Heterobifunctional PEG-grafted black phosphorus quantum dots: "Three-in-One" nano-platforms for mitochondria-targeted photothermal cancer therapy.
ABSTRACT: Black phosphorus (BP) nano-materials, especially BP quantum dots (BPQDs), performs outstanding photothermal antitumor effects, excellent biocompatibility and biodegradability. However, there are several challenges to overcome before offering real benefits, such as poor stability, poor dispersibility as well as difficulty in tailoring other functions. Here, a "three-in-one" mitochondria-targeted BP nano-platform, called as BPQD-PEG-TPP, was designed. In this nano-platform, BPQDs were covalently grafted with a heterobifunctional PEG, in which one end was an aryl diazo group capable of reacting with BPQDs to form a covalent bond and the other end was a mitochondria-targeted triphenylphosphine (TPP) group. In addition to its excellent near-infrared photothermal properties, BPQD-PEG-TPP had much enhanced stability and dispersibility under physiological conditions, efficient mitochondria targeting and promoted ROS production through a photothermal effect. Both in vitro and in vivo experiments demonstrated that BPQD-PEG-TPP performed much superior photothermal cytotoxicity than BPQDs and BPQD-PEG as the mitochondria targeted PTT. Thus this "three-in-one" nanoplatform fabricated through polymer grafting, with excellent stability, dispersibility and negligible side effects, might be a promising strategy for mitochondria-targeted photothermal cancer therapy.
Project description:Organelle-targeting nanosystems are envisioned as promising tools for phototherapy, which can generate heat or reactive oxygen species (ROS) induced cytotoxicity in the targeted location but leave the surrounding biological tissues undamaged. In this work, an imaging-guided mitochondria-targeting photothermal/photodynamic nanosystem has been developed on the basis of functionalized black phosphorus (BP) nanosheets (NSs). In the nanosystem, BP NSs are coated with polydopamine (PDA) and then covalently linked with both chlorin e6 (Ce6) and triphenyl phosphonium (TPP) through carbodiimide reaction between the amino group and the carboxyl group, forming BP@PDA-Ce6&TPP NSs. Due to the strong absorbance of BP@PDA in the near-infrared region and the highly efficient ROS generation of Ce6, the as-prepared nanosystem with mitochondria-targeting capacity (TPP moiety) shows remarkably enhanced efficiency in cancer cell killing. Combined photothermal and photodynamic therapy is implemented and monitored by <i>in vivo</i> fluorescence imaging, achieving excellent performance in inhibiting tumor growth. This study presents a novel nanotheranostic agent for mitochondria-targeting phototherapy, which may open new horizons for biomedicine.
Project description:Due to the inherent limitations, single chemo or photothermal therapies (PTT) are always inefficient. The combination of chemotherapy and PTT for the treatment of cancers has attracted a great interest during the past few years. As a photothermal agent, black phosphorus quantum dots (BPQDs) possess an excellent extinction coefficient, high photothermal conversion efficacy, and good biocompatibility. Herein, we developed a photo- and pH-sensitive nanoparticle based on BPQDs for targeted chemo-photothermal therapy. Doxorubicin (DOX) was employed as a model drug. This nanosystem displayed outstanding photothermal performance both in vitro and in vivo. Folic acid conjugation onto the surface endowed this system an excellent tumor-targeting effect, which was demonstrated by the cellular targeting assay. The BPQDs-based drug delivery system exhibited pH- and photo-responsive release properties, which could reduce the potential damage to normal cells. The in vitro cell viability study showed a synergistic effect in suppressing cancer cell proliferation. Therefore, this BPQDs-based drug delivery system has substantial potential for future clinical applications.
Project description:Poor water-solubility of artesunate (ARS) hampers its clinical application. We here covalently linked ARS to PEGylated nanographene oxide (nGO-PEG) to obtain ARS-modified nGO-PEG (nGO-PEG-ARS) with excellent photothermal effect and dispersibility in physiological environment. nGO-PEG-ARS induced reactive oxygen species (ROS) and peroxynitrite (ONOO?) generations. Although nGO-PEG with near-infrared (NIR) irradiation did not induce cytotoxicity, the photothermal effect of nGO-PEG under NIR irradiation enhanced not only cell uptake but also ONOO? generation of nGO-PEG-ARS, resulting in the synergistic chemo-photothermal effect of nGO-PEG-ARS in killing HepG2 cells. Pretreatment with Fe(III) 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato chloride (FeTTPS, a ONOO? scavenger) instead of antioxidant N-Acetyle-Cysteine (NAC, an ROS scavenger) significantly blocked the cytotoxicity of nGO-PEG-ARS with or without NIR irradiation, demonstrating that ONOO? instead of ROS dominated the synergistic chemo-photothermal anti-cancer action of nGO-PEG-ARS. nGO-PEG-ARS with NIR irradiation resulted in a complete tumor cure within 15 days earlier than other treatment groups, and did not induce apparent histological lesion for the mice treated with nGO-PEG-ARS with or without NIR irradiation for 30 days, further proving the synergistic chemo-photothermal anti-cancer effect of nGO-PEG-ARS. Collectively, nGO-PEG-ARS is a versatile nano-platform for multi-modal synergistic cancer therapy.
Project description:Photothermal therapy (PTT) offers many advantages such as high efficiency and minimal invasiveness, but clinical adoption of PTT nanoagents have been stifled by unresolved concerns such as the biodegradability as well as long-term toxicity. Herein, poly (lactic-co-glycolic acid) (PLGA) loaded with black phosphorus quantum dots (BPQDs) is processed by an emulsion method to produce biodegradable BPQDs/PLGA nanospheres. The hydrophobic PLGA not only isolates the interior BPQDs from oxygen and water to enhance the photothermal stability, but also control the degradation rate of the BPQDs. The in vitro and in vivo experiments demonstrate that the BPQDs/PLGA nanospheres have inappreciable toxicity and good biocompatibility, and possess excellent PTT efficiency and tumour targeting ability as evidenced by highly efficient tumour ablation under near infrared (NIR) laser illumination. These BP-based nanospheres combine biodegradability and biocompatibility with high PTT efficiency, thus promising high clinical potential.
Project description:Chlorin e6 conjugated gold nanostars (GNS-PEG-Ce6) are used to perform simultaneous photodynamic/plasmonic photothermal therapy (PDT/PPTT) upon single laser irradiation. The early-phase PDT effect is coordinated with the late-phase PPTT effect to obtain synergistic anticancer efficiency. The prepared GNS-PEG-Ce6 shows excellent water dispersibility, good biocompatibility, enhanced cellular uptake and remarkable anticancer efficiency upon irradiation in vivo.
Project description:NIR-II fluorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been discovered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion-mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency.
Project description:Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and ?-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer's disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer's disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.
Project description:Ultrasound molecular imaging as a promising strategy, which involved the use of molecularly targeted contrast agents, combined the advantages of contrast-enhanced ultrasound with the photothermal effect of reduced graphene oxide (rGO).<h4>Methods and results</h4>The heparin sulfate proteoglycan glypican-3 (GPC3) is a potential molecular target for hepatocellular carcinoma (HCC). In this study, we covalently linked biotinylated GPC3 antibody to PEGylated nano-rGO to obtain GPC3-modified rGO-PEG (rGO-GPC3), and then combined rGO-GPC3 with avidinylated nanobubbles (NBs) using biotin-avidin system to prepare NBs-GPC3-rGO with photothermal effect and dispersibility, solubility in physiological environment. The average size of NBs-GPC3-rGO complex was 700.4±52.9 nm due to the polymerization of biotin-avidin system. Scanning electron microscope (SEM) showed NBs-GPC3-rGO attached to human hepatocellular carcinoma HepG2 cell. The ultrasound-targeted nanobubble destruction (UTND) technology make use of the physical energy of ultrasound exposure for the improvement of rGO delivery. Compared with other control groups, the highest nanobubble destruction efficiency of NBs-GPC3-rGO was attributed to the dissection effect of rGO on UTND. This is a positive feedback effect that leads to an increase in the concentration of rGO around the HepG2 cell. So NBs-GPC3-rGO using UTND and near-infrared (NIR) irradiation resulted in cell viability within 24 h, 48 h, 72 h lower than other treatment groups.<h4>Conclusion</h4>This work established NBs-GPC3-rGO as an ultrasonic photothermal agent due to its suitable size, imaging capability, photothermal efficiency for visual photothermal therapy in vitro.
Project description:Bacterial biofilm-related diseases cause serious hazard to public health and bring great challenge to the traditional antibiotic treatment. Photothermal therapy (PTT) has been recognized as a promising alternative solution. However, the therapeutic efficacy of PTT is often compromised by the collateral damage to normal tissues due to the lack of bacteria-targeting capability. Here, a Staphylococcus aureus (S. aureus)-targeted PTT nanoagent is prepared based on antibody (anti-protein A IgG), polydopamine (PDA), and PEG-SH (thiolated poly (ethylene glycol)) functionalized MoS2 nanosheets (MoS2@PDA-PEG/IgG NSs, MPPI NSs). The PDA was used as bio-nano interface to facilitate the covalent conjugation of antibody and PEG-SH onto the surface of MoS2 NSs via facile catechol chemistry. Targeted PTT of MPPI NSs shows excellent inactivation efficiency of larger than 4 log (>99.99%) to S. aureus both in biofilms (in vitro) and in infected tissues (in vivo) without causing damage to normal mammalian cells. By contrast, non-targeted PTT of MoS2@PDA-PEG NSs (MPP NSs) only kills S. aureus by <90% in vitro and <50% in vivo. As a result, S. aureus focal infection in mice healed much faster after PTT of MPPI NSs than that of MPP NSs. The superiority of targeted PTT may originate from the efficient accumulation and close binding of PTT agents to bacterial cells. Therefore, MPPI NSs with bacteria-targeting capability are promising photothermal agents for effective treatment of S. aureus focal infection.
Project description:The preparation of blue-emitting black phosphorus quantum dots (BPQDs) is based on the liquid-phase exfoliation of bulk BP. We report the synthesis of soluble BPQDs showing a strong visible blue-light emission. Highly fluorescent (photoluminescence quantum yield of ?5% with the maximum emission (?max) at ?437 nm) and dispersible BPQDs in various organic solvents are first prepared by simple ultrasonication of BP crystals in chloroform in the ambient atmosphere. Furthermore, simple mussel-inspired surface functionalization of BPQDs with catechol-grafted poly(ethylene glycol) in basic buffer afforded water-soluble blue-emitting BPQDs showing long-term fluorescence stability, very low cytotoxicity, and excellent fluorescence live cell imaging capability.