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1.
Theranostics ; 10(26): 12127-12143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204333

RESUMO

Rationale: The tumor microenvironment (TME) determines tumor progression and affects clinical therapy. Its basic components include cancer-associated fibroblasts (CAFs) and tumor-associated endothelial cells (TECs), both of which constitute the tumor matrix and microvascular network. The ability to simulate interactions between cells and extracellular matrix in a TME in vitro can assist the elucidation of cancer growth and evaluate the efficiency of therapies. Methods: In the present study, an in vitro 3D model of tumor tissue that mimicked in vivo cell physiological function was developed using tumor-associated stromal cells. Colorectal cancer cells, CAFs, and TECs were co-cultured on 3D-printed scaffolds so as to constitute an extracellular matrix (ECM) that allowed cell processes such as adhesion, stemness, proliferation, and vascularization to take place. Normal stromal cells were activated and reprogrammed into tumor-related stromal cells to construct a TME of tumor tissues. Results: The activated stromal cells overexpressed a variety of tumor-related markers and remodeled the ECM. Furthermore, the metabolic signals and malignant transformation of the in vitro 3D tumor tissue was substantially similar to that observed in tumors in vivo. Conclusions: The 3D tumor tissue exhibited physiological activity with high drug resistance. The model is suitable for research studies of tumor biology and the development of personalized treatments for cancer.

2.
Nat Rev Mater ; : 1-14, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33078077

RESUMO

The ongoing SARS-CoV-2 pandemic highlights the importance of materials science in providing tools and technologies for antiviral research and treatment development. In this Review, we discuss previous efforts in materials science in developing imaging systems and microfluidic devices for the in-depth and real-time investigation of viral structures and transmission, as well as material platforms for the detection of viruses and the delivery of antiviral drugs and vaccines. We highlight the contribution of materials science to the manufacturing of personal protective equipment and to the design of simple, accurate and low-cost virus-detection devices. We then investigate future possibilities of materials science in antiviral research and treatment development, examining the role of materials in antiviral-drug design, including the importance of synthetic material platforms for organoids and organs-on-a-chip, in drug delivery and vaccination, and for the production of medical equipment. Materials-science-based technologies not only contribute to the ongoing SARS-CoV-2 research efforts but can also provide platforms and tools for the understanding, protection, detection and treatment of future viral diseases.

3.
Nanoscale ; 12(42): 21571-21582, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33108432

RESUMO

Tumor microenvironment (TME)-responsive nanodevices are essential tools for cancer imaging and therapy. Exploiting the advantages of molecular engineering, nanodevices are emerging for biomedical applications. In order to reach targeted cancer areas, activated nanodevices first respond to the TME and then serve as an actuator for sensing, imaging and therapy. Most nanodevices depend on a single parameter as an input for their downstream activation, potentially leading to inaccurate diagnostic results and poor therapeutic outcomes. However, in the TME, some biomarkers are cross-linked, and such correlated biomarkers are potentially useful for cancer imaging and theranostic applications. Based on this phenomenon, researchers have developed approaches for the construction of multiparameter-activated nanodevices (MANs) to improve accuracy. This minireview summarizes the recent advances in the development of MANs for cancer imaging including fluorescence imaging, photoacoustic (PA) imaging, magnetic resonance imaging (MRI) and computed tomography (CT) imaging, as well as cancer therapy including radiotherapy, chemotherapy, photoinduced therapy and immunotherapy. We highlight different approaches for improving the specificity and precision of cancer imaging and therapy. In the future, MANs will show promise for clinical work in multimodal diagnosis and therapeutics.

4.
Chembiochem ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33051959

RESUMO

Functional nucleic acids (FNAs) are garnering tremendous interest owing to their high modularity and unique bioactivity. Three-dimensional FNAs have been developed to overcome the issues of nuclease degradation and limited cell uptake. We herein developed a new facile approach to the synthesis of multiple three-dimensional FNA nanostructures by harnessing photo-polymerization-induced self-assembly. Sgc8 aptamer and CpG oligonucleotide were modified as macro chain transfer reagents to mediate in situ polymerization and self-assembly. Diverse structures, including micelles, rods, and short worms, afford these two FNAs with higher nuclease resistance from serum, greater cellular uptake efficiency, and increased bioactivity.

5.
Theranostics ; 10(23): 10652-10664, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929372

RESUMO

Rationale: Tumors are commonly treated by resection, which usually leads to massive hemorrhage and tumor cell residues, thereby increasing the risk of local recurrence and distant metastasis. Methods: Herein, an intelligent 3D-printed poly(lactic-co-glycolic acid), gelatin, and chitosan scaffold loaded with anti-cancer drugs was prepared that showed hemostatic function and good pH sensitivity. Results: Following in situ implantation in wounds, the scaffolds absorbed hemorrhage and cell residues after surgery, and promoted wound healing. In an in vivo environment, the scaffold responded to the slightly acidic environment of the tumor to undergo sustained drug release to significantly inhibit the recurrence and growth of the tumor, and reduced drug toxicity, all without causing damage to healthy tissues and with good biocompatibility. Conclusions: The multifunctional intelligent scaffold represents an excellent treatment modality for breast cancer following resection, and provides great potential for efficient cancer therapy.

6.
ACS Nano ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32897687

RESUMO

Biological membrane channels, considered as molecular gatekeepers, control the transportation of molecules and ions across live cell membranes. Developing synthetic passable channels with predictable structures, high transport efficiency, and low cytotoxicity on live cells is of great interest for replicating the functions of endogenous protein channels, but remains challenging. The development of DNA nanotechnology provides possible solutions for making synthetic channels with precise structures and controllable functionalization. Therefore, in this work, we constructed a phosphorothioate-modified DNA nanopore able to structurally mimic biological channels for molecular transport across live cell membranes. With its stable structure with small hollow size (<2 nm) and the ability to interact with the lipid molecules, this DNA nanopore could show stable insertion into the plasma membrane. We further proved that this membrane-spanning channel could transport ions and antitumor drugs to neurons and cancer cells, respectively, and do so within a certain time window. We expect that this live cell membrane-spanning synthetic DNA nanopore will provide a tool for studying cellular communication, building synthetic cells, and achieving controlled transmembrane transport to cells.

7.
Anal Chem ; 92(19): 13588-13594, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32894943

RESUMO

In this work, a label-free and highly sensitive fluorescence assay was constructed for microRNA detection. Nicking-enhanced rolling circle amplification (RCA) induced by G-quadruplex formation is coupled with inner filter effect (IFE)-based quenching effects of MoS2 quantum dots (MoS2 QDs). The padlock probe contains a recognition sequence to target microRNA and an accessible nicking site. The padlock probe is cyclized upon hybridization with target microRNA. Sequentially, amplification initiates a production of a long-concatenated sequence of circular probes. Abundant G-quadruplex sequences are produced via the nicking process and then used as the trigger to initiate the next RCA. In the presence of hemin, numerous hemin/G-quadruplex DNAzymes are formed, which catalyze the oxidation of o-phenylenediamine (OPD) into the colored product 2,3-diaminophenazine, resulting in quenching of the fluorescence of MoS2 QDs. This sensing strategy enables detection of microRNA let-7a with high selectivity and a detection limit of 4.6 fM. The as-prepared sensor was applied for detecting microRNA let-7a in dilute human serum samples and achieved a satisfactory recovery rate, demonstrating its potential in clinic diagnosis of microRNA-associated disease and biochemical research.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32918358

RESUMO

Organic dye based NIR-II fluorescent probes, owing to their high signal-to-background ratio and deeper penetration, are highly useful for deep-tissue high-contrast imaging in vivo. However, it is still a challenge to design activatable NIR-II fluorescent probes. Here, a novel class of polymethine dyes (NIRII-RTs), with bright (quantum yield up to 2.03 %), stable, and anti-solvent quenching NIR-II emission, together with large Stokes shifts, was designed. Significantly, the novel NIR-II dyes NIRII-RT3 and NIRII-RT4, equipped with a carboxylic acid group, can serve as effective NIR-II platforms for the design of activatable bioimaging probes with high contrast. As a proof of concept, a series of target-activatable NIRII-RT probes (NIRII-RT-pH, NIRII-RT-ATP and NIRII-RT-Hg) for pH, adenosine triphosphate (ATP), and metal-ion detection, were synthesized. By applying the NIRII-RT probe, the real-time monitoring of drug-induced hepatotoxicity was realized.

9.
Small ; 16(35): e2001177, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32762022

RESUMO

Photoacoustic imaging-guided photothermal therapy in the second near-infrared (NIR-II) window shows promise for clinical deep-penetrating tumor phototheranostics. However, ideal photothermal agents in the NIR-II window are still rare. Here, the emeraldine salt of polyaniline (PANI-ES), especially synthesized by a one-pot enzymatic reaction on sodium bis(2-ethylhexyl) sulfosuccinate (AOT) vesicle surface (PANI-ES@AOT, λmax  ≈ 1000 nm), exhibits excellent dispersion in physiological environment and remarkable photothermal ability at pH 6.5 (photothermal conversion efficiency of 43.9%). As a consequence of the enhanced permeability and retention effect of tumors and the doping-induced photothermal effect of PANI-ES@AOT, this pH-sensitive NIR-II photothermal agent allows tumor acidity phototheranostics with minimized pseudosignal readout and subdued normal tissue damage. Moreover, the enhanced fluidity of vesicle membrane triggered by heating is beneficial for drug release and allows precise synergistic therapy for an improved therapeutic effect. This study highlights the potential of template-oriented (or interface-confined) enzymatic polymerization reactions for the construction of conjugated polymers with desired biomedical applications.

10.
J Am Chem Soc ; 142(33): 14234-14239, 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32677826

RESUMO

The requirement of special expensive instruments for quantitative information readout has significantly restricted sustainable development, from ideation to execution, of advanced artificial networks. Here we present a step toward a paradigm of evolutionary signaling networks that enable translating complex signaling information into easy-to-read temperature output. Combining DNA molecular engineering with basic optical mechanisms, a DNA/Hemin complex-derived versatile temperature-output transducer is established, which can be coupled with other functional modules to fabricate diverse portable DNA signaling networks by dynamic programming of DNA chemical reactions. Its versatility is successfully demonstrated by constructing self-amplified and logic-circuit-based DNA signaling networks to monitor trace and multibit nucleic acid interactions using a thermometer. This affordable yet powerful DNA signaling network design may portend an era of point-of-care signaling network methodology.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32671906

RESUMO

The photorelease of bioactive molecules has emerged as a valuable tool in biochemistry. Nevertheless, many important bioactive molecules, such as pyridine derivatives, cannot benefit from currently available organic photoremovable protecting groups (PPGs). We found that the inefficient photorelease of pyridines is attributed to intramolecular photoinduced electron transfer (PET) from PPGs to pyridinium ions. To alleviate PET, we rationally designed a strategy to drive the excited state of PPG from S1 to T1 with a heavy atom, and synthesized a new PPG by substitution of the H atom at the 3-position of 7-dietheylamino-coumarin-4-methyl (DEACM) with Br or I. This resulted in an improved photolytic efficiency of the pyridinium ion by hundreds-fold in aqueous solution. The PPG can be applied to various pyridine derivatives. The successful photorelease of a microtubule inhibitor, indibulin, in living cells was demonstrated for the potential application of this strategy in biochemical research.

12.
ACS Appl Mater Interfaces ; 12(34): 37845-37850, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32706235

RESUMO

Understanding how a cell membrane protein functions on living cells remains a challenge for cell biology. Specific placement of functional molecules on specific proteins in their native environment would allow comprehensive study of proteins' dynamic functions. Existing methods cannot facilely achieve multiple modifications on specific membrane proteins. In this report, we describe an aptamer-induced, protein-specific bio-orthogonal modification technology for precise nongenetic immobilization of multiple small functional molecules on target membrane glycoproteins by combining metabolic technology and aptamer targeting. In brief, DNA probes were designed by modifying aptamers, which bind to target proteins on the surfaces of living cells pretreated with N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz). The cyclooctynes tagged of DNA probes will approach the azide groups to trigger the bio-orthogonal reactions. After UV irradiation and hybridization with cDNA (complementary DNA), the aptamers can be removed, and the process can be repeated to achieve multiple modifications for multicolor imaging and cell surface nanoengineering on specific proteins.

13.
Adv Drug Deliv Rev ; 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32712197

RESUMO

Deoxyribonucleic acid (DNA) is a promising synthesizer for precisely constructing almost arbitrary geometry in two and three dimensions. Among various DNA-based soft materials, DNA hydrogels are comprised of hydrophilic polymeric networks of crosslinked DNA chains. For their properties of biocompatibility, porosity, sequence programmability and tunable multifunctionality, DNA hydrogels have been widely studied in bioanalysis and biomedicine. In this review, recent developments in DNA hydrogels and their applications in drug delivery systems are highlighted. First, physical and chemical crosslinking methods for constructing DNA hydrogels are introduced. Subsequently, responses of DNA hydrogels to nonbiological and biological stimuli are described. Finally, DNA hydrogel-based delivery platforms for different types of drugs are detailed. With the emergence of gene therapy, this review also gives future prospects for combining DNA hydrogels with the gene editing toolbox.

14.
J Am Chem Soc ; 142(28): 12079-12086, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32516525

RESUMO

Antibody drugs have been used to treat many diseases, and to date, this has been the most rapidly growing drug class. However, the lack of suitable methods for real-time and high-throughput monitoring of antibody production and quality control has been a hindrance to the further advancement of antibody drugs or biosimilars. Therefore, we herein report a versatile tool for one-step fluorescence monitoring of antibody production by using aptamer probes selected through the in vitro SELEX method. In this case, DNA aptamers were selected against the humanized IgG1 antibody drug trastuzumab with high specificity and affinity with a Kd value of aptamer CH1S-3 of 10.3 nM. More importantly, the obtained aptamers were able to distinguish native from heat-treated, whereas antibodies failed this test. On the basis of the advantages of rapid detection for aptamers, we designed aptamer molecular beacons for direct and sensitive detection of trastuzumab in complex samples. Unlike traditional antibody-based ELISA, the signal was observed directly upon interaction with the target without the need for time-consuming binding and multiple washing steps. To further highlight biomedical applications, the use of aptamers as potential tools for quality control and traceless purification of antibody drugs was also demonstrated. Thus, aptamers are shown to be promising alternatives for antibody production monitoring, quality control, and purification, providing technical support to accelerate antibody drug development.

15.
Chem Commun (Camb) ; 56(58): 8103-8106, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32555855

RESUMO

A FRET-based probe for mapping the fluctuation of ONOO- in cisplatin-induced acute kidney injury was constructed. It exhibits ratiometric near infrared fluorescence and a dramatic decrease of its peak absorbance at 719 nm upon addition of ONOO- that is converted into remarkable signal changes in fluorescence and photoacoustic images respectively.

16.
Anal Chem ; 92(15): 10375-10380, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32527079

RESUMO

Artificial bases have emerged as a useful tool to expand genetic alphabets and biomedical applications of oligonucleotides. Herein, we reported that the conformation conversion enhances cellular uptake of hydrophobic 3,5-bis(trifluoromethyl)benzene (F) base double-strand-conjugated oligonucleotides. The formation of the F base double-strand caged the hydrophobic F base in the duplex strand, thus preventing F base from interacting with cells to some extent. However, upon conversion of F base double-strand-conjugated oligonucleotide to F base single-strand-conjugated oligonucleotide, F bases then were allowed to interact with cells by stronger hydrophobic interactions, followed by cellular uptake. The results were concluded as a pairing-induced cage effect of F base and have the potential for the construction of stimuli-responsive cellular uptake of functional nucleic acids.

17.
ACS Nano ; 14(8): 9562-9571, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32584540

RESUMO

Adoptive T cell immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has proven to be highly efficient in the treatment of hematologic malignancies. However, it is challenged by complicated ex vivo engineering, systemic side effects, and low expression of tumor-specific antigen, especially in solid tumors. In this paper, we present a "recognition-then-activation" strategy, which first assists naïve T cells to recognize and adhere to cancer cells and then activates the accumulated T cell in situ to specifically kill cancer cells. In this way, we could unleash the antitumor power of the T cell without complicated and time-consuming cell engineering. To this end, circular bispecific aptamers (cb-aptamers), a class of chemically cyclized aptamers with improved stability and molecular recognition ability which can simultaneously bind to two different types of cells, were first constructed to form artificial intercellular recognition between naïve T cells and tumor cells. After T cell accumulation in the tumor mediated by cb-aptamers, T cells in the tumor site were subsequently activated in situ via commercial CD3/CD28 T cell activator beads to induce tumor-specific killing. Furthermore, by simply choosing different anticancer aptamers, the application of this "recognition-then-activation" strategy can be expanded for targeted treatment of various types of cancer. This may represent a simple T cell immunotherapy that is useful for the treatment of multiple cancers.

18.
Anal Chem ; 92(11): 7404-7408, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32403919

RESUMO

Synthetic DNAzyme motors or machines hold great potential in the detection of intracellular microRNA (miRNA) and mRNA. However, to make intracellular DNAzyme motors or machines operate efficiently, adding exogenous metal ion cofactors as fuel is imperative, which limits their applications. Here, we reported a Na+-specific DNAzyme-based DNAzyme motor differentiating cell subtypes of nonsmall cell lung cancer by simultaneously sensing intracellular miRNA-21 and miRNA-205. The DNAzyme motor could be fueled by intracellular Na+, which avoids the necessity of adding exogenous cofactors. It could be also designed to detect other miRNAs or mRNAs by changing 12-nt DNA domain. Meanwhile, our DNAzyme motor had high sensitivity, excellent specificity, high biostability, and little cytotoxicity. Therefore, the miRNA-initiated and intracellular Na+-fueled DNAzyme motor can expand the application of DNAzyme motors or machines in sensing miRNA and has potential value in cancer clinical diagnosis and prognosis.

19.
Bioconjug Chem ; 31(7): 1766-1774, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32463664

RESUMO

Although the extensive clinical use of the ADC trastuzumab-DM1(T-DM1) for human epidermal growth factor receptor 2 (HER2) targeted cancer therapy, many patients who initially respond to T-DM1 treatment eventually met the insufficient efficacy issue, which is partly attributed to the decreased amount of surface HER2 caused by HER2 degradation in target cells. In our study, we have engineered a HER2 targeted DNA aptamer-DM1 conjugate (HApDC) that can maintain the homeostasis of surface HER2 on the target cancer cell. These conclusions are supported by determining the efficient internalization of HApDC into HER2 overexpressed BT474 and SKBR3 cancer cell lines and by identifying the membranal HER2 level on HApDC-treated BT474 cells. Consistent with the impressive in vitro properties of our newly developed anticancer agent, DM1 could precisely be delivered to the tumor tissue in BT474 xenografted mouse models, because of the specific recognition of aptamer. Noteworthy, HApDC exhibited excellent in vivo tumor inhibition function with much lower healthy organ toxicity, compared with the free drug, which might be explained by the persistently targeted DM1 delivery, which is attributed to the remaining HER2 levels on cells.

20.
Biomaterials ; 246: 119971, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32247202

RESUMO

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt-CHO-PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt-CHO-PEG shows "stealth-like" long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt-CHO-PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ, allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs.

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