoplasmic reticulum, and their pH sensing with surface regulated carbon dots (CDs). Carbon dots functionalized with amine groups (ACDs) are first prepared by hydrothermal treatment of citric acid and urea, and then laurylamine functionalized CDs (LCDs) are obtained via the conjugation of laurylamine with ACDs. The as-prepared ACDs and LCDs provide clear and bright imaging results for the lysosome and endoplasmic reticulum, respectively. The subcellular targeting features of the two CDs are attributed to their surface chemistries and cellular uptake pathways. Moreover, both the CDs are pH responsive within a certain pH range, i.e., 4.0–5.4 for ACDs and 6.2–7.2 for LCDs. The ACDs and LCDs are thus successfully applied to visualize the pH fluctuations of the lysosome and endoplasmic reticulum in MCF-7 cells.

Delivery of DNAzyme targeting aurora kinase A to inhibit the proliferation and migration of human prostate cancer

Zhen Xing,Sai Gao,Yan Duan,Haobo Han,Li Li,Yan Yang,Quanshun Li

Endocytosis mechanism of a novel proteoglycan, extracted from Ganoderma lucidum, in HepG2 cells

Zhou Yang,Fan Wu,Hongjie Yang,Ping Zhou

A novel protein tyrosine phosphatase 1B (PTP1B) inhibitor, FYGL, extracted from Ganoderma lucidum, was first reported to have an efficient hypoglycemic effect and high safety in vivo in our previous study. However, the underlying mechanism of the anti-diabetes activity was still unclear. The dominant effective component of FYGL was demonstrated to be a neutral hyperbranched proteoglycan macromolecule. Therefore, it is necessary to first elucidate how the biomacromolecule works at the cellular level, in order to understand its possible functional mechanism in vivo. Herein, we focused on demonstrating the cell internalization and endocytosis mechanism of FYGL in HepG2 cells. A series of cellular uptake pathways was explored, including clathrin-mediated endocytosis, caveolae/lipid-mediated endocytosis, and macropinocytosis. Confocal laser scanning microscopy and flow cytometry were used to demonstrate the absorption of FYGL by HepG2 cells. Furthermore, pharmacologically selective inhibitors and Western blot methods were used to demonstrate that macropinocytosis mediated by c-Src/PI3K cascades was the preferred route for the uptake of FYGL in cells. Our study provided the basis of uptake of FYGL for an efficient hypoglycemic effect. The functional mechanism of the signaling pathway in vivo will be reported in the future.

A peptide-decorated and curcumin-loaded mesoporous silica nanomedicine for effectively overcoming multidrug resistance in cancer cells

Xian Sun,Yingping Luo,Liwei Huang,Bo-Yang Yu,Jiangwei Tian

Multidrug resistance (MDR) is a major obstacle to the success of cancer chemotherapy, which is closely associated with the overexpression of P-glycoprotein (P-gp) and the endolysosomal capture of drug. Therefore, to explore a strategy that could down-regulate P-gp expression and promote drugs escaping from the endolysosome is highly desired for overcoming MDR in chemotherapeutic treatment. This work reports a peptide-functionalized mesoporous silica nanomedicine (MSN) for encapsulation of curcumin (CUR) and doxorubicin (DOX) to significantly reverse the MDR in consequence of rapid endolysosomal escape and the inhibition of P-gp function. The nanomedicine is modified with the peptide of GFLGHHHRRGDS to encapsulate CUR and DOX with high loading efficiency and content. It can be selectively uptaken by the DOX resistant MCF-7/ADR cells via the specific recognition between RGDS and αvβ3 integrin to enter into lysosomes. Afterwards, the GFLG is cleaved by the lysosomal cathepsin B to release CUR and DOX from MSN. Furthermore, the imidazole-rich HHHR peptide can induce effective lysosomal membrane permeability which is beneficial for drug escape from lysosome, CUR-mediated inhibition of P-gp, and nuclear import of DOX in MCF-7/ADR cells. Confocal fluorescence imaging, flow cytometry and MTT assays demonstrate that the combination of CUR and the peptide-functionalized MSN markedly enhances the intracellular DOX concentration and achieves a successful chemotherapeutic treatment to MCF-7 or MCF-7/ADR cells, thus this work offers an effective strategy to overcome MDR.

Discovery of the cell-penetrating function of A2 domain derived from LTA subunit of Escherichia coli heat-labile enterotoxin

Liu Di,Guo Hua,Zheng Wenyun,Zhang Na,Wang Tianwen,Wang Ping,Ma Xingyuan

Heat-labile enterotoxin (LT) is a protein toxin produced by enterotoxigenic Escherichia coli (ETEC). As a bacterial toxin, LT holotoxin can enter intestinal epithelial cells and cause diarrhea. In addition, LT is also a powerful mucosal adjuvant capable of enhancing the strong immune responses to co-administered antigens. However, the LT immunological mechanism is still not clear in some aspects, especially with the respect to how the LTA subunit functions alone. Here, we discovered that the A 2 domain of LTA could carry a fluorescent protein into cells, whose function is similar to a cell-penetrating peptide. The transmembrane-transporting ability of the A 2 domain is non-specific in its cell-penetrating function, which was shown through testing with different cell types. Moreover, the LTA 2 fusion protein penetrated a fluorescently labeled cell membrane that identified LTA 2 internalization through membrane transport pathways, and showed it finally localized in the endoplasmic reticulum. Furthermore, low-temperature stress and pharmacological agent treatments showed that the LTA 2 internalization route is a temperature-dependent process involving the clathrin-mediated endocytosis and the macropinocytosis pathways. These results could explain the internalization of the LTA subunit alone without the LTB pentamer, contributing to a better understanding of LTA working as a mucosal adjuvant; they also suggest that the A 2 domain could be used as a novel transport vehicle for research and treatment of disease.

Dual-Carriers of Tartary Buckwheat-Derived Exosome-Like Nanovesicles Synergistically Regulate Glucose Metabolism in the Intestine-Liver Axis

Dan Li,Gaoyang Yi,Guifang Cao,Adam C. Midgley,Yongli Yang,Dan Yang,Wenguang Liu,Yujuan He,Xiaolin Yao,Guoliang Li

The utilization of plant-derived exosome-like nanovesicles (ELNs) as nanocarriers for oral delivery of bioactives has garnered significant attention. However, their distinctive lipid membrane composition may result in elevated membrane permeability within the gastrointestinal environment, leading to the leakage of carried bioactives. Inspired by the concept of projectile design, Tartary buckwheat-derived ELNs (TB-ELNs) based dual-carriers are fabricated by loading chlorogenic acid (CGA) into the cores and bonding selenium nanoparticles (SeNPs) to the lipid membrane. The results indicate that SeNPs bond markedly augments the membrane rigidity, and therefore enhances the stability of TB-ELNs and the retention rate of the loaded CGA during gastrointestinal digestion. In vitro and in vivo studies indicates that the TB-ELNs based dual-carriers are internalized by epithelial cells and transcytosis via the endoplasmic reticulum, and show the synergistic regulatory effect on high-fat diet-induced hyperglycemia in the intestine-liver axis. These results may be attributed to the fact that SeNPs combination reduces the gastrointestinal degradation of the carried bioactives. Moreover, SeNPs with antioxidant property can protect ELNs and their carried bioactives from oxidative damage, thereby enhancing their biological activities. Collectively, this study offers a new strategy to develop highly efficient oral delivery systems for bioactives to alleviate hyperglycemia and diabetes.