Huixiong Xu

Ultrasmall Cu2‐xS Nanodots for Highly Efficient Photoacoustic Imaging‐Guided Photothermal Therapy

Monodisperse, ultrasmall (<5 nm) Cu(2-x)S nanodots (u-Cu(2-x)S NDs) with significantly strong near-infrared absorption and conversion are successfully demonstrated for effective deep-tissue photoacoustic imaging-guided photothermal therapy both in vitro and in vivo. Owing to ultrasmall nanoparticle size and high water dispersibility as well as long stability, such nanodots possess a prolonged circulation in blood and good passive accumulation within tumors through the enhanced permeability and retention effect. These u-Cu(2-x)S NDs have negligible side effects to both blood and normal tissues according to in vivo toxicity evaluations for up to 3 months, showing excellent hemo/histocompatibility. Furthermore, these u-Cu(2-x)S NDs can be thoroughly cleared through feces and urine within 5 days, showing high biosafety for further potential clinical translation. This novel photoacoustic imaging-guided photothermal therapy based on u-Cu(2-x)S NDs composed of a single component shows great prospects as a multifunctional nanoplatform with integration and multifunction for cancer diagnosis and therapy.

Dual-Enzyme-Loaded Multifunctional Hybrid Nanogel System for Pathological Responsive Ultrasound Imaging and T2-Weighted Magnetic Resonance Imaging

A dual-enzyme-loaded multifunctional hybrid nanogel probe (SPIO@GCS/acryl/biotin-CAT/SOD-gel, or SGC) has been developed for dual-modality pathological responsive ultrasound (US) imaging and enhanced T2-weighted magnetic resonance (MR) imaging. This probe is composed of functionalized superparamagnetic iron oxide particles, a dual enzyme species (catalase and superoxide dismutase), and a polysaccharide cationic polymer glycol chitosan gel. The dual-modality US/MR imaging capabilities of the hybrid nanogel for responsive US imaging and enhanced T2-weighted MR imaging have been evaluated both in vitro and in vivo. These results show that the hybrid nanogel SGC can exhibit efficient dual-enzyme biocatalysis with pathological species for responsive US imaging. SGC also demonstrates increased accumulation in acidic environments for enhanced T2-weighted MR imaging. Further research on these nanogel systems may lead to the development of more efficient US/MR contrast agents.

An Intelligent Nanotheranostic Agent for Targeting, Redox‐Responsive Ultrasound Imaging, and Imaging‐Guided High‐Intensity Focused Ultrasound Synergistic Therapy

A novel multifunctional nanotheranostic agent with targeting, redox-responsive ultrasound imaging and ultrasound imaging-guided high-intensity focused ultrasound (HIFU) therapy (MSNC-PEG-HA(SS)-PFH, abbreviated as MPH(SS)-PFH) capabilities is developed. The redox-responsive guest molecule release and ultrasound imaging functions can be both integrated in such a smart theranostic agent, which is accomplished by the redox-triggered transition from the crosslinking state to retrocrosslinking state of the grafted polyethylene glycol-disulfide hyaluronic acid molecules on the particle surface when reaching a reducing environment in vitro. More importantly, under the tailored ultrasound imaging guiding, in vivo Hela tumor-bearing nude mice can be thoroughly and spatial-accurately ablated during HIFU therapy, due to the targeted accumulation, responsive ultrasound imaging guidance and the synergistic ablation functions of nanotheranostic agent MPH(SS)-PFH in the tumors. This novel multifunctional nano-platform can serve as a promising candidate for further studies on oncology therapy, due to its high stability, responsive and indicative ultrasound imaging of tumors, and enhanced HIFU therapeutic efficiency and spatial accuracy under ultrasound-guidance.

Perfluoropentane-Encapsulated Hollow Mesoporous Prussian Blue Nanocubes for Activated Ultrasound Imaging and Photothermal Therapy of Cancer

Hollow mesoporous nanomaterials have gained tremendous attention in the fields of nanomedicine and nanobiotechnology. Herein, n-perfluoropentane (PFP)-encapsulated hollow mesoporous Prussian blue (HPB) nanocubes (HPB-PFP) with excellent colloidal stability have been synthesized for concurrent in vivo tumor diagnosis and regression. The HPB shell shows excellent photothermal conversion efficiency that can absorb near-infrared (NIR) laser light and convert it into heat. The generated heat can not only cause tumor ablation by raising the temperature of tumor tissue but also promote the continuous gasification and bubbling of encapsulated liquid PFP with low boiling point. These formed PFP bubbles can cause tissue impedance mismatch, thus apparently enhancing the signal of B-mode ultrasound imaging in vitro and generating an apparent echogenicity signal for tumor tissues of nude mice in vivo. Without showing observable in vitro and in vivo cytotoxicity, the designed biocompatible HPB-PFP nanotheranostics with high colloidal stability and photothermal efficiency are anticipated to find various biomedical applications in activated ultrasound imaging-guided tumor detection and therapy.

A Drug–Perfluorocarbon Nanoemulsion with an Ultrathin Silica Coating for the Synergistic Effect of Chemotherapy and Ablation by High‐Intensity Focused Ultrasound

The synergistic effect of chemotherapy and ablation using high-intensity focused ultrasound (HIFU) is realized with a newly developed drug-delivery system. The system comprises an ultrathin silica shell surrounding a poly(lactic-co-glycolic acid) nanoemulsion core containing the drug (CPT) and a perfluorocarbon (PFOB). This nanosystem presents many advantages in drug delivery, such as excellent structural stability, high drug-loading capacity, and rapid HIFU-mediated drug release.

A facile synthesis of versatile Cu2-xS nanoprobe for enhanced MRI and infrared thermal/photoacoustic multimodal imaging.

A novel type of intelligent nanoprobe by using single component of Cu2-xS for multimodal imaging has been facilely and rapidly synthesized in scale via thermal decomposition followed by biomimetic phospholipid modification, which endows them with uniform and small nanoparticle size (ca.15 nm), well phosphate buffer saline (PBS) dispersity, high stability, and excellent biocompatibility. The as-synthesized Cu2-xS nanoprobes (Cu2-xS NPs) are capable of providing contrast enhancement for T1-weighted magnetic resonance imaging (MRI), as demonstrated by the both in vitro and in vivo imaging investigations for the first time. In addition, due to their strong near infrared (NIR) optical absorption, they can also serve as a candidate contrast agent for enhanced infrared thermal/photoacoustic imaging, to meet the shortfalls of MRI. Hence, complementary and potentially more comprehensive information can be acquired for the early detection and accurate diagnosis of cancer. Furthermore, negligible systematic side effects to the blood and tissue were observed in a relatively long period of 3 months. The distinctive multimodal imaging capability with excellent hemo/histocompatibility of the Cu2-xS NPs could open up a new molecular imaging possibility for detecting and diagnosing cancer or other diseases in the future.

Multifunctional Bi2S3/PLGA nanocapsule for combined HIFU/radiation therapy.

A multifunctional organic-inorganic hybrid nanocapsule based on Bi2S3-embedded poly (lactic-co-glycolic acid) (PLGA) nanocapsule has been elaborately designed to combine the merits of both polymeric shell structure and Bi2S3 nanoparticles. Hydrophobic Bi2S3 nanoparticles were successfully introduced into the PLGA nanocapsules via a facile and efficient water/oil/water (W/O/W) emulsion strategy. The elastic polymeric PLGA shell provides the excellent capability of ultrasound contrast imaging to the Bi2S3/PLGA. Meanwhile, the potential of these microcapsules to enhance the high intensity focused ultrasound (HIFU) therapy was demonstrated. Importantly, this research provided the first example of both inxa0vitro and inxa0vivo to demonstrate the radiosensitization effect of Bi2S3-embedded PLGA hybrid nanocapsules against prostate cancer under external X-ray irradiation. Thus, the successful integration of the Bi2S3 and PLGA nanocapsules provided an alternative strategy for the highly efficient ultrasound guided HIFU/RT synergistic therapy.

A continuous tri-phase transition effect for HIFU-mediated intravenous drug delivery

Aiming at substantially enhanced efficacy and biosafety of clinical HIFU therapy, a natural solid medium, L-menthol (LM), characteristic of mild and controllable solid-liquid-gas (SLG) tri-phase transition, was adopted, instead of those conventional explosive liquid-gas (LG) bi-phase transitional media, in constructing a multifunctional theranostic system. Owing to the continuous and controllable characteristics of SLG tri-phase transition, such a novel tri-phase transition-based theranostic system has been demonstrated of the repeatedly enhanced HIFU efficacy exxa0vivo and inxa0vivo under once intravenous injection and the significantly improved treatment precision, controllability and biosafety when comparing to the traditional bi-phase transition medium, perfluorohexane (PFH), thus promising great application potential in clinical HIFU treatment. Moreover, this theranostic system has been demonstrated a long blood-circulation lifetime and continuous accumulation in tumor in 24xa0h, which is very beneficial for the enhanced tumor ablation inxa0vivo along with SLG tri-phase transition. More importantly, after loading multiple model drugs and real drug, such a theranostic system presents a HIFU-mediated temperature-responsive drug release property, and depending on the versatile miscibility of LM, co-loadings with hydrophobic and hydrophilic drugs are also achieved, which provides the possibility of synergistic treatment combining HIFU therapy and chemotherapy.

A combined “RAFT” and “Graft From” polymerization strategy for surface modification of mesoporous silica nanoparticles: towards enhanced tumor accumulation and cancer therapy efficacy

A novel modification route integrating the copolymers of positive charged quaternary amines and polyethylene glycol (PEG) units using a combination of reversible addition-fragmentation chain-transfer polymerization (RAFT) and Graft From strategy, has been proposed and developed, for the first time, to decorate the surface of mesoporous silica nanoparticles (MSNs). These MSNs are shown to have a greatly reduced hydrodynamic particle size in physiological solution. It is demonstrated that such an efficient copolymer surface modification strategy, resulting in PEG coating with high positive zeta potential, can achieve a nearly 2-fold enhanced permeability and retention (EPR) effect, and longer blood half-life compared to coating with PEG only. Besides, the in vivo results demonstrated that this surface modification strategy could lead to a higher efficacy of doxorubicin (DOX) drug delivery and greater suppression of side effects compared to the free drug. Based on this novel strategy of combining RAFT and Graft From polymerization, it is anticipated that this efficient modification of tumor-specific targeting of MSNs can be widely used in future nanomedicine research.

Ultrasound-Triggered Nitric Oxide Release Platform Based on Energy Transformation for Targeted Inhibition of Pancreatic Tumor

Inspired by considerable application potential in various diseases, nitric oxide (NO) has gained increasing attention. Nevertheless, current NO release scaffolds suffer from some inevitable drawbacks, for example, high toxicity for NO donor byproducts, poor specificity, shallow penetration depth, and strong ionizing irradiation for triggers, all of which remain obstacles to clinical application. Herein, an ultrasound-triggered NO on-demand release system is constructed using natural l-arginine as NO donor and local ultrasound as trigger. The focused ultrasound can activate H2O2 to generate more oxygen-contained species (ROS) of stronger oxidation ability than H2O2 for oxidizing LA via the energy transformation from ultrasound mechanical energy to chemical energy, and thus produce more NO for ultimately suppressing the highly aggressive and lethal Panc-1 tumor. Moreover, a blood vessel-intercellular matrix-cell relay targeting strategy has been established and relying on it, over 7-fold higher retention of such NO release system in a subcutaneous xenograft mouse model of Panc-1 is obtained, which consequently results in a more evident inhibitory effect and a prolonged survival rate (80% ± 5% improvement in 60-day survival).