Shi-Bo Wang

Ratiometric Biosensor for Aggregation-Induced Emission-Guided Precise Photodynamic Therapy

Photodynamic therapy faces the barrier of choosing the appropriate irradiation region and time. In this paper, a matrix metalloproteinase-2 (MMP-2) responsive ratiometric biosensor was designed and synthesized for aggregation-induced emission (AIE)-guided precise photodynamic therapy. It was found that the biosensor presented the MMP-2 responsive AIE behavior. Most importantly, it could accurately differentiate the tumor cells from the healthy cells by the fluorescence ratio between freed tetraphenylethylene and protoporphyrin IX (PpIX, internal reference). In vivo study demonstrated that the biosensor could preferentially accumulate in the tumor tissue with a relative long blood retention time. Note that the intrinsic fluorescence of PpIX and MMP-2-triggered AIE fluorescence provided a real-time feedback which guided precise photodynamic therapy in vivo efficiently. This strategy demonstrated here opens a window in the precise medicine, especially for phototherapy.

Tumor-Triggered Geometrical Shape Switch of Chimeric Peptide for Enhanced in Vivo Tumor Internalization and Photodynamic Therapy

Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this article, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy, and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self-Synergistic Tumor Targeting Therapy.

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self-synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell-penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor-made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self-synergistically therapeutic capacity opens new avenues for cancer therapy.

A FRET-based dual-targeting theranostic chimeric peptide for tumor therapy and real-time apoptosis imaging.

iii) Asp–Glu–Val–Asp–Gly (DEVDG) peptide sequence as the caspase-3 cleavage segment [ 19 ] and stearic acid as the hydrophobic tail. As illustrated in Figure 1 , carboxyfl uorescein (FAM) and Dabcyl (quencher) were conjugated on the terminal of DEVDG in chimeric peptide to insure a close proximity. Glycine was further added to endow the chimeric peptide with fi ne fl exibility and reduced potential interference among subunits. The amphiphilic chimeric peptide can form nanoparticles and then be specifi cally uptaken by α v β 3 overexpressed tumor cells. Importantly, the fl uorescence keeps quenched due to the effi cient FRET between FAM and Dabcyl. After diffusion to cytosol in tumor cells, the chimeric peptide will preferentially interact with the mitochondrion, and then the pro-apoptosis sequence D (KLAKLAK) 2 mediates apoptosis in the tumor cells. During the apoptosis, the caspase-3 enzyme emerges, which can specifi cally cleave DEVDG sequence between aspartic acid and glycine, leading to the detachment of Dabcyl quencher. As a result, the fl uorescence of FAM gets recovered, realizing the simultaneous apoptosis imaging in the killed tumor cells. The chimeric peptide was prepared based on the standard FMOC solid-phase peptide synthesis technique. [ 20,21 ] The optimized preparation process was presented in detail (see Scheme S1, Supporting Information). FMOC-Lys(Dde)-OH/ FMOC-Lys(Mtt)-OH were employed during the preparation. It is known that Dde group can be easily cleaved by hydrazine hydrate Driven by the ever-increasing demand for individualized care, theranostics has rapidly emerged as a compelling treatment modality in tumor therapy. [ 1,2 ] This treatment modality can track the biological response to the given therapy noninvasively, and provide the signifi cative feedback to avoid repeated doses or inappropriate therapy. [ 3 ] To date, several theranostic agents have been proposed and fabricated. [ 4,5 ] However, the clinical trials of these theranostic agents are still hampered since the therapeutic effi cacy of theranostic agents is evaluated via measuring the change of tumor volume, but obvious change of tumor volume is always much delayed. [ 6 ] On the other hand, theranostic agents at present are always based on gold, [ 7 ]

A redox-responsive mesoporous silica nanoparticle with a therapeutic peptide shell for tumor targeting synergistic therapy

In this study, we report a novel redox-responsive mesoporous silica nanoparticle (MSN)-based nanocarrier, capping with a therapeutic peptide ((RGDWWW)2KC) containing a RGD target motif, for tumor targeting synergistic therapy, which is designated as TTSTMSN. The MSN was decorated with a tumor-targeting therapeutic peptide as a potential gatekeeper. The two branched peptides containing rich tryptophans allowed the pores to be blocked via π-π stacking and hydrophobic interactions. Once the drug loaded nanoparticles were taken up by the cancer cells through integrin-mediated endocytosis, the therapeutic peptide capping shells on the surface of MSNs were released, inducing the loaded drug to diffuse into the cytoplasm after breaking of the disulfide bonds, triggered by the high concentration of glutathione (GSH) in cancer cells. At the same time, the falling therapeutic rich tryptophans in the branched chains interacted with DNA due to the indole rings, leading to disturbance of the DNA structure through the strong π interactions and causing cell apoptosis. There is no such report on capping of drug loaded porous silica with a therapeutic peptide shell, co-delivering an anticancer drug and therapeutic agent for tumor targeting synergistic therapy, which will have great potential in developing multifunctional nanocarriers based on therapeutic peptides for synergistic treatment.

Tumor targeted gold nanoparticles for FRET-based tumor imaging and light responsive on-demand drug release

In this work, a new type of gold nanoparticles (AuNPs) is designed to achieve the programmed tumor imaging and light manipulated controlled drug release. In vitro results demonstrate that these AuNPs undergo matrix metalloproteinase-2 (MMP-2) responsive fluorescence recovery of photosensitizers, protoporphyrin IX (PpIX), in the tumor region, which can differentiate tumor cells from healthy ones. Subsequently, light irradiation activates PpIX, which cleaves the reactive oxygen species (ROS) sensitive thioketal linker, leading to on-demand drug release as well as free drug diffusion into nuclei. More importantly, in vitro studies indicate the good performance of AuNPs in combined photodynamic therapy and chemotherapy with limited side effects. This AuNP based nanoplatform provides great potential for tumor targeted on-demand combination therapy.

Multifunctional Nanosystem for Synergistic Tumor Therapy Delivered by Two-Dimensional MoS2

A multifunctional nanosystem based on two-dimensional molybdenum disulfide (MoS2) was developed for synergistic tumor therapy. MoS2 was stabilized with lipoic acid (LA)-modified poly(ethylene glycol) and modified with a pH-responsive charge-convertible peptide (LA-K11(DMA)). Then, a positively charged photosensitizer, toluidine blue O (TBO), was loaded on MoS2 via physical absorption. The negatively charged LA-K11(DMA) peptide was converted into a positively charged one under acidic conditions. Charge conversion of the peptide could reduce the binding force between positively charged TBO and MoS2, leading to TBO release. Furthermore, the positively charged nanosystem was easily endocytosed by cells. Photo-induced hyperthermia of MoS2 in the tumor areas could promote TBO release and exhibited photothermal therapy. In vitro and in vivo results demonstrated that fluorescence and photo-induced reactive oxygen species (ROS) generation of TBO were severely decreased by MoS2 under normal conditions. While in the acidic condition, the pH-responsive nanosystem exhibited a highly specific and efficient antitumor effect with TBO release and photo-induced ROS generation, suggesting to be a promising accessory for synergistic tumor therapy.

Self-defensive nano-assemblies from camptothecin-based antitumor drugs

Camptothecin (CPT)-based drugs always undergo the reversible, pH-dependent lactone ring-opening reaction, yielding the inactive but toxic carboxylate form. Self-assembly strategy provides an effective route for preserving their bio-stability. In this article, nano-sized self-assemblies from CPT-based antitumor drugs were simply built up by directly diluting the stock dimethylsulfoxide solutions of (S)-(+)-CPT, (S)-10-hydroxyl camptothecin and carboxylic CPT with water/phosphate-buffered saline solution. Because of their different molecular structures in A-ring or modification on the 20-OH group, CPT self-assembled into helical nano-ribbons, whereas 10-hydroxycamptothecin and carboxylic CPT self-aggregated into flat nano-ribbons and cylindric nano-rods, respectively. Attractively, the self-assembly of CPT-based drugs could occur within 1 min at a low concentration of 1 × 10−5 M. Adopting the J-type self-aggregation, self-assemblies were stable in aqueous solution and could effectively protect the CPT-based drugs from hydrolysis, which thereby kept their bioactivity for tumor therapy.

Fluorescence light-up AIE probe for monitoring cellular alkaline phosphatase activity and detecting osteogenic differentiation

Alkaline phosphatase (ALP) is an important monophosphate hydrolase during cell mineralization and osteogenic differentiation. Though traditional methods are provided for evaluating the ALP expression in the fixed and lysed cells, at present it is still challenging to monitor the ALP activity in living cells. In this work, three phosphorylated tetraphenylethylene (TPE) probes (TPE-PA, TPE-2PA and TPE-4PA) with different numbers of -PO3H2 groups were synthesized for monitoring the ALP activity. It was found that in aqueous solution, both the TPE-PA and TPE-2PA probes were highly sensitive to ALP. In the presence of ALP, they could be quickly hydrolysed, resulting in an aggregation-induced emission (AIE) to light up ALP. While in living cells, only TPE-2PA showed good cell penetrability and high fluorescence signal-to-noise ratio during osteogenic differentiation. This probe provides us a new strategy to screen the ALP activity in living stem cells for detecting osteogenic differentiation.

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.