Light-Induced Caspase-3-Responsive Chimeric Peptide for Effective PDT/Chemo Combination Therapy with Good Compatibility.

Activated doxorubicin (DOX) often has severe systemic toxicity and side effects due to its inability to distinguish tumor cells from normal cells, which seriously affects the prognosis of patients. Here, we synthesized an inactivated a DOX prodrug that could be selectively activated by a light-induced caspase-3 enzyme in the tumor site. In the absence of light, this uniformly dispersed nanoparticle avoided the unnecessary toxicity under physiological conditions. Upon the laser irradiating to the tumor area of interest, the nanoparticles can produce a large amount of reactive oxygen species (ROS) to induce cell apoptosis and activate caspase-3 enzyme to release DOX selectively. Meanwhile, the produced ROS can also combine with activated DOX to cause more potent tumor damage. The experiments demonstrated that the light can effectively activate DOX drug through a series of cascade events and the subsequent synergistic therapy both in vitro and in vivo. This strategy achieved excellent therapeutic outcomes and minimal adverse effects, which should significantly improve the dilemma of traditional chemotherapy.

Tumor-triggered transformation of chimeric peptide for dual-stage-amplified magnetic resonance imaging and precise photodynamic therapy.

Despite the great success in clinical magnetic resonance imaging (MRI), Gd3+-based contrast agents still suffer from low proton relaxation efficiency, rapid metabolic clearance as well as poor sensitivity. In this work, we designed a matrix metalloproteinase-2 (MMP-2) responsive chimeric peptide for dual-stage-amplified MRI and precise photodynamic therapy. Both in vitro and in vivo studies indicated that this chimeric peptide could self-assembly into spherical nanoparticles at physiological condition with r1 value of 28.17 mM-1s-1. Meanwhile, the spherical shape endowed chimeric peptide with efficient tumor accumulation via enhanced penetration and retention (EPR) effect. Importantly, the overexpressed MMP-2 in tumor region could specifically hydrolyze chimeric peptide, leading to sphere-to-fiber transformation. This transformation enhanced both the tumor accumulation and the relaxivity of contrast agent. Consequently, the r1 value was remarkably elevated to 51.52 mM-1s-1, which guided precise photodynamic therapy. This tumor microenvironment-triggered transformable strategy should show great potential for tumor-targeted imaging and phototherapy.

Ru(bpy)32+-Silica@Poly-L-lysine-Au as labels for electrochemiluminescence lysozyme aptasensor based on 3D graphene.

In this work, the feasibility of a novel sensitive electrochemiluminescence aptasensor for the detection of lysozyme using Ru(bpy)32+-Silica@Poly-L-lysine-Au (RuSiNPs@PLL-Au) nanocomposites labeling as an indicator was demonstrated. The substrate electrode of the aptasensor was prepared by depositing gold nanoparticles (AuNPs) on 3D graphene-modified electrode. The lysozyme binding aptamer (LBA) was attached to the 3D graphene/AuNPs electrode through gold-thiol affinity, hybridized with a complementary single-strand DNA (CDNA) of the lysozyme aptamer labeled by RuSiNPs@PLL-Au as an electrochemiluminescence intensity amplifier. Thanks to the synergistic amplification of the 3D graphene, the AuNPs and RuSiNPs@PLL-Au NPs linked to Ru(bpy)32+-ECL further enhanced the ECL intensity of the aptasensor. In presence of lysozyme, the CDNA segment of the self-assembled duplex was displaced by the lysozyme, resulting in decreased electrochemiluminescence signal. Under the optimized conditions, the decrease in electrochemiluminescence intensity varied proportionally with the logarithmic concentration of the lysozyme from 2.25 × 10-12 to 5.0 × 10-8 mol L-1, and the detection limit was estimated to 7.5 × 10-13 mol L-1. The aptasensor was further tested in real samples and found reliable for the detection of lysozyme, thus holding great potential application in food safety researches and bioassay analysis.

pH-Responsive Nanoscale Coordination Polymer for Efficient Drug Delivery and Real-Time Release Monitoring.

Both excess dosages of drug and unwanted drug carrier can lead to severe side effects as well as the failure of tumor therapy. Here, an Fe3+ -gallic acid based drug delivery system is designed for efficient monitoring of drug release in tumor. Fe3+ and polyphenol gallic acid can form polygonal nanoscale coordination polymer in aqueous solution, which exhibits certain antitumor effect. Importantly, this coordination polymer possesses extremely high doxorubicin (DOX) loading efficacy (up to 48.3%). In vitro studies demonstrate that the fluorescence of DOX can be quenched efficiently when DOX is loaded on the coordination polymer. The acidity in lysosome also triggers the release of DOX and fluorescence recovery simultaneously, which realizes real-time monitoring of drug release in tumor cells. In vivo studies further indicate that this polyphenol-rich drug delivery system can significantly inhibit tumor growth with negligible heart toxicity of DOX. This system with minimal side effects should be a promising nanoplatform for tumor treatment.

Acidity-Triggered Tumor Retention/Internalization of Chimeric Peptide for Enhanced Photodynamic Therapy and Real-Time Monitoring of Therapeutic Effects.

Photodynamic therapy (PDT) holds great promise in tumor treatment. Nevertheless, it remains highly desirable to develop easy-to-fabricated PDT systems with improved tumor accumulation/internalization and timely therapeutic feedback. Here, we report a tumor-acidity-responsive chimeric peptide for enhanced PDT and noninvasive real-time apoptosis imaging. Both in vitro and in vivo studies revealed that a tumor mildly acidic microenvironment could trigger rapid protonation of carboxylate anions in chimeric peptide, which led to increased ζ potential, improved hydrophobicity, controlled size enlargement, and precise morphology switching from sphere to spherocylinder shape of the chimeric peptide. All of these factors realized superfast accumulation and prolonged retention in the tumor region, selective cellular internalization, and enhanced PDT against the tumor. Meanwhile, this chimeric peptide could further generate reactive oxygen species and initiate cell apoptosis during PDT. The subsequent formation of caspase-3 enzyme hydrolyzed the chimeric peptide, achieving a high signal/noise ratio and timely fluorescence feedback. Importantly, direct utilization of the acidity responsiveness of a biofunctional Asp-Glu-Val-Asp-Gly (DEVDG, caspase-3 enzyme substrate) peptide sequence dramatically simplified the preparation and increased the performance of the chimeric peptide furthest.

Mitochondria-Targeted Chimeric Peptide for Trinitarian Overcoming of Drug Resistance.

In this report, an amphiphilic mitochondria-targeted chimeric peptide-based drug delivery system (DDS) was designed to overcome drug resistance. In vitro studies revealed that chimeric peptide could encapsulate doxorubicin (DOX) with high efficacy and target tumor mitochondria, realizing controlled release of DOX and in situ photodynamic therapy (PDT) in mitochondria. Importantly, reactive oxygen species (ROS) during PDT significantly disrupted mitochondria, leading to a dramatic decrease of intracellular adenosine 5'-triphophate (ATP). As a result, ATP-dependent efflux of DOX was remarkably inhibited. Trinitarian therapeutic strategy was developed to ablation of drug-resistant cells, that is, (1) enhanced cellular uptake of hydrophobic DOX via encapsulation in DDS, (2) combined chemo-/photodynamic therapies, and (3) suppressed generation of intracellular ATP as well as drug efflux via in situ PDT in mitochondria. This trinitarian strategy may open a new window in the fabrication of subcellular organelle destructive DDS in overcoming drug resistance.

Biocompatible and highly luminescent near-infrared CuInS2/ZnS quantum dots embedded silica beads for cancer cell imaging.

Bright and stable CuInS2/ZnS@SiO2 nanoparticles with near-infrared (NIR) emission were competently prepared by incorporating the as-prepared hydrophobic CuInS2/ZnS quantum dots (QDs) directly into lipophilic silane micelles and subsequently an exterior silica shell was formed. The obtained CuInS2/ZnS@SiO2 nanoparticles homogeneously comprised both single-core and multicore remarkable CuInS2/ZnS QDs, while the silica shell thickness could be controlled to within 5-10 nm and their overall size was 17-25 nm. Also, the functionalized CuInS2/ZnS QDs encapsulated in the silica spheres, expedited their bioconjugation with holo-Transferrin (Tf) for further cancer cell imaging. The CuInS2/ZnS@SiO2 nanoparticles not only showed a dominant NIR band-edge luminescence at 650-720 nm with a quantum yield (QY) between 30 and 50%, without a recognized photoluminescence (PL) red shift, but also exhibited excellent PL and colloidal stability in aqueous media. Impressively, the cytotoxicity studies revealed minor suppression on cell viability under both CuInS2/ZnS@SiO2 and CuInS2/ZnS@SiO2@Tf concentrations up to 1 mg/mL. The application in live-cell imaging revealed that the potential of CuInS2/ZnS QDs as biocompatible, robust, cadmium-free, and brilliant NIR emitters is considered promising for fluorescent labels.

Aqueous one-pot synthesis of bright and ultrasmall CdTe/CdS near-infrared-emitting quantum dots and their application for tumor targeting in vivo.

CdTe/CdS core(small)/shell(thick) quantum dots (QDs) with tunable near-infrared fluorescence were directly synthesized in aqueous phase through a facile one-step strategy. The QDs possessed bright fluorescence, ultrasmall size, excellent photostability and good biocompatibility. Their applicability for biological imaging was demonstrated with the in vivo active tumor targeting of nude mice.

[Study on the synchronous interactions between different thiol-capped CdTe quantum dots and BSA].

The modifier of quantum dots plays an important role in synthesis and nature of quantum dots, however the effect on the interaction between quantum dots and protein is not very clear until up to now. In the present paper, the interactions of CdTe quantum dots with bovine serum album (BSA) were studied by spectroscopy methods including ultraviolet-visible absorption spectrometry (UV-Vis), fluorescence spectrometry (FL) and infrared spectrometry (IR). The CdTe quantum dots were modified by three different thiol-complex including thioglycolic acid, L-cysteine and glutathione, i. e. thioglycolic acid capped CdTe quantum dots (CdTe(T)), L-cysteine capped CdTe quantum dots (CdTe(L)) and glutathione capped CdTe quantum dots (CdTe(G)) respectively. The quenching constant K(sv) and corresponding thermodynamic parameters, such as enthalpy change (deltaH(theta)), entropy change (deltaS(theta)), Gibbs free energy change (deltaG(theta)), were calculated according to Stern-Volmer equations. The results showed that CdTe(T), CdTe(L) and CdTe(G) all have a strong ability of quenching the fluorescence of bovine serum albumin, and the interactions of the three types of thiol-capped CdTe quantum dots with BSA were static quenching process. The quenching constant of K(sv)(TGA) is similar to K(sv)(GSH), which is much less than K(sv)(L-Cys). The binding forces of CdTe(T) and CdTe(L) with the BSA were the main contributions from hydrophobic force according to the thermodynamic parameters (deltaH(theta) > 0, deltaS(theta) > 0 and deltaG(theta) < 0), while the binding forces of CdTe(G) with BSA were composed of both hydrogen bonding force and hydrophobic force according to the thermodynamic parameters(deltaH(theta) < 0, deltaS(theta) > 0 and deltaG(theta) < 0). It was found that different functional group and molecular volume size of thiol surface modified reagent played an important role in the interactions between CdTe QDs and BSA.

Study on the interaction between CdSe quantum dots and hemoglobin.

The interaction between CdSe quantum dots (QDs) and hemoglobin (Hb) was investigated by ultraviolet and visible (UV-vis) absorption spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and fluorescence (FL) spectroscopy. The intensity of UV-vis absorption spectrum of a mixture of CdSe QDs and Hb was obviously changed at the wavelength of 406nm at pH 7.0, indicating that CdSe QDs could bind with Hb. The influences of some factors on the interactions between CdSe QDs and Hb were studied in detail. The binding molar ratio of CdSe QDs and Hb was 12:1 by a mole-ratio method. The mechanism of the interaction between CdSe QDs and Hb was also discussed.