28 research outputs found

    In Vivo Imaging Tracking and Immune Responses to Nanovaccines Involving Combined Antigen Nanoparticles with a Programmed Delivery

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    Combined nanovaccine can generate robust and persistent antigen-specific immune responses. A combined nanovaccine was developed based on antigen-loaded genipin-cross-linked-polyethyleneimineā€“antigen nanoparticles and in vivo multispectral fluorescence imaging tracked the antigen delivery of combined nanovaccine. The inner layer antigen nanoparticles carried abundant antigens by self-cross-linking for persistent immune response, whereas the outer antigen on the surface of antigen nanoparticles provided the initial antigen exposure. The delivery of combined nanovaccine was tracked dynamically and objectively by the separation of inner genipin cross-linked antigen nanoparticle and the outer fluorescent antigen. The immune responses of the combined nanovaccine were evaluated including antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses, IgG antibody level, immunological memory, and CD8<sup>+</sup> cytotoxic T lymphocyte responses. The results indicated that the inner and outer antigens of combined vaccine can be tracked in real time with a programmed delivery by the dual fluorescence imaging. The programmed delivery of the inner and outer antigens induced strong immune responses with a combination of a quick delivery and a persistent delivery. With adequate antigen exposure, the dendritic cells were effectively activated and matured, and following T cells were further activated for immune response. Compared with a single nanoparticle formulation, the combined nanovaccine exactly elicited a stronger antigen-specific immune response

    Surface-Induced Hydrogelation for Fluorescence and Naked-Eye Detections of Enzyme Activity in Blood

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    Fluorescence probes have been widely applied for the detection of important analytes with high sensitivity and specificity. However, they cannot be directly applied for the detection in samples with autofluorescence such as blood. Herein, we demonstrated a simple but effective method of surface-induced self-assembly/hydrogelation for fluorescence detection of an enzyme in biological fluids including blood and cell lysates. The method utilizes an attracting glass surface to induce self-assembly of an enzyme-generating fluorescent probe. After removing the upper solution, the fluorescence turn-on at the glass surface can therefore be used for the detection of enzyme activity. By judging the thickness and color depth of hydrogels at the surface of the glass plates, we could also estimate the enzyme activity by naked eyes. Our study not only expands the application of molecular self-assembly but also provides a useful method that can be applied for direct detection of enzyme activity in complex biological samples such as blood and cell lysates

    ONOO<sup>ā€“</sup> and ClO<sup>ā€“</sup> Responsive Organic Nanoparticles for Specific in Vivo Image-Guided Photodynamic Bacterial Ablation

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    Bacterial infection poses serious medical and public concerns. Herein, ā€œ33%IRTPā€ nanoparticles (NPs) are reported for in vivo bacterial infection detection and photodynamic treatment, serving as an alternative to antibiotic therapy. 33%IRTP nanoparticles have been developed by self-assembly of an ONOO<sup>ā€“</sup> and ClO<sup>ā€“</sup> responsive near-infrared dye ā€œIR786Sā€ and an amphiphilic polymer ā€œTBD-PEGā€ containing a highly effective photosensitizer with aggregation-induced emission characteristics. As an energy acceptor, IR786S not only shows near-infrared emission for fluorescence imaging but also quenches both fluorescence and singlet oxygen generation of TBD-PEG, thus eliminating the phototoxicity of 33%IRTP nanoparticles in normal tissues. Once 33%IRTP NPs reach bacterial infection sites, IR786S could be decomposed by the overexpressed ONOO<sup>ā€“</sup> and ClO<sup>ā€“</sup> to turn on the red fluorescence and singlet oxygen generation of TBD-PEG, which offers image-guided photodynamic bacterial ablation. Considering their negligible in vivo dark toxicity, 33%IRTP nanoparticles demonstrate great potential in antibacterial applications

    Responsive Small Molecular Hydrogels Based on Adamantaneā€“Peptides for Cell Culture

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    The development of responsive small molecular hydrogels that can be applied for recovery of cells postculture attract extensive interests for researchers in fields of cell biology, stem cell differentiation, and tissue engineering. We report in this study several responsive small molecular hydrogels based on adamantaneā€“peptides whose gel to clear solution phase transition can be achieved by addition of Ī²-cyclodextrin (Ī²-CD) derivatives. The small molecular hydrogels are formed by our recently developed method of disulfide bond cleavage by glutathione (GSH). Mouse fibroblast 3T3 cells attach and grow well at the surface of hydrogels. Furthermore, 3T3 cells postculture can be recovered from the gels by the addition of a Ī²-CD derivative due to formation of clear solutions by the adamantaneāˆ’Ī²-CD interaction. The culture on hydrogels and recovery process do not cause obvious effects on behaviors of 3T3 cells. The results shown in this study indicate that small molecular hydrogels based on adamantaneā€“peptides have great potentials in research fields where further analysis of cells is needed

    Real-Time Imaging Tracking of a Dual Fluorescent Drug Delivery System Based on Zinc Phthalocyanine-Incorporated Hydrogel

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    Real-time tracking of a drug delivery system and its therapeutic effects in vivo are crucial to designing a novel pharmaceutical system and revealing the mechanism of drug therapy. Multispectral fluorescence imaging can locate the drug and carrier simultaneously without interference. This advanced method enables the tracking of a drug delivery system. Herein, a doxorubicin (Dox) loaded zinc phthalocyanine incorporated hydrogel was developed as a dual fluorescent drug delivery system to monitor the release of the drug and the degradation of the carrier. An injectable thermosensitive hydrogel based on a four-arm polyĀ­(ethylene glycol) (PEG)ā€“polyĀ­(Īµ-Caprolactone) (PCL) copolymer was prepared and characterized with a zinc phthalocyanine core as the drug carrier. The hydrogel degradation and drug delivery in vivo were tracked by a multispectral fluorescence imaging system in nude mice bearing hepatic tumors. Moreover, the real-time tumor inhibition progress was tracked in vivo for 18 days by bioluminescence imaging. A multispectral analysis can separate the fluorescence signals from the drug and carrier in the Dox loaded hydrogel and provide their location in the tumor tissue. The drug release and hydrogel degradation can be drastically tracked respectively without mutual interference. The fluorescence imaging results reveal improved tumor inhibitory effects of the Dox loaded hydrogel. Optical imaging allows for visible tracking of the entire drug delivery process. The Dox loaded phthalocyanine incorporated thermosensitive hydrogel is a potential visible drug delivery system for tumor therapy

    Fluorine Meets Amine: Reducing Microenvironment-Induced Amino-Activatable Nanoprobes for <sup>19</sup>Fā€‘Magnetic Resonance Imaging of Biothiols

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    <sup>19</sup>F-magnetic resonance imaging (MRI) is of great significance for noninvasive imaging and detection of various diseases. However, the main obstacle in the application of <sup>19</sup>F-MRI agents stems from the unmet signal sensitivity due to the poor water solubility and restricted mobility of segments with high number of fluorine atoms. Herein, we report a kind of intracellular reducing microenvironment-induced amino-activatable <sup>19</sup>F-MRI nanoprobe, which can be used for specific imaging of biothiols. In principle, the nanoprobe has an initial architecture of hydrophobic core, where the trifluoromethyl-containing segments are compactly packed and <sup>19</sup>F NMR/MRI signals are quenched (ā€œOFFā€ state). Upon encountering sulfydryl, the strong electron-withdrawing 2,4-dinitrobenzenesulfonyl groups are excised to recover secondary amino groups, whose p<i>K</i><sub>a</sub> is proved to be 7.21. As a consequence, the molecular weight loss of the hydrophobic segment and the protonation of amino groups induce significant disturbance of hydrophilic/hydrophobic balance, leading to the disassembly of the nanoprobes and regain of spinā€“spin relaxation and <sup>19</sup>F NMR/MRI signals (ā€œONā€ state, <i>T</i><sub>2</sub> up to 296 Ā± 5.3 ms). This nanoprobe shows high sensitivity and selectivity to biothiols, enabling intracellular and intratumoral imaging of glutathione. Our study not only provides a new nanoprobe candidate for biothiols imaging in vivo but also a promising strategy for the molecular design of real water-soluble and highly sensitive <sup>19</sup>F-MRI nanoprobes

    Self-Assembling Peptide of dā€‘Amino Acids Boosts Selectivity and Antitumor Efficacy of 10-Hydroxycamptothecin

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    d-peptides, which consist of d-amino acids and can resist the hydrolysis catalyzed by endogenous peptidases, are one of the promising candidates for construction of peptide materials with enhanced biostability in vivo. In this paper, we report on a self-assembling supramolecular nanostructure of d-amino acid-based peptide Nap-G<sup>D</sup>F<sup>D</sup>F<sup>D</sup>YGRGD (d-fiber, <sup>D</sup>F meant d-phenylalanine, <sup>D</sup>Y meant d-tyrosine), which were used as carriers for 10-hydroxycamptothecin (HCPT). Transmission electron microscopy observations demonstrated the filamentous morphology of the HCPT-loaded peptides (d-fiber-HCPT). The better selectivity and antitumor activity of d-fiber-HCPT than l-fiber-HCPT were found in the in vitro and in vivo antitumor studies. These results highlight that this model d-fiber system holds great promise as vehicles of hydrophobic drugs for cancer therapy

    Bioinspired Coordination Micelles Integrating High Stability, Triggered Cargo Release, and Magnetic Resonance Imaging

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    Catechol-Fe<sup>3+</sup> coordinated micelles show the potential for achieving on-demand drug delivery and magnetic resonance imaging in a single nanoplatform. Herein, we developed bioinspired coordination-cross-linked amphiphilic polymeric micelles loaded with a model anticancer agent, doxorubicin (Dox). The nanoscale micelles could tolerate substantial dilution to a condition below the critical micelle concentration (9.4 Ā± 0.3 Ī¼g/mL) without sacrificing the nanocarrier integrity due to the catechol-Fe<sup>3+</sup> coordinated core cross-linking. Under acidic conditions (pH 5.0), the release rate of Dox was significantly faster compared to that at pH 7.4 as a consequence of coordination collapse and particle de-cross-linking. The cell viability study in 4T1 cells showed no toxicity regarding placebo cross-linked micelles. The micelles with improved stability showed a dramatically increased Dox accumulation in tumors and hence the enhanced suppression of tumor growth in a 4T1 tumor-bearing mouse model. The presence of Fe<sup>3+</sup> endowed the micelles <i>T</i><sub>1</sub>-weighted MRI capability both in vitro and in vivo without the incorporation of traditional toxic paramagnetic contrast agents. The current work presented a simple ā€œthree birds with one stoneā€ approach to engineer the robust theranostic nanomedicine platform

    Surface-Induced Hydrogelation Inhibits Platelet Aggregation

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    We demonstrate that a tripeptide hydrogelator, Nap-FFG, can selectively self-assemble at the surface of platelets, thus inhibiting ADP-, collagen-, thrombin- and arachidonic acid (AA)-induced human platelet aggregations with the IC<sub>50</sub> values of 0.035 (41), 0.14 (162), 0.062 (68), and 0.13 mg/mL (148 Ī¼M), respectively. Other tripeptide hydrogelators with chemical structures of Nap-FFX (X = A, K, S, or E) could not or possessed less potencies to inhibit platelet aggregations. We observed higher amounts of Nap-FFG at the platelet surface by the techniques of LC-MS and confocal microscopy. We also observed self-assembled nanofibers around the platelet incubated with the Nap-FFG by cryo-TEM. The Ī¶ potential of Nap-FFG treated platelets was a little bit more negative than that of untreated ones. The amount of Nap-FFG at the surface of NIH 3T3 cells was much less than that of platelets. These observations suggested that Nap-FFG could selectively self-assemble through unknown ligandā€“receptor interactions and form thin layers of hydrogels at the surface of platelets, thus preventing the aggregation of them. This study not only broadened the application and opened up a new door for biomedical applications of molecular hydrogels but also might provide a novel strategy to counteract infection diseases through selective surface-induced hydrogelations at pathogens, such as bacteria and virus

    Alleviating the Liver Toxicity of Chemotherapy via pH-Responsive Hepatoprotective Prodrug Micelles

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    Nanocarriers have been extensively utilized to enhance the anti-tumor performance of chemotherapy, but it is very challenging to eliminate the associated hepatotoxicity. This was due to the significant liver accumulation of cytotoxic drug-loaded nanocarriers as a consequence of systemic biodistribution. To address this, we report a novel type of nanocarrier that was made of hepatoprotective compound (oleanolic acid/OA) with a model drug (methotrexate/MTX) being physically encapsulated. OA was covalently connected with methoxy polyĀ­(ethylene glycol) (mPEG) via a hydrazone linker, generating amphiphilic mPEGā€“OA prodrug conjugate that could self-assemble into pH-responsive micelles (ca. 100 nm), wherein the MTX loading was ca. 5.1% (w/w). The micelles were stable at pH 7.4 with a critical micelle concentration of 10.5 Ī¼M. At the acidic endosome/lysosome microenvironment, the breakdown of hydrazone induced the micelle collapse and fast release of payloads (OA and MTX). OA also showed adjunctive anti-tumor effect with a low potency, which was proved in 4T1 cells. In the mouse 4T1 breasttumor model, MTX-loaded mPEGā€“OA micelles demonstrated superior capability regarding in vivo tumorgrowth inhibition because of the passive tumor targeting of nanocarriers. Unsurprisingly, MTX induced significant liver toxicity, which was evidenced by the increased liver mass and increased levels of alanine transaminase, aspartate transaminase, and lactate dehydrogenase in serum as well as in liver homogenate. MTX-induced hepatotoxicity was also accompanied with augmented oxidative stress, for example, the increase of the malondialdehyde level and the reduction of glutathione peroxidase and superoxide dismutase concentration in the liver. As expected, mPEGā€“OA micelles significantly reduced the liver toxicity induced by MTX because of the hepatoprotective action of OA, which was supported by the reversal of all the above biomarkers and qualitative histological analysis of liver tissue. This work offers an efficient approach for reducing the liver toxicity associated with chemotherapy, which can be applied to various antitumor drugs and hepatoprotective materials
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