Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

Sensitive and selective ctDNA detection based on functionalized black phosphorus nanosheets.

Circulating tumor DNA (ctDNA) identification is one of the most meaningful approaches towards early cancer diagnosis. However, effective and practical methods for analyzing this emerging class of biomarkers are still lacking. In this work, a biosensor based on nitrophenyl functionalized black phosphorus nanosheets (NP-BPs) is fabricated for sensitive and selective detection of ctDNA. In this work, a nitrophenyl functionalized black phosphorus nanosheets (NP-BPs) biosensor is fabricated for sensitive and selective detection of ctDNA. Due to the successful nitrophenyl functionalization, the NP-BPs biosensor shows higher quenching efficiency and stronger affinity towards single-stranded DNA (ssDNA), as compared with double-stranded DNA (dsDNA). Therefore, the NP-BPs biosensor exhibits 5.4-fold fluorescence enhancement when dye-labelled ssDNA probe forms dsDNA in the presence of its specific ctDNA target. This biosensor exhibits a detection limit of 50 fM and a wide linear detection range of 50 fM-80 pM, provides reliable readout in a short time (15 min). Moreover, the NP-BPs-based biosensor could be applied to discriminate single nucleotide polymorphisms in clinical serum samples. It is envisioned that the NP-BPs-based sensing platform has great potentials in early cancer diagnosis and monitoring cancer progression.

Bioactive phospho-therapy with black phosphorus for in vivo tumor suppression.

Background and Purpose: Although inorganic nanomaterials have been widely used in multimodal cancer therapies, the intrinsic contributions of the materials are not well understood and sometimes underestimated. In this work, bioactive phospho-therapy with black phosphorus nanosheets (BPs) for in vivo tumor suppression is studied. Methods: Orthotopic liver tumor and acute myeloid leukemia are chosen as the models for the solid tumor and hematological tumor, respectively. BPs are injected into mice through the tail vein and tumor growth is monitored by IVIS bioluminescence imaging. Tumor tissues and serum samples are collected to determine the suppression effect and biosafety of BPs after treatment. Results: The in vitro studies show that BPs with high intracellular uptake produce apoptosis- and autophagy-mediated programmed cell death of human liver carcinoma cells but do not affect normal cells. BPs passively accumulate in the tumor site at a high concentration and inhibit tumor growth. The tumor weight is much less than that observed from the doxorubicin (DOX)-treated group. The average survival time is extended by at least two months and the survival rate is 100% after 120 days. Western bolt analysis confirms that BPs suppress carcinoma growth via the apoptosis and autophagy pathways. In addition, administration of BPs into mice suffering from leukemia results in tumor suppression and long survival. Conclusions: This study reveals that BPs constitute a type of bioactive anti-cancer agents and provides insights into the application of inorganic nanomaterials to cancer therapy.

InSe Nanosheets for Efficient NIR-II-Responsive Drug Release.

Near-infrared-II (NIR-II) biowindow is appealing from the perspectives of larger maximum permissible exposure in comparison with the near-infrared-I biowindow, so the NIR-II-responsive drug-delivery nanoplatform is highly desirable. In this work, two-dimensional InSe nanosheets (InSe NSs) are modified with poly(ethylene glycol) and evaluated as an effective NIR-II-responsive cancer treatment nanoplatform. The InSe NSs synthesized by liquid exfoliation exhibit prominent NIR-II-responsive photothermal conversion efficiency (39.5%) and photothermal stability. Moreover, the InSe NSs have a doxorubicin (DOX) loading capacity as high as 93.6%, along with excellent NIR-II-responsive DOX release characteristic. The superior synergistic chemo/photothermal effects have also been demonstrated by the in vitro experiments in killing cancer cells. In combination with good biocompatibility, the InSe NSs have great potential in therapeutic applications.

Black Phosphorus: Bioactive Nanomaterials with Inherent and Selective Chemotherapeutic Effects.

Black phosphorus nanosheets (BPs) are demonstrated to be highly bioactive anti-cancer agents because of their inherent and selective chemotherapeutic effects. Fast intracellular biodegradation of BPs and acute elevation of phosphate anions were observed from different types of cancer cells due to the stronger intracellular oxidative stress and accelerated energy metabolism, but normal cells are not affected. Selective biodegradation of BPs induced G2/M phase arrest and subsequent apoptosis- and autophagy-mediated cell death in cancer cells but not normal cells. The selectivity was superior to that of the traditional chemotherapeutic agent, doxorubicin (DOX). In vivo assessment confirmed the efficiency of BPs in suppressing tumor growth. This study provides insights into nanostructured bioactive anti-cancer agents and reveals a new direction for nanomedicine research.

Enhanced Cytosolic Delivery and Release of CRISPR/Cas9 by Black Phosphorus Nanosheets for Genome Editing.

A biodegradable two-dimensional (2D) delivery platform based on loading black phosphorus nanosheets (BPs) with Cas9 ribonucleoprotein engineered with three nuclear localization signals (NLSs) at C terminus (Cas9N3) is successfully established. The Cas9N3-BPs enter cells effectively via membrane penetration and endocytosis pathways, followed by a BPs biodegradation-associated endosomal escape and cytosolic releases of the loaded Cas9N3 complexes. The Cas9N3-BPs thus provide efficient genome editing and gene silencing in vitro and in vivo at a relatively low dose as compared with other nanoparticle-based delivery platforms. This biodegradable 2D delivery platform offers a versatile cytosolic delivery approach for CRISPR/Cas9 ribonucleoprotein and other bioactive macromolecules for biomedical applications.

Synthesis of lipid-black phosphorus quantum dot bilayer vesicles for near-infrared-controlled drug release.

Black phosphorus quantum dots are incorporated into liposomal bilayers to produce a drug delivery system with excellent near-infrared (NIR) photothermal properties and drug release capability controlled by light. In vitro experiments demonstrate its good biocompatibility and NIR-light-induced chemo-photothermal antitumor efficiency.

Fluorine-free preparation of titanium carbide MXene quantum dots with high near-infrared photothermal performances for cancer therapy.

Titanium carbide MXene quantum dots (QDs) were synthesized using an effective fluorine-free method as a biocompatible and highly efficient nanoagent for photothermal therapy (PTT) applications. In contrast to the traditional, hazardous and time-consuming process of HF pretreatment, our fluorine-free method is safe and simple. More importantly, abundant Al oxoanions were found to be modified on the MXene QD surface by the fluorine-free method, which endowed the QDs with strong and broad absorption in the NIR region. As a result, the as-prepared MXene QDs exhibited an extinction coefficient as large as 52.8 Lg-1 cm-1 at 808 nm and a photothermal conversion efficiency as high as 52.2%. Both the values are among the best reported so far. The as-prepared MXene QDs achieved simultaneous photoacoustic (PA) imaging and the remarkable PTT effect of tumors. Moreover, MXene QDs showed great biocompatibility without causing noticeable toxicity in vitro and in vivo, indicating their high potential for clinical applications.

TiL4 -Coordinated Black Phosphorus Quantum Dots as an Efficient Contrast Agent for In Vivo Photoacoustic Imaging of Cancer.

Black phosphorus quantum dots coordinated with a sulfonic ester of the titanium ligand are prepared and exhibit enhanced stability. In vitro and in vivo photoacoustic imaging applications demonstrate that the quantum dots can efficiently accumulate inside the tumor producing tumor profiles with high spatial resolution, demonstrating their potential as an efficient agent for photoacoustic imaging.

Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy.

An active cell membrane-camouflaged nanoparticle, owning to membrane antigens and membrane structure, can achieve special properties such as specific recognition, long blood circulation, and immune escaping. Herein, we reported a cancer cell membrane-cloaked nanoparticle system as a theranostic nanoplatform. The biomimetic nanoparticles (indocyanine green (ICG)-loaded and cancer cell membrane-coated nanoparticles, ICNPs) exhibit a core-shell nanostructure consisting of an ICG-polymeric core and cancer cell membrane shell. ICNPs demonstrated specific homologous targeting to cancer cells with good monodispersity, preferable photothermal response, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. Benefited from the functionalization of the homologous binding adhesion molecules from cancer cell membranes, ICNPs significantly promoted cell endocytosis and homologous-targeting tumor accumulation in vivo. Moreover, ICNPs were also good at disguising as cells to decrease interception by the liver and kidney. Through near-infrared (NIR)-FL/PA dual-modal imaging, ICNPs could realize real-time monitored in vivo dynamic distribution with high spatial resolution and deep penetration. Under NIR laser irradiation, ICNPs exhibited highly efficient photothermal therapy to eradicate xenografted tumor. The robust ICNPs with homologous properties of cancer cell membranes can serve as a bionic nanoplatform for cancer-targeted imaging and phototherapy.

Indocyanine green-loaded polydopamine-iron ions coordination nanoparticles for photoacoustic/magnetic resonance dual-modal imaging-guided cancer photothermal therapy.

Multi-modal imaging-guided cancer photothermal therapy (PTT) with advanced theranostic nanoagents can efficiently improve therapeutic efficacy and reduce treatment side effects. Herein, we have developed a theranostic nanoagent based on indocyanine green (ICG)-loaded polydopamine (PDA)-iron ions coordination nanoparticles (PDA-Fe3+-ICG NPs), which are used for photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging-guided cancer PTT treatments. In this nanoplatform, ICG molecules, the U.S. Food and Drug Administration approved near-infrared (NIR) dye, absorbing on PDA NPs (a melanin-like biopolymer) to significantly increase the NIR optical absorption of PDA NPs nearly 6 times and decreases their fluorescence emission, which can improve the PA contrast ability and promote the photothermal conversion efficiency of PDA NPs. Meanwhile, Fe3+ ions chelated on the PDA NPs act as a T1-weighted MRI contrast agent (r1 = 14 mM-1 s-1). In a mouse 4T1 breast tumor model, PA/MRI dual-modal imaging and highly efficient PTT treatments with low laser density were achieved with remarkable therapeutic efficiency and minimal side effects. This study illustrates that the highly integrated and biocompatible PDA-based NPs can serve as a versatile nanoplatform by loading different imaging molecules and drugs for multi-modal imaging and cancer combination therapy.

Smart hyaluronidase-actived theranostic micelles for dual-modal imaging guided photodynamic therapy.

We here report smart hyaluronidase-actived theranostic nanoparticles based on hyaluronic acid (HA) coupled with chlorin e6 (Ce6) via adipic dihydrazide (ADH) forming HA-ADH-Ce6 conjugates and self-assembling into HACE NPs. The resulting nanoparticles showed stable nano-structure in aqueous condition with uniform size distribution and can be actively disassembled in the presence of hyaluronidase (over-expressed in tumor cells), exhibiting hyaluronidase-responsive "OFF/ON" behavior of fluorescence signal. The HACE NPs were rapidly taken up to human lung cancer cells A549 via CD44 (the HA receptor on the surface of tumor cells) receptor mediated endocytosis. Upon laser irradiation, the HACE NPs realized good near-infrared fluorescence imaging and photoacoustic imaging in the tumor bearing mice, which showed 5-fold higher fluorescence intensity and 3-fold higher photoacoustic (PA) intensity than free Ce6, respectively. In addition, under low dose of laser power, the HACE NPs presented more effective photodynamic therapy to suppression of tumor growth than free Ce6 in vitro and in vivo. Overall, these results suggest that the well-defined HACE NPs is a biocompatible theranostic nanoplatform for in vivo dual-modal tumor imaging and phototherapy simultaneously.

Indocyanine Green-Loaded Polydopamine-Reduced Graphene Oxide Nanocomposites with Amplifying Photoacoustic and Photothermal Effects for Cancer Theranostics.

Photoacoustic (PA) imaging and photothermal therapy (PTT) as light-induced theranostic platforms have been attracted much attention in recent years. However, the development of highly efficient and integrated phototheranostic nanoagents for amplifying PA imaging and PTT treatments poses great challenges. Here, we report a novel phototheranostic nanoagent using indocyanine green-loaded polydopamine-reduced graphene oxide nanocomposites (ICG-PDA-rGO) with amplifying PA and PTT effects for cancer theranostics. The results demonstrate that the PDA layer coating on the surface of rGO could effectively absorb a large number of ICG molecules, quench ICG's fluorescence, and enhance the PDA-rGO's optical absorption at 780 nm. The obtained ICG-PDA-rGO exhibits stronger PTT effect and higher PA contrast than that of pure GO and PDA-rGO. After PA imaging-guided PTT treatments, the tumors in 4T1 breast subcutaneous and orthotopic mice models are suppressed completely and no treatment-induced toxicity being observed. It illustrates that the ICG-PDA-rGO nanocomposites constitute a new class of theranostic nanomedicine for amplifying PA imaging and PTT treatments.