Deciphering the Effects of 2D Black Phosphorus on Disrupted Hematopoiesis and Pulmonary Immune Homeostasis Using a Developed Flow Cytometry Method.

As an emerging two-dimensional nanomaterial with promising prospects, mono- or few-layer black phosphorus (BP) is potentially toxic to humans. We investigated the effects of two types of BPs on adult male mice through intratracheal instillation. Using the flow cytometry method, the generation, migration, and recruitment of immune cells in different organs have been characterized on days 1, 7, 14, and 21 post-exposure. Compared with small BP (S-BP, lateral size at ∼188 nm), large BP (L-BP, lateral size at ∼326 nm) induced a stronger stress lymphopoiesis and B cell infiltration into the alveolar sac. More importantly, L-BP dramatically increased peripheral neutrophil (NE) counts up to 1.9-fold on day 21 post-exposure. Decreased expression of the CXCR4 on NEs, an important regulator of NE retention in the bone marrow, explained the increased NE release into the circulation induced by L-BP. Therefore, BP triggers systemic inflammation via the disruption of both the generation and migration of inflammatory immune cells.

Metal-Organic-Framework-Derived Carbon Nanostructures for Site-Specific Dual-Modality Photothermal/Photodynamic Thrombus Therapy.

Although near-infrared (NIR)-light-mediated photothermal thrombolysis has been investigated to overcome the bleeding risk of clinical clot-busting agents, the secondary embolism of post-phototherapy fragments (>10 µm) for small vessels should not be ignored in this process. In this study, dual-modality photothermal/photodynamic thrombolysis is explored using targeting nanoagents with an emphasis on improving biosafety as well as ameliorating the thrombolytic effect. The nanoagents can actively target glycoprotein IIb/IIIa receptors on thrombus to initiate site-specific thrombolysis by hyperthermia and reactive oxygen species under NIR laser irradiation. In comparison to single photothermal thrombolysis, an 87.9% higher re-establishment rate of dual-modality photothermal/photodynamic thrombolysis by one-time treatment is achieved in a lower limb thrombosis model. The dual-modality thrombolysis can also avoid re-embolization after breaking fibrin into tiny fragments. All the results show that this strategy is a safe and validated protocol for thrombolysis, which fits the clinical translational trend of nanomedicine.

Improved Healing of Diabetic Foot Ulcer upon Oxygenation Therapeutics through Oxygen-Loading Nanoperfluorocarbon Triggered by Radial Extracorporeal Shock Wave.

Diabetic foot ulcers (DFUs), the most serious complication of diabetes mellitus, can induce high morbidity, the need to amputate lower extremities, and even death. Although many adjunctive strategies have been applied for the treatment of DFUs, the low treatment efficiency, potential side effects, and high cost are still huge challenges. Recently, nanomaterial-based drug delivery systems (NDDSs) have achieved targeted drug delivery and controlled drug release, offering great promises in various therapeutics for diverse disorders. Additionally, the radial extracorporeal shock wave (rESW) has been shown to function as a robust trigger source for the NDDS to release its contents, as the rESW harbors a potent capability in generating pressure waves and in creating the cavitation effect. Here, we explored the performance of oxygen-loaded nanoperfluorocarbon (Nano-PFC) combined with the rESW as a treatment for DFUs. Prior to in vivo assessment, we first demonstrated the high oxygen affinity in vitro and great biocompatibility of Nano-PFC. Moreover, the rESW-responsive oxygen release behavior from oxygen-saturated Nano-PFC was also successfully verified in vitro and in vivo. Importantly, the wound healing of DFUs was significantly accelerated due to improved blood microcirculation, which was a result of rESW therapy (rESWT), and the targeted release of oxygen into the wound from oxygen-loaded Nano-PFC, which was triggered by the rESW. Collectively, the oxygen-saturated Nano-PFC and rESW provide a completely new approach to treat DFUs, and this study highlights the advantages of combining nanotechnology with rESW in therapeutics.

Black Phosphorus-Based Multimodal Nanoagent: Showing Targeted Combinatory Therapeutics against Cancer Metastasis.

In breast cancer chemophotothermal therapy, it is a great challenge for the development of multifunctional nanoagents for precision targeting and the effective treatment of tumors, especially for metastasis. Herein, we successfully design and synthesize a multifunctional black phosphorus (BP)-based nanoagent, BP/DTX@PLGA, to address this challenge. In this composite nanoagent, BP quantum dots (BPQDs) are loaded into poly(lactic-co-glycolic acid) (PLGA) with additional conjugation of a chemotherapeutic agent, docetaxel (DTX). The in vivo distribution results demonstrate that BP/DTX@PLGA shows striking tropism for targeting both primary tumors and lung metastatic tumors. Moreover, BP/DTX@PLGA exhibits outstanding controllable chemophotothermal combinatory therapeutics, which dramatically improves the efficacy of photothermal tumor ablation when combined with near-light irradiation. Mechanistically, accelerated DTX release from the nanocomplex upon heating and thermal treatment per se synergistically incurs apoptosis-dependent cell death, resulting in the elimination of lung metastasis. Meanwhile, in vitro and in vivo results further confirm that BP/DTX@PLGA possesses good biocompatibility. This study provides a promising BP-based multimodal nanoagent to constrain cancer metastasis.

Activation of Prodrugs by NIR-Triggered Release of Exogenous Enzymes for Locoregional Chemo-photothermal Therapy.

Enzymes have been used to direct the conversion of prodrugs in cancer therapy. However, non-specific distribution of endogenous enzymes seriously hinders their bioapplications. Herein, we developed a near-infrared-triggered locoregional chemo-photothermal therapy based on the exogenous enzyme delivery and remolded tumor mivroenvironment. The catalytic efficiency of enzymes was enhanced by the hyperthermia, and the therapeutic efficacy of photothermal therapy (PTT) was improved owing to the inhibition of heat shock protein 90 by chemotherapeutics. The locoregional chemo-phototherapy achieved a one-time successful cure in 4T1 tumor-bearing mice model. Thus, a mutually reinforcing feedback loop between PTT and chemotherapy can be initiated by the irradiation, which holds a promising future in cancer therapy.

Biodegradable Poly(amino acid)-Gold-Magnetic Complex with Efficient Endocytosis for Multimodal Imaging-Guided Chemo-photothermal Therapy.

Gold complexes can serve as efficient photothermal converters for cancer therapy, but their non-biodegradability hinders clinical bioapplications. Although enormous effort has been devoted, the conventionally adopted synthetic methods of biodegradation are characterized by high cost and complicated procedures, which delay the process of further clinical translation of gold complexes. Here, we report a multifunctional poly(amino acid)-gold-magnetic complex with self-degradation properties for synergistic chemo-photothermal therapy via simple and green chemistry methods. Nanoparticles of ∼3 nm in the biodegradation product were observed in simulated body fluid in 4 days. The biodegradability mainly benefits from the weakened internal electrostatic interaction of the poly(amino acid) by the ions in simulated body fluid. It is demonstrated that the poly(amino acid)-gold-magnetic complex has great cellular endocytosis by taking advantage of the guanidine group in arginine and possesses multimodal imaging and efficient tumor ablation (94%). This study reports a possibility for gold-magnetic complexes composed of poly(amino acid) to serve as a biodegradable nanotherapeutic for clinical applications.

A Comparative Study of Clinical Intervention and Interventional Photothermal Therapy for Pancreatic Cancer.

Although nanoparticle-based photothermal therapy (PTT) has been intensively investigated recently, its comparative efficiency with any clinical cancer treatments has been rarely explored. Herein for the first time we report a systematic comparative study of clinical iodine-125 (125 I) interstitial brachytherapy (IBT-125-I) and interventional PTT (IPTT) in an orthotopic xenograft model of human pancreatic cancer. IPTT, based on the nanoparticles composing of anti-urokinase plasminogen activator receptor (uPAR) antibody, polyethylene glycol (PEG), and indocyanine green (ICG) modified gold nanoshells (hereinafter uIGNs), is directly applied to local pancreatic tumor deep in the abdomen. In comparison to IBT-125-I, a 25% higher median survival rate of IPTT with complete ablation by one-time intervention has been achieved. The IPTT could also inhibit pancreatic tumor metastasis which can be harnessed for effective cancer immunotherapy. All results show that this IPTT is a safe and radical treatment for eradicating tumor cells, and may benefit future clinical pancreatic cancer patients.

Bacterial magnetic nanoparticles for photothermal therapy of cancer under the guidance of MRI.

The bacterial magnetic nanoparticles (BMPs) are biomineralized by the magnetotactic bacteria and naturally covered with a layer of biomembrane. Herein, BMPs were isolated and firstly used for the photothermal therapy (PTT) of cancer under the guidance of magnetic resonance imaging (MRI) in vitro and in vivo. The results showed that BMPs could rapidly convert the energy of 808 nm near-infrared (NIR) light into heat. After internalization by the HepG2 tumor cells, BMPs with good biocompatibility could induce an efficient killing effect after NIR light irradiation, along with a change of mitochondrial membrane potential (ΔΨm) and level of intracellular reactive oxygen species (ROS). The in vivo therapy also confirms that PTT with BMPs could effectively and completely ablate the tumor in mice without inducing observable toxicity. T2-weighted MRI showed a clear tumor boundary and a 25% enhancement of negative contrast enhancement at the tumor site, suggesting that BMPs can act as an effective MRI contrast agent for guiding the PTT. Our results indicate that BMPs could be a potential theranostic agent for simultaneous MRI and PTT of cancer.

Metal-Organic-Framework-Derived Mesoporous Carbon Nanospheres Containing Porphyrin-Like Metal Centers for Conformal Phototherapy.

Mesoporous carbon nanospheres containing porphyrin-like metal centers (denoted as "PMCS") are successfully synthesized by the pyrolysis of an imidazolate framework using a mesoporous-silica protection strategy. The PMCS allow infrared and photoacoustic imaging and synergetic photothermal therapy/photodynamic therapy derived from the porphyrin-like moieties, offering the possibility of real-time monitoring of therapeutic processes and image-guided precise conformal phototherapy. PMCS thus represent a novel multifunctional theranostic platform for improved treatment efficiencies.