Light-activated drug release from a hyaluronic acid targeted nanoconjugate for cancer therapy.

Hyaluronic acid (HA)-based nanocarriers are of great interest in the drug delivery field due to the tumor targetability via CD44-mediated recognition and endocytosis. However, sufficient tumor-specific release of encapsulated cargoes with steady controllability is necessary to optimize their outcome for cancer therapy. In this study, we constructed a light-activated nanocarrier TKHCENPDOX to enable on-demand drug release at the desired site (tumor). Particularly, TKHCENPDOX encapsulating doxorubicin (DOX) was self-assembled from a HA-photosensitizer conjugate (HA-TK-Ce6) containing reactive oxygen species (ROS)-sensitive thioketal (TK) linkers. Following i.v. injection, TKHCENPDOX was accumulated in the MDA-MB-231 breast tumor xenograft more efficiently through preventing drug leakage in the bloodstream and the HA-mediated targeting effect. Upon internalization into tumoral cells, 660 nm laser irradiation generated ROS during a photodynamic (PDT) process to cleave the TK linker next to Ce6, resulting in light-induced TKHCENPDOX dissociation and selective DOX release in the tumor area. Consequently, TKHCENPDOX showed a remarkable therapeutic effect and minimized toxicity in vivo. This strategy might provide new insight for designing cancer-selective nanoplatforms with active targeting and locoregional drug release simultaneously.

Spatiotemporally Light-Activatable Platinum Nanocomplexes for Selective and Cooperative Cancer Therapy.

Highly efficient nanoarchitectures are of great interest for achieving precise chemotherapy with minimized adverse side effects in cancer therapy. However, a major challenge remains in exploring a rational approach to synthesize spatiotemporally selective vehicles for precise cancer chemotherapy. Here, we demonstrate a rational design of bifunctional light-activatable platinum nanocomplexes (PtNCs) that produce dually cooperative cancer therapy through spatiotemporally selective thermo-chemotherapy. The Pt4+-coordinated polycarboxylic nanogel is explored as the nanoreactor template, which is exploited to synthesize bifunctional PtNCs consisting of a zero-valent Pt0 core and a surrounding bivalent Pt2+ shell with tunable ratios through a facile and controllable reduction. Without light exposure, chemotherapeutic Pt2+ ions are tightly bound on the surface of PtNCs, efficiently reducing undesirable drug leakage and nonselective damage on normal tissues/cells. Upon light exposure, PtNCs generate much heat via photothermal conversion from the Pt0 core and simultaneously trigger a rapid release of chemotherapeutic Pt2+ ions, thereby leading to the spatiotemporally light-activatable synergistic effect of thermo-chemotherapy. Moreover, PtNCs show enhanced tumor accumulation through the heat-triggered hydrophilicity-hydrophobicity transition upon immediate light exposure after injection, dramatically facilitating in vivo tumor regression through their cooperative anticancer efficiency. This rational design of spatiotemporally activatable nanoparticles provides an insightful tool for precise cancer therapy.

Extracellular vesicles based self-grown gold nanopopcorn for combinatorial chemo-photothermal therapy.

Here, we generated a popcorn-like gold nanostructure exploiting extracellular vesicles (EVs). EVs can first serve as the vehicle for chemotherapeutic drug doxorubicin (DOX). Taking advantages of EVs, gold nanoparticles can be then self-grown surrounding the EVs, assembling into popcorn-like nanostructure. The formulated nanopopcorn, consisting of self-grown gold nanoparticles and EVs encapsulated with DOX, retained the photothermal transduction from gold nanoparticle assemblies and cytotoxicity of DOX. Under external near infrared irradiation, gold nanopopcorn can produce hyperthermia to induce tumor ablation and trigger drug release, achieving combinatorial chemo-photothermal therapy. The nanoplatform demonstrated improved cellular internalization, controlled drug release, enhanced antitumor efficacy with tumor inhibitory rate up to 98.6% and reduced side effects. Our design of popcorn-like nanostructure will contribute a novel modality for facile and green synthesis of complex metal nanostructures exploiting natural properties of EVs for combinational therapy.

Light-triggered release of drug conjugates for an efficient combination of chemotherapy and photodynamic therapy.

Herein, we present a series of light-triggered porphyrin-based polymeric drug conjugates PSDTD-m for combined chemo-photodynamic therapy of cancer. The controlled release of a drug through a ROS-cleavable linker combined with photodynamic therapy showed enhanced anticancer efficacy, proving the effectiveness of this light triggered smart nanocarrier platform for enhancing the therapy efficacy.

Tissue-Specific Near-Infrared Fluorescence Imaging.

Near-infrared (NIR) fluorescence light has been widely utilized in clinical imaging by providing surgeons highly specific images of target tissue. The "NIR window" from 650 to 900 nm is especially useful due to several special features such as minimal autofluorescence and absorption of biomolecules in tissue, as well as low light scattering. Compared with visible wavelengths, NIR fluorescence light is invisible, thus allowing highly sensitivity real-time image guidance in human surgery without changing the surgical field. The benefit of using NIR fluorescence light as a clinical imaging technology can be attributed to its molecular fluorescence as an exogenous contrast agent. Indeed, whole body preoperative imaging of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains important in diagnostic utility, but they lack the efficacy of innocuous and targeted NIR fluorophores to simultaneously facilitate the real-time delineation of diseased tissue while preserving vital tissues. Admittedly, NIR imaging technology has been slow to enter clinical use mostly due to the late-coming development of truly breakthrough contrast agents for use with current imaging systems. Therefore, clearly defining the physical margins of tumorous tissue remains of paramount importance in bioimaging and targeted therapy. An equally noteworthy yet less researched goal is the ability to outline healthy vital tissues that should be carefully navigated without transection during the intraoperative surgery. Both of these paths require optimizing a gauntlet of design considerations to obtain not only an effective imaging agent in the NIR window but also high molecular brightness, water solubility, biocompatibility, and tissue-specific targetability. The imaging community recognizes three strategic approaches which include (1) passive targeting via the EPR effect, (2) active targeting using the innate overall biodistribution of known molecules, and (3) activatable targeting through an internal stimulus, which turns on fluorescence from an off state. Recent advances in nanomedicine and bioimaging offer much needed promise toward fulfilling these stringent requirements as we develop a successful catalog of targeted contrast agents for illuminating both tumors and vital tissues in the same surgical space by employing spectrally distinct fluorophores in real time. These tissue-specific contrast agents can be versatile arsenals to physicians for real-time intraoperative navigation as well as image-guided targeted therapy. There is a versatile library of tissue-specific fluorophores available in the literature, with many discussed herein, which offers clinicians an array of possibilities that will undoubtedly improve intraoperative success and long-term postoperation prognosis.

Biomimetic membrane-conjugated graphene nanoarchitecture for light-manipulating combined cancer treatment in vitro.

We report that through facile lipid self-assembly, biomimetic membrane-conjugated mesoporous silica-coated graphene oxide is constructed as targeting nanocarrier toward efficient combination of photothermal therapy and chemotherapy. Impressively, the simple surface modification with folate-contained lipid bilayer allows the graphene-based nanoarchitecture above to be selectively internalized by tumor cells overexpressing relevant receptors. Compared to pure drug, 7-fold doxorubicin is delivered into tumor cells by the nanoarchitecture. After cellular internalization, upon near infrared light illumination, graphene oxide in the nanoarchitecture can convert light energy into heat to kill cancer cells partially. Simultaneously, hyperthermia will drive rapid release of doxorubicin from the nanoarchitecture above to further cause the death of more cancer cells. Thus, integrated cancer treatment with higher efficacy is achieved in vitro compared to that of individual therapy.

Synthesis and sensing integration: A novel enzymatic reaction modulated Nanoclusters Beacon (NCB) "Illumination" strategy for label-free biosensing and logic gate operation.

A novel fluorescent label-free "turn-on" NAD(+) and adenosine triphosphate (ATP) biosensing strategy is proposed by fully exploiting ligation triggered Nanocluster Beacon (NCB). In the presence of the target, the split NCB was brought to intact, which brought the C-rich sequence and enhancer sequence in close proximity resulting in the lightening of dark DNA/AgNCs ("On" mode). Further application was presented for logic gate operation and aptasensor construction. The feasibility was investigated by Ultraviolet-visible spectroscopy (UV-vis), Fluorescence, lifetime and High Resolution Transmission Electron Microscopy (HRTEM) etc. The strategy displayed good performance in the detection of NAD(+) and ATP, with the detection limit of 0.002nM and 0.001mM, the linear range of 10-1000nM and 0.003-0.01mM, respectively. Due to the DNA/AgNCs as fluorescence reporter, the completely label-free fluorescent strategy boasts the features of simplicity and low cost, and showing little reliance on the sensing environment. Meanwhile, the regulation by overhang G-rich sequence not relying on Förster energy transfer quenching manifests the high signal-to-background ratios (S/B ratios). This method not only provided a simple, economical and reliable fluorescent NAD(+) assay but also explored a flexible G-rich sequence regulated NCB probe for the fluorescent biosensors. Furthermore, this sensing mode was expanded to the application of a logic gate design, which exhibited a high performance for not only versatile biosensors construction but also for molecular computing application.

Photoinduced electron transfer between Fe(III) and adenosine triphosphate-BODIPY conjugates: Application to alkaline-phosphatase-linked immunoassay.

Fluorescent boron dipyrromethene (BODIPY) analogs are often used as sensors for detecting various species because of their relatively high extinction coefficients, outstanding fluorescence quantum yields, photostability, and pH-independent fluorescence. However, there is little-to-no information in the literature that describes the use of BODIPY analogs for detecting alkaline phosphatase (ALP) activity and inhibition. This study discovered that the fluorescence of BODIPY-conjugated adenosine triphosphate (BODIPY-ATP) was quenched by Fe(III) ions through photoinduced electron transfer. The ALP-catalyzed hydrolysis of BODIPY-ATP resulted in the formation of BODIPY-adenosine and phosphate ions. The fluorescence of the generated BODIPY-adenosine was insensitive to the change in the concentration of Fe(III) ions. Thus, the Fe(III)-induced fluorescence quenching of BODIPY-ATP can be paired with its ALP-mediated dephosphorylation to design a turn-on fluorescence probe for ALP sensing. A method detection limit at a signal-to-noise ratio of 3 for ALP was estimated to be 0.02 units/L (~6 pM; 1 ng/mL). This probe was used for the screening of ALP inhibitors, including Na3VO4, imidazole, and arginine. Because ALP is widely used in enzyme-linked immunosorbent assays, the probe was coupled to an ALP-linked immunosorbent assay for the sensitive and selective detection of immunoglobulin G (IgG). The lowest detectable concentration for IgG in this system was 5 ng/mL. Compared with the use of 3,6-fluorescein diphosphate as a signal reporter in an ALP-linked immunosorbent assay, the proposed system provided comparable sensitivity, large linear range, and high stability over temperature and pH changes.

Structure and antioxidant activity of soy protein isolate-dextran conjugates obtained by TiO2 photocatalysis.

The aim of this study was to investigate the structural characteristics and antioxidant activities of soy protein isolate- (SPI-) dextran conjugates obtained by TiO2 photocatalysis treatment. Results revealed that the UV-vis absorption and the fluorescence intensity increased as the photocatalytic power increased (P < 0.05). Higher photocatalytic power could promote the extent of glycation and the formation of high molecular weight SPI-dextran conjugates, which were evidenced by free amino group content and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The Fourier transform infrared (FT-IR) spectra suggested that the amide I, II, and III bands of SPI were altered by the glycation induced by TiO2 photocatalysis. Moreover, significant changes of secondary structure occurred in SPI-dextran conjugates. The α-helix, ß-sheet, ß-turns, and random coil were changed from approximately 10.6%, 37.9%, 12.9%, and 38.6% to 3.8%, 10.4%, 17.7%, and 68.8%, respectively, after treatment at photocatalytic power of 1000 W. In addition, SPI-dextran conjugates obtained by TiO2 photocatalysis treatment exhibited high hydroxyl radical scavenging activity and possessed increased reducing power. All data indicated that TiO2 photocatalysis was an efficient method for promoting protein-polysaccharide copolymerisation.

Nano "Chocolate Waffle" for near-IR Responsive Drug Releasing System.

A majority of the photo-responsive drug-delivery systems that are currently being studied require a complicated synthesis method. Here, we prepare a near-infrared responsive, photothermally controllable, drug-delivery carrier by a simple mixing and extraction process without the incorporation of toxic chemicals. A blend of doxorubicin (DOX), an anticancer drug, and a phase-change material (PCM) are loaded onto the mesoporous structure of silica-coated graphene oxide (GO@MS) to form a waffle-like structure, which is confirmed by various physicochemical analyses. The cytotoxicity of DOX/PCM-loaded GO@MS (DOX/PCM-GO@MS) against HeLa cells is 50 times higher than that of free DOX, and this improved activity can be attributed to the photothermal effectiveness of GO@MS. Additionally, the cytotoxicity and uptake mechanism of the PCM-based material are analyzed by flow cytometry. Taken together, our results suggest an enormous potential for spatio-temporal control in photothermally responsive drug-delivery systems.

Multifunctional carbon nanomaterial hybrids for magnetic manipulation and targeting.

Nanosized materials and multifunctional nanoscale platforms have attracted in the last years considerable interest in a variety of different fields including biomedicine. Carbon nanotubes and graphene are some of the most widely used carbon nanomaterials (CNMs) due to their unique morphology and structure and their characteristic physicochemical properties. Their high surface area allows efficient drug loading and bioconjugation and makes them the ideal platforms for decoration with magnetic nanoparticles (MNPs). In the biomedical area, MNPs are of particular importance due to their broad range of potential applications in drug delivery, non-invasive tumor imaging and early detection based on their optical and magnetic properties. The remarkable characteristics of CNMs and MNPs can be combined leading to CNM/MNP hybrids which offer numerous promising, desirable and strikingly advantageous properties for improved performance in comparison to the use of either material alone. In this minireview, we attempt to comprehensively report the most recent advances made with CNMs conjugated to different types of MNPs for magnetic targeting, magnetic manipulation, capture and separation of cells towards development of magnetic carbon-based devices.

Photo-cross-linkable methacrylated gelatin and hydroxyapatite hybrid hydrogel for modularly engineering biomimetic osteon.

Modular tissue engineering holds great potential in regenerating natural complex tissues by engineering three-dimensional modular scaffolds with predefined geometry and biological characters. In modular tissue-like construction, a scaffold with an appropriate mechanical rigidity for assembling fabrication and high biocompatibility for cell survival is the key to the successful bioconstruction. In this work, a series of composite hydrogels (GH0, GH1, GH2, and GH3) based on a combination of methacrylated gelatin (GelMA) and hydroxyapatite (HA) was exploited to enhance hydrogel mechanical rigidity and promote cell functional expression for osteon biofabrication. These composite hydrogels presented a lower swelling ratio, higher mechanical moduli, and better biocompatibility when compared to the pure GelMA hydrogel. Furthermore, on the basis of the composite hydrogel and photolithograph technology, we successfully constructed an osteon-like concentric double-ring structure in which the inner ring encapsulating human umbilical vascular endothelial cells (HUVECs) was designed to imitate blood vessel tubule while the outer ring encapsulating human osteoblast-like cells (MG63s) acts as part of bone. During the coculture period, MG63s and HUVECs exhibited not only satisfying growth status but also the enhanced genic expression of osteogenesis-related and angiogenesis-related differentiations. These results demonstrate this GelMA-HA composite hydrogel system is promising for modular tissue engineering.

Spatial temperature mapping within polymer nanocomposites undergoing ultrafast photothermal heating via gold nanorods.

Heat emanates from gold nanorods (GNRs) under ultrafast optical excitation of the localized surface plasmon resonance. The steady state nanoscale temperature distribution formed within a polymer matrix embedded with GNRs undergoing pulsed femtosecond photothermal heating is determined experimentally using two independent ensemble optical techniques. Physical rotation of the nanorods reveals the average local temperature of the polymer melt in the immediate spatial volume surrounding each rod while fluorescence of homogeneously-distributed perylene molecules monitors temperature over sample regions at larger distances from the GNRs. Polarization-sensitive fluorescence measurements of the perylene probes provide an estimate of the average size of the quasi-molten region surrounding each nanorod (that is, the boundary between softened polymer and solid material as the temperature decreases radially away from each particle) and distinguishes the steady state temperature in the solid and melt regions. Combining these separate methods enables nanoscale spatial mapping of the average steady state temperature distribution caused by ultrafast excitation of the GNRs. These observations definitively demonstrate the presence of a steady-state temperature gradient and indicate that localized heating via the photothermal effect within materials enables nanoscale thermal manipulations without significantly altering the bulk sample temperature in these systems. These quantitative results are further verified by re-orienting nanorods within a solid polymer nanofiber without inducing any morphological changes to the highly temperature-sensitive nanofiber surface. Temperature differences of 70-90 °C were observed over a distances of ∼ 100 nm.

siRNA delivery mediated by copolymer nanoparticles, phospholipid stabilized sulphur hexafluoride microbubbles and ultrasound.

The combination of ultrasound (US) and microbubbles (MB) is a promising physical method for improving the nanoparticles (NPs) delivery efficiency. However, few concerns over comparable delivery effect of the passive or active targeting property's NPs mediated by US and MB have limited their translation towards further application. For this, we prepared small interfering RNA (siRNA)-loaded mPEG-PLGA-PLL (siRNA/mPPP) NPs with passive targeting property and siRNA-loaded mPEG-PLGA-PLL-cRGD (siRNA/mPPPR) NPs with active targeting property, and evaluated the effect of US and MB for their delivery efficiency. The experimental results demonstrated that US and MB effectively enhance the siRNA delivery efficiency of the mPPP NPs compared with the mPPP NPs alone. In contrast, an improved delivery efficiency of siRNA was not observed in PC-3 cells treated with the mPPPR NPs mediated by US and MB, suggesting that the delivery efficiency of NPs mediated US and MB also depend on its targeting properties.