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Now showing items 17 - 32 of 47

  • Two-dimensional LDH nanodisks modified with hyaluronidase enable enhanced tumor penetration and augmented chemotherapy

    Gaoming Li   Yu Fan   Lizhou Lin   Rong Wu   Mingwu Shen   Xiangyang Shi  

    The condensed tumor extracellular matrix(ECM) consisting of cross-linked hyaluronic acid(HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase(HAase)-modified layered double hydroxide(LDH) nanoplatform loaded with anticancer drug doxorubicin(DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.
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  • Dendrimer-decorated nanogels: Efficient nanocarriers for biodistribution in vivo and chemotherapy of ovarian carcinoma

    Xin Li   Zhijun Ouyang   Helin Li   Chaolei Hu   Pabitra Saha   Lingxi Xing   Xiangyang Shi   Andrij Pich  

    Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy. Here, the PAMAM dendrimer decorated PVCL-GMA nanogels (NGs) were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma. By an ingenious design, the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization. After G2 dendrimer decoration, the overall charge is changed from neutral to positive, and the NGs-G2 display the whole charge nature of positively charged corona and neutral core. Importantly, the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo . As a consequence of this alteration, the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation, enhanced tumor uptake, and promoted drug release, resulting in the significantly augmented antitumor efficacy with low side effects. Remarkably, this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake. Moreover, the NGs-G2 also displayed thermal/pH dual-responsive behaviors, excellent biocompatibility, improved cellular uptake, and stimuli-responsive drug release. Encouragingly, this work demonstrates a novel insight into the strategy for optimizing design, improving biodistribution and enhancing theranostic efficacy of nanocarriers.
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  • RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cells

    Xuedan He   Carla S. Alves   Nilsa Oliveira   João Rodrigues   Jingyi Zhu   István Bányai   Helena Tomás   Xiangyang Shi  

    Graphical abstract Highlights • G5 dendrimers can be modified with RGD peptide via a PEG spacer. • DOX can be encapsulated within G5.NHAc-FI-PEG-RGD dendrimers to form stable complexes. • G5.NHAc-FI-PEG-RGD/DOX complexes display a pH-responsive release behavior. • G5.NHAc-FI-PEG-RGD/DOX complexes exhibit non-compromised therapeutic efficacy. • G5.NHAc-FI-PEG-RGD/DOX complexes specifically inhibit α v β 3 integrin-overexpressing cancer cells. Abstract Development of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing α v β 3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water-soluble, stable, and able to release DOX in a sustained manner. One- and two-dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc-FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target α v β 3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of α v β 3 integrin-overexpressing cancer cells.
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  • The aggregation and phase separation behavior of a hydrophobically modified poly(N-isopropylacrylamide)

    Xiangyang Shi   Junbai Li   Caomin Sun   Shikang Wu  

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  • Dendrimer-Functionalized Shell-crosslinked Iron Oxide Nanoparticles for In-Vivo Magnetic Resonance Imaging of Tumors

    Xiangyang Shi   Su He Wang   Scott D. Swanson   Song Ge   Zhengyi Cao   Mary E. Van Antwerp   Kevin J. Landmark   James R. Baker Jr  

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  • Antitumor efficacy of doxorubicin-loaded electrospun nano-hydroxyapatite-poly(lactic-co-glycolic acid) composite nanofibers

    Fuyin Zheng   Shige Wang   Mingwu Shen   Meifang Zhu   Xiangyang Shi  

    Electrospun composite nanofibrous scaffolds have attracted much interest for use as drug delivery vehicles in recent years. Herein, we attempted to first encapsulate the anticancer drug doxorubicin (DOX) using inorganic rod-like nano-hydroxyapatite (n-HA) as a carrier. Then, the DOX-loaded n-HA particles were mixed with poly(lactic-co-glycolic acid) (PLGA) solution to fabricate electrospun hybrid nanofibers. The formation of drug-n-HA complexes and the drug-loaded composite nanofibers were characterized using different techniques. In vitro DOX release behavior was examined using UV-vis spectroscopy under both neutral and acidic conditions. The anticancer activity of the drug-loaded composite nanofibers was evaluated via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay and phase contrast microscopic morphology observation of a model KB cancer cell line (a human epithelial carcinoma cell line). We show that DOX can be successfully loaded onto the surface of the n-HA and the formed composite fibers have a uniform and continuous fibrous morphology. Importantly, the loaded DOX shows a sustained release profile, and the released DOX from the nanofibers displays noncompromised antitumor activity towards the growth inhibition of KB cells. With the significantly reduced burst release profile and the improved mechanical durability of the composite nanofiber system compared with n-HA-free PLGA nanofibers, the designed organic-inorganic hybrid nanofibers could be used as a versatile drug delivery system for encapsulation and sustained release of different drugs with prolonged therapeutic efficacy for different biomedical applications.
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  • Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles

    Jingyi Zhu   Linfeng Zheng   Shihui Wen   Yueqin Tang   Mingwu Shen   Guixiang Zhang   Xiangyang Shi  

    Abstract Development of multifunctional theranostic nanoplatforms for targeted cancer imaging and therapy still remains a great challenge. Herein, we report the use of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) covalently linked with α-tocopheryl succinate (α-TOS) as a platform for targeted cancer computed tomography (CT) imaging and therapy. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH 2 ) conjugated with fluorescein isothiocyanate (FI), polyethylene glycol (PEG)-modified α-TOS, and PEGylated folic acid (FA) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. We show that the Au DENPs conjugated with approximately 9.8 α-TOS molecules per dendrimer and with an Au core size of 3.3 nm are water-dispersible, and stable under different pH and temperature conditions and in different aqueous media. The FA modification onto the Au DENPs enables efficient targeting of the particles to cancer cells overexpressing FA receptors (FAR), and effective targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo . Likewise, the covalent conjugation of α-TOS does not compromise its therapeutic activity, instead significantly improves its water solubility. Importantly, thanks to the role of FA-directed targeting, the formed multifunctional Au DENPs are able to exert the specific therapeutic efficacy of α-TOS to the FAR-overexpressing cancer cells in vitro and the xenografted tumor model in vivo . The developed multifunctional Au DENPs may hold a great promise to be used as a unique theranostic nanoplatform for targeted CT imaging and therapy of different types of cancer.
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  • The aggregation behavior of collagen in aqueous solution and its property of stabilizing liposomes in vitro

    Xiangyang Shi   Wanyun Ma   Caomin Sun   Shikang Wu  

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  • Analysis of poly(amidoamine)-succinamic acid dendrimers by slab-gel electrophoresis and capillary zone electrophoresis

    Xiangyang Shi   Anil K. Patri   Wojciech Lesniak   Mohammad T. Islam   Chunxin Zhang   James R. Baker Jr   Lajos P. Balogh  

    Ethylenediamine (EDA)-core poly(amidoamine) (PAMAM) succinamic acid dendrimers (Ex.SAH, where x refers to the generation) were synthesized and analyzed by polyacrylamide gel electrophoresis (PAGE), size-exclusion chromatography (SEC), potentiometric acid-base titration, and capillary zone electrophoresis (CZE). Various generations (E1.SAH-E7.SAH) PAMAMs and a succinamic acid terminated core-shell tecto(dendrimer) (E5(E3.SAH)(n)) were first analyzed by PAGE. PAGE results show that the relative mobilities of generation 2 to generation 7 dendrimers decreased with the increasing number of generations. The molecular mass of a generation 5 core generation 3 shell tecto(dendrimer) (denoted as E5(E3.SAH)(n)) was determined to be between the Mw of E6.SAH and E7.SAH. CZE analysis allowed the evaluation of electrophoretic properties of given-generation dendrimers. The electrophoretic mobilities of individual generations PAMAM polyanions are similar, indicating that the separation mainly depends on their approximately identical charge/mass ratio. The E5(E3.SAH)(n) tectodendrimer had a lower electrophoretic mobility, which was consistent with its lower charge/mass ratio. The combination of PAGE and CZE analysis provides an alternative and effective way to characterize this group of PAMAM-succinamic acid dendrimers.
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  • Targeted tumor dual mode CT/MR imaging using multifunctional polyethylenimine-entrapped gold nanoparticles loaded with gadolinium

    Benqing Zhou   Zuogang Xiong   Peng Wang   Chen Peng   Mingwu Shen   Serge Mignani   Jean-Pierre Majoral   Xiangyang Shi  

    We report the construction and characterization of polyethylenimine (PEI)-entrapped gold nanoparticles (AuNPs) chelated with gadolinium (Gd) ions for targeted dual mode tumor CT/MR imaging in vivo. In this work, polyethylene glycol (PEG) monomethyl ether-modified PEI was sequentially modified with Gd chelator and folic acid (FA)-linked PEG (FA-PEG) was used as a template to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining PEI surface amines. The formed FA-targeted PEI-entrapped AuNPs loaded with Gd (FA-Gd-Au PENPs) were well characterized in terms of structure, composition, morphology, and size distribution. We show that the FA-Gd-Au PENPs with an Au core size of 3.0 nm are water dispersible, colloidally stable, and noncytotoxic in a given concentration range. Thanks to the coexistence of Au and Gd elements within one nanoparticulate system, the FA-Gd-Au PENPs display a better X-ray attenuation property than clinical iodinated contrast agent (e.g. Omnipaque) and reasonable r1 relaxivity (1.1 mM−1s−1). These properties allow the FA-targeted particles to be used as an efficient nanoprobe for dual mode CT/MR imaging of tumors with excellent FA-mediated targeting specificity. With the demonstrated organ biocompatibility, the designed FA-Gd-Au PENPs may hold a great promise to be used as a nanoprobe for CT/MR dual mode imaging of different FA receptor-overexpressing tumors.
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  • Comprehensive characterization of surface-functionalized poly(amidoamine) dendrimers with acetamide, hydroxyl, and carboxyl groups

    Xiangyang Shi   Wojciech Lesniak   Mohammad T. Islam   Maria C. Mu?iz   Lajos P. Balogh   James R. Baker Jr.  

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  • Electrospun laponite-doped poly(lactic-co-glycolic acid) nanofibers for osteogenic differentiation of human mesenchymal stem cells

    Shige Wang   Castro, R.   Xiao An   Chenlei Song   Yu Luo   Mingwu Shen   Tomas, H.   Meifang Zhu   Xiangyang Shi  

    We report the fabrication of uniform electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers incorporated with laponite (LAP) nanodisks, a synthetic clay material for osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study, a solution mixture of LAP suspension and PLGA was electrospun to form composite PLGA-LAP nanofibers with different LAP doping levels. The PLGA-LAP composite nanofibers formed were systematically characterized via different techniques. We show that the incorporation of LAP nanodisks does not significantly change the uniform PLGA fiber morphology, instead significantly improves the mechanical durability of the nanofibers. Compared to LAP-free PLGA nanofibers, the surface hydrophilicity and protein adsorption capacity of the composite nanofibers slightly increase after doping with LAP, while the hemocompatibility of the fibers does not appreciably change. The cytocompatibility of the PLGA-LAP composite nanofibers was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of L929 mouse fibroblasts and porcine iliac artery endothelial cells cultured onto the surface of the nanofibers. The results reveal that the incorporated LAP is beneficial to promote the cell adhesion and proliferation to some extent likely due to the improved surface hydrophilicity and protein adsorption capability of the fibers. Finally, the PLGA-LAP composite nanofibers were used as scaffolds for osteogenic differentiation of hMSCs. We show that both PLGA and PLGA-LAP composite nanofibers are able to support the osteoblast differentiation of hMSCs in osteogenic medium. Most strikingly, the doped LAP within the PLGA nanofibers is able to induce the osteoblast differentiation of hMSCs in growth medium without any inducing factors. The fabricated smooth and uniform organic-inorganic hybrid LAP-doped PLGA nanofibers may find many applications in the field of tissue engineering.
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  • Multifunctional PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells

    Lingdan Kong   Jieru Qiu   Xiangyang Shi  

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  • Multifunctional polyethylenimine-based nanoplatform for targeted anti-cancer drug delivery to tumors in vivo

    Benqing Zhou   Lingzhou Zhao   Jinhua Zhao   Xiangyang Shi  

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  • Safe and efficient 2D molybdenum disulfide platform for cooperative imaging-guided photothermal-selective chemotherapy: A preclinical study

    Xin Li   Lingdan Kong   Wei Hu   Changchang Zhang   Andrij Pich   Xiangyang Shi   Xipeng Wang   Lingxi Xing  

    Introduction The striking imbalance between the ever-increasing amount of nanomedicines and low clinical translation of products has become the focus of intense debate. For clinical translation, the critical issue is to select the appropriate agents and combination regimen for targeted diseases, not to prepare increasingly complex nanoplatforms. Objectives A safe and efficient platform, α-tocopheryl succinate (α-TOS) married 2D molybdenum disulfide, was devised by a facile method and applied for cooperative imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Methods A novel platform of PEGylated α-TOS and folic acid (FA) conjugated 2D MoS 2 nanoflakes was fabricated  for the cooperative multimode computed tomography (CT)/photoacoustic (PA)/thermal imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Results The photothermal efficiency (65.3%) of the platform under safe near-infrared irradiation is much higher than that of other photothermal materials reported elsewhere. Moreover, the covalently linked α-TOS renders platform with selective chemotherapy for cancer cells. Remarkably, with these excellent properties, the platform can be used to completely eliminate the solid tumor by safe photothermal therapy, and then kill the residual cancer cells by selective chemotherapy to prevent tumor recurrence. More significantly, barely side effects occur in the whole treatment process. The excellent efficacy and safety benefits in vivo lead to the prominent survival rate of 100% over 91 days. Conclusion The safe and efficient platform might be a candidate of clinical nanomedicines for multimode theranostics. This study demonstrates an innovative thought in precise nanomedicine regarding the design of next generation of cancer theranostic protocol for potential clinical practice.
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  • Electrospun attapulgite-doped poly(lactic-<em>co</em>-glycolic acid) nanofibers for osteogenic differentiation of human mesenchymal stem cells

    Zhe Wang   Yili Zhao   Yu Luo   Shige Wang   Leqiang Zhang   Xiangyang Shi  

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