Targeted co-delivery of curcumin and erlotinib by MoS2 nanosheets for the combination of synergetic chemotherapy and photothermal therapy of lung cancer.

BACKGROUND: Curcumin (Cur), a bioactive component of Chinese traditional medicine, has demonstrated inhibitory properties against cancer cell proliferation while synergistically enhancing the anticancer efficacy of erlotinib (Er). However, the individual limitations of both drugs, including poor aqueous solubility, lack of targeting ability, short half-life, etc., and their distinct pharmacokinetic profiles mitigate or eliminate their combined antitumor potential. RESULTS: In this study, we developed a molybdenum disulfide (MoS2)-based delivery system, functionalized with polyethylene glycol (PEG) and biotin, and co-loaded with Cur and Er, to achieve efficient cancer therapy. The MoS2-PEG-Biotin-Cur/Er system effectively converted near-infrared (NIR) light into heat, thereby inducing direct photothermal ablation of cancer cells and promoting controlled release of Cur and Er. Biotin-mediated tumor targeting facilitated the selective accumulation of MoS2-PEG-Biotin-Cur/Er at the tumor site, thus enhancing the synergistic antitumor effects of Cur and Er. Remarkably, MoS2-PEG-Biotin-Cur/Er achieved the combination of synergistic chemotherapy and photothermal therapy (PTT) upon NIR irradiation, effectively suppressing lung cancer cell proliferation and inhabiting tumor growth in vivo. CONCLUSIONS: The as-synthesized MoS2-PEG-Biotin-Cur/Er, featuring high targeting ability, NIR light-responsive drug release, and the integration of synergistic chemotherapy and PTT, may provide a promising strategy for the treatment of lung cancer in clinical practice.

MoS2 nanosheets supported on anodic aluminum oxide membrane: An effective interface for label-free electrochemical detection of microRNA.

The interesting adsorption affinity of two-dimensional nanosheets to single stranded over double stranded nucleic acids have stimulated the exploration of these materials in biosensing. Herein, MoS2 nanosheets decorated anodic aluminum oxide (AAO) membrane was simply prepared by suction filtration. The MoS2/AAO hybrid membrane was initially applied to the electrochemical detection of microRNA using let-7a as the model. When let-7a was incubated with its complementary DNA, double stranded DNA-RNA formed and which displayed weak adsorption capability to the hybrid membrane. And thus the steric effect combining the electrostatic repulsion of the backbone phosphate of nucleic acids for [Fe(CN)6]3- transport across the hybrid membrane varied with the concentration of let-7a. In this way, a label-free electrochemical detection method for microRNA was established by monitoring the change of the redox current of [Fe(CN)6]3-. To further improve the detection sensitivity of the method, we proposed two separate strategies focusing on the amplification of the target-induced steric hindrance with DNA nanostructure and the magnification of the electrode sensitivity for [Fe(CN)6]3- by electrode modification. By using the two strategies, the hybrid membrane based-detection method exhibited broad linear range, low detection limit and good selectivity as well as reproducibility. Therefore, this study provided a proof-of-concept for the application of two-dimensional material to nucleic acids detection.

Aptamer-functionalized molybdenum disulfide nanosheets for tumor cell targeting and lysosomal acidic environment/NIR laser responsive drug delivery to realize synergetic chemo-photothermal therapeutic effects.

Molybdenum disulfide (MoS2), one representative 2D nanomaterial, has recently emerged as a unique platform in the biomedical field. However, its application in drug delivery systems should be further exploited. Here, we report a novel tumor cell targeting and lysosomal acidic environment/NIR laser dual responsive drug delivery system for synergetic chemo-photothermal treatment of cancer cells. The MoS2 nanosheets were loaded with chemotherapy drug doxorubicin (DOX) and coated with polydopamine (PDA) layer. Then, thiolated aptamer AS1411 and polyethylene glycol (PEG) were modified onto MoS2 nanosheets through Michael addition reaction to construct DOX@Apt-PEG-PDA-MoS2 nanosheets. The aptamer modification endowed the nanoplatform with targeting ability to breast cancer MCF-7 cells. MoS2 and PDA converted 808 nm NIR laser into heat and played the role of photothermal therapy (PTT). Tumor lysosomal acidic environment and NIR laser irradiation accelerated the release of DOX from the nanosheets. The nanocarrier Apt-PEG-PDA-MoS2 showed good biocompatibility, and DOX@Apt-PEG-PDA-MoS2 showed synergetic chemo-photothermal therapy effects with significantly enhanced anti-tumor efficacy, suggesting that this MoS2-based drug delivery platform is promising for targeted and synergetic treatment of cancer.

A colorimetric aptamer-based method for detection of cadmium using the enhanced peroxidase-like activity of Au-MoS2 nanocomposites.

In this work, a colorimetric aptamer-based method for detection of cadmium using gold nanoparticles modified MoS2 nanocomposites as enzyme mimic is established. In short, biotinylated Cd2+ aptamers are immobilized by biotin-avidin binding on the bottoms of the microplate, the complementary strands of Cd2+ aptamers are connected to the Au-MoS2 nanocomposites which have the function of enhanced peroxidase-like activity. The csDNA-Au-MoS2 signal probe and target Cd2+ compete for binding Cd2+ aptamer, the color change can be observed by addition of chromogenic substrate, thereby realizing visual detection of Cd2+. The absorbance of the solution at 450 nm has a clear linear relationship with the Cd2+ concentration. The linear range is 1-500 ng/mL, and the limit of detection is 0.7 ng/mL. The assay was used to test white wine samples, the results are consistent with those of atomic absorption spectrometry; which prove that this method can be used for detection of Cd2+ in real samples.

Immunostimulatory Potential of MoS2 Nanosheets: Enhancing Dendritic Cell Maturation, Migration and T Cell Elicitation.

BACKGROUND: Due to their extraordinary physical and chemical properties, MoS2 nanosheets (MSNs) are becoming more widely used in nanomedicine. However, their influence on immune systems remains unclear. MATERIALS AND METHODS: Two few-layered MSNs at sizes of 100-250 nm (S-MSNs) and 400-500 nm (L-MSNs) were used in this study. Bone marrow-derived dendritic cells (DCs) were exposed to both MSNs at different doses (0, 8, 16, 32, 64, 128 µg/mL) for 48 h and subjected to analyses of surface marker expression, cytokine secretion, lymphoid homing and in vivo T cell priming. RESULTS: Different-sized MSNs of all doses did not affect the viability of DCs. The expression of CD40, CD80, CD86 and CCR7 was significantly higher on both S-MSN- and L-MSN-treated DCs at a dose of 128 µg/mL. As the dose of MSN increased, the secretion of IL-12p70 remained unchanged, the secretion of IL-1ß decreased, and the production of TNF-α increased. A significant increase in IL-6 was observed in the 128 µg/mL L-MSN-treated DCs. In particular, MSN treatment dramatically improved the ex vivo movement and in vivo homing ability of both the local resident and blood circulating DCs. Furthermore, the cytoskeleton rearrangement regulated by ROS elevation was responsible for the enhanced homing ability of the MSNs. More robust CD4+ and CD8+ T cell proliferation and activation (characterized by high expression of CD107a, CD69 and ICOS) was observed in mice vaccinated with MSN-treated DCs. Importantly, exposure to MSNs did not interrupt LPS-induced DC activation, homing and T cell priming. CONCLUSION: Few-layered MSNs ranging from 100 to 500 nm in size could play an immunostimulatory role in enhancing DC maturation, migration and T cell elicitation, making them a good candidate for vaccine adjuvants. Investigation of this study will not only expand the applications of MSNs and other new transition metal dichalcogenides (TMDCs) but also shed light on the in vivo immune-risk evaluation of MSN-based nanomaterials.

A multifunctional nanoplatform based on MoS2-nanosheets for targeted drug delivery and chemo-photothermal therapy.

Synergistic tumor treatment has recently attracted more and more attention due to its remarkable therapeutic effect. Herein, a multifunctional drug delivery system based on hyaluronic acid (HA) targeted dual stimulation responsive MoS2 nanosheets (HA-PEI-LA-MoS2-PEG, HPMP) for active interaction with CD44 receptor positive MCF-7 cells is reported. Melanin (Mel), a new type of photothermal agent and doxorubicin (DOX) are both loaded onto the HPMP nanocomposite and can be released by mild acid or hyperthermia. The prepared HPMP nanocomposite has a uniform hydrodynamic diameter (104 nm), a high drug loading (944.3 mg.g-1 HPMP), a remarkable photothermal effect (photothermal conversion efficiency: 55.3%) and excellent biocompatibility. The DOX release from HPMP@(DOX/Mel) can be precisely controlled by the dual stimuli of utilizing the acidic environment in the tumor cells and external laser irradiation. Meanwhile, loading of Mel onto the surface can enhance the photothermal effect of the MoS2 nanosheets. In vitro experiments showed that the HPMP@(DOX/Mel) nanoplatform could efficiently deliver DOX into MCF-7 cells and demonstrated enhanced cytotoxicity compared to that of the non-targeted nanoplatform. In vivo experiments in a breast cancer model of nude mice further confirmed that the HPMP@(DOX/Mel) significantly inhibited tumor growth under near infrared (NIR) laser irradiation, which is superior to any single therapy. In summary, this flexible nanoplatform, based on multi-faceted loaded MoS2 nanosheets, exhibits considerable potential for efficient pH/NIR-responsive targeted drug delivery and chemo-photothermal synergistic tumor therapy.

Layered MoS2 nanosheets modified by biomimetic phospholipids: Enhanced stability and its synergistic treatment of cancer with chemo-photothermal therapy.

Cancer is a huge challenge humanity facing today, and single chemical treatments inevitably have shortcomings such as poor selectivity and large side effects. This paper constructed an egg yolk phospholipids modified molybdenum disulfide (MoS2) nanocarrier system for the treatment of tumors via the combination of chemotherapy and photothermal therapy. The lipid-modified layered MoS2 (MoS2-Lipid) nanocomposite was synthesized by simple physical adsorption. The lipid modification strongly enhanced the stability of MoS2 nanosheets and the nanocarrier has a large drug loading amount with pH dependent DOX release profile, an excellent photothermal property, and an ideal cellular uptake property. Therefore, we combined chemotherapy and photothermal therapy to treat tumors synergistically. Through in vitro cell experiments, pure nanocomposite had no obvious cytotoxicity to cells, and the synergistic treatment of tumors by chemotherapy and photothermal therapy was more effective than any single treatment. More importantly, in vivo experiments indicated that lipid modification enhanced the accumulation of the nanocarrier in mice tumors, thus a better photothermal performance could be seen compared with original MoS2 nanosheets. In summary, the MoS2-lipid nanocomposite is a promising nanocarrier for the treatment of tumors by chemo and photothermal therapy.

Redox/NIR dual-responsive MoS2 for synergetic chemo-photothermal therapy of cancer.

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.

Molybdenum disulfide-based hyaluronic acid-guided multifunctional theranostic nanoplatform for magnetic resonance imaging and synergetic chemo-photothermal therapy.

The construction of multifunctional theranostic nanoplatforms to integrate accurate imaging and enhanced therapy to treat tumors is highly attractive but remains a challenge. Here, we developed a molybdenum disulfide (MoS2)-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving the targeted co-delivery of the gadolinium (Gd)-based contrast agents (CAs) and the anticancer drug gefitinib (Gef) for magnetic resonance imaging (MRI) and synergetic chemo-photothermal therapy of tumors. Gd3+ ions were coupled to HA-grafted MoS2 nanosheets with diethylenetriaminepentaacetic acid (DTPA) as a linker, followed by the incorporation of Gef. The resulting MoS2-HA-DTPA-Gd/Gef exhibited enhanced relaxivity, 3.3 times greater than that of the commercial CA DTPA-Gd, which facilitated the MRI in vivo. Moreover, the nanoplatform effectively converted the absorbed near-infrared (NIR) light into heat, which not only induced the photothermal ablation of cancer cells but also triggered the release of Gef from MoS2-HA-DTPA-Gd/Gef, enabling the synergetic chemo-photothermal therapy. The results of in vitro and in vivo experiments revealed that MoS2-HA-DTPA-Gd/Gef upon NIR irradiation effectively blocked the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway and activated apoptosis-related proteins to induce cell apoptosis and suppress cell proliferation, thus inhibiting the tumor growth in lung cancer cell-bearing mice. Taken together, this multifunctional theranostic nanoplatform has significant promise for the diagnosis and treatment of cancer.

Morphological Evolution of Vertically Standing Molybdenum Disulfide Nanosheets by Chemical Vapor Deposition.

In this study, we demonstrated the chemical vapor deposition (CVD) of vertically standing molybdenum disulfide (MoS2) nanosheets, with an unconventional combination of molybdenum hexacarbonyl (Mo(CO)6) and 1,2-ethanedithiol (C2H6S2) as the novel kind of Mo and S precursors respectively. The effect of the distance between the precursor’s outlet and substrates (denoted as d) on the growth characteristics of MoS2, including surface morphology and nanosheet structure, was investigated. Meanwhile, the relationship between the structure characteristics of MoS2 nanosheets and their catalytic performance for hydrogen evolution reaction (HER) was elucidated. The formation of vertically standing nanosheets was analyzed and verified by means of an extrusion growth model. The crystallinity, average length, and average depth between peak and valley (Rz) of MoS2 nanosheets differed depending on the spatial location of the substrate. Good crystalized MoS2 nanosheets grown at d = 5.5 cm with the largest average length of 440 nm, and the highest Rz of 162 nm contributed to a better HER performance, with a respective Tafel slope and exchange current density of 138.9 mV/decade, and 22.6 μA/cm² for raw data (127.8 mV/decade and 19.3 μA/cm² for iR-corrected data).

Sensitive Chronocoulometric Detection of miRNA at Screen-Printed Electrodes Modified by Gold-Decorated MoS2 Nanosheets.

Developing novel simple and ultrasensitive strategies for detecting microRNAs (miRNAs) is highly desirable because of their association with early cancer diagnostic and prognostic processes. Here a new chronocoulometric sensor, based on semiconducting 2H MoS2 nanosheets (MoS2 NSs) decorated with a controlled density of monodispersed small gold nanoparticles (AuNPs@MoS2), was fabricated via electrodeposition, for the highly sensitive detection of miRNA-21. The size and interparticle spacing of AuNPs were optimized by controlling nucleation and growth rates through the tuning of deposition potential and Au precursor concentration and by getting simultaneous feedback from morphological and electrochemical activity studies. The sensing strategy, involved the selective immobilization of the thiolated capture probe DNA (CP) at AuNPs and hybridization of CP to a part of the miRNA target, whereas the remaining part of the target was complementary to a signaling nonlabeled DNA sequence that served to amplify the target upon hybridization. Chronocoulometry provided precise quantification of nucleic acids at each step of the sensor assay by interrogating [Ru(NH3)6]3+ electrostatically bound to phosphate backbones of oligonucleotides. A detailed and systematic optimization study demonstrated that the thinnest and smallest MoS2 NSs improved the sensitivity of the AuNP@MoS2 sensor, achieving an impressive detection limit of ≈100 aM, which is 2 orders of magnitude lower than that of a bare Au electrode and also enhanced the DNA-miRNA hybridization efficiency by 25%. Such an improved performance can be attributed to the controlled packing density of CPs achieved by their self-assembly on AuNPs, large interparticle density, small size, and intimate coupling between AuNPs and MoS2. Alongside the outstanding sensitivity, the sensor exhibited an excellent selectivity down to femtomolar concentrations, for discriminating a complementary miRNA-21 target in a complex system composed of different foreign targets including mismatched and noncomplementary miRNA-155. These advantages make our sensor a promising contender in the point of care miRNA sensor family for medical diagnostics.

Facile synthesis of soybean phospholipid-encapsulated MoS2 nanosheets for efficient in vitro and in vivo photothermal regression of breast tumor.

Two-dimensional MoS2 nanosheet has been extensively explored as a photothermal agent for tumor regression; however, its surface modification remains a great challenge. Herein, as an alternative to surface polyethylene glycol modification (PEGylation), a facile approach based on "thin-film" strategy has been proposed for the first time to produce soybean phospholipid-encapsulated MoS2 (SP-MoS2) nanosheets. By simply vacuum-treating MoS2 nanosheets/soybean phospholipid/chloroform dispersion in a rotary evaporator, SP-MoS2 nanosheet was successfully constructed. Owing to the steric hindrance of polymer chains, the surface-coated soybean phospholipid endowed MoS2 nanosheets with excellent colloidal stability. Without showing detectable in vitro and in vivo hemolysis, coagulation, and cyto-/histotoxicity, the constructed SP-MoS2 nanosheets showed good photothermal conversion performance and photothermal stability. SP-MoS2 nanosheet was shown to be a promising platform for in vitro and in vivo breast tumor photothermal therapy. The produced SP-MoS2 nanosheets featured low cost, simple fabrication, and good in vivo hemo-/histocompatibility and hold promising potential for future clinical tumor therapy.

Iron oxide decorated MoS2 nanosheets with double PEGylation for chelator-free radiolabeling and multimodal imaging guided photothermal therapy.

Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites, which are then modified with two types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, (64)Cu, a commonly used positron-emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging, which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon intravenous injection, in vivo photothermal therapy is finally conducted, achieving effective tumor ablation in an animal tumor model. Our study highlights the promise of constructing multifunctional theranostic nanocomposites based on 2D transitional metal dichalcogenides for multimodal imaging-guided cancer therapy.

Biocompatible PEGylated MoS2 nanosheets: controllable bottom-up synthesis and highly efficient photothermal regression of tumor.

Two-dimensional transition metal dichalcogenides, particularly MoS2 nanosheets, have been deemed as a novel category of NIR photothermal transducing agent. Herein, an efficient and versatile one-pot solvothermal synthesis based on "bottom-up" strategy has been, for the first time, proposed for the controlled synthesis of PEGylated MoS2 nanosheets by using a novel "integrated" precursor containing both Mo and S elements. This facile but unique PEG-mediated solvothermal procedure endowed MoS2 nanosheets with controlled size, increased crystallinity and excellent colloidal stability. The photothermal performance of nanosheets was optimized via modulating the particulate size and surface PEGylation. PEGylated MoS2 nanosheets with desired photothermal conversion performance and excellent colloidal and photothermal stability were further utilized for highly efficient photothermal therapy of cancer in a tumor-bearing mouse xenograft. Without showing observable in vitro and in vivo hemolysis, coagulation and toxicity, the optimized MoS2-PEG nanosheets showed promising in vitro and in vivo anti-cancer efficacy.