Biomimetic Nanocomposites for Glioma Imaging and Therapy.

Glioma, the most common primary brain tumor, is highly invasive and grows rapidly. As such, the survival of glioma patients is relatively short, highlighting the vital importance of timely diagnosis and treatment of glioma. However, the blood brain barrier (BBB) and the non-targeting delivery systems of contrast agents and drugs greatly hinder the effective glioma imaging and therapy. Fortunately, in recent years, investigators have constructed various biomimetic delivery platforms utilizing the exceptional advantages of biomimetic nanocomposites, such as immune evasion, homologous targeting ability, and BBB penetrating ability, to achieve efficient and precise delivery of substances to glioma sites for improved diagnosis and treatment. In this concept, we present the application of these biomimetic nanocomposites in fluorescence imaging (FI), magnetic resonance imaging (MRI), and multi-modal imaging, as well as in chemotherapy, phototherapy, and combined therapy for glioma. Lastly, we provide our perspective on this research field.

Biomimetic Nanocomposites Camouflaged with Hybrid Cell Membranes for Accurate Therapy of Early-Stage Glioma.

Glioma features high fatality rate and short survival time of patients due to its fast growth speed and high invasiveness, hence timely treatment of early-stage glioma is extremely important. However, the blood brain barrier (BBB) severely prevents therapeutic agents from entering the brain; meanwhile, the non-targeted distribution of agents always causes side effects to vulnerable cerebral tissues. Therefore, delivery systems that possess both BBB penetrability and precise glioma targeting ability are keenly desired. We herein proposed a hybrid cell membrane (HM) camouflage strategy to construct therapeutic nanocomposites, in which HM consisting of brain metastatic breast cancer cell membrane and glioma cell membrane was prepared with a simple membrane fusion pathway. By coating HM onto drug-loaded nanoparticles, the as-obtained biomimetic therapeutic agent (termed HMGINPs) inherited satisfying BBB penetrability and homologous glioma targeting ability simultaneously from the two source cells. HMGINPs exhibited good biocompatibility and superior therapeutic efficacy towards early-stage glioma.

Tracking Hepatic Ischemia-Reperfusion Injury in Real Time with a Reversible NIR-IIb Fluorescent Redox Probe.

Hepatic ischemia-reperfusion injury (HIRI) is responsible for liver dysfunction, which involves reactive oxygen species (ROS) as the most critical marker. Real-time monitoring of ROS during HIRI can provide significant chance for early diagnosis and timely intervention. However, there is no probe available to track ROS fluctuations during HIRI in vivo, as it is extremely challenging to design reversibly responsive fluorescent probe in near-infrared region. Here, a reversible redox probe REPOMs emitting beyond 1500 nm is proposed to fill the blank, using rare earth ions-doped nanoparticles as emitter, and molybdenum-based polyoxometalate nanoclusters as the ROS-recognition site and emission modulator. REPOMs exhibited excellent response towards the repeated cycle between ROS and glutathione, based on which the time-resolved ROS changes during HIRI were successfully obtained. This reversible probe may provide a powerful tool to promote the hepatology research in the future.

Brain Tumor Cell Membrane-Coated Lanthanide-Doped Nanoparticles for NIR-IIb Luminescence Imaging and Surgical Navigation of Glioma.

Intraoperative visualization of the full extent of brain tumor by luminescence imaging helps to improve the degree and accuracy of brain tumor resection, thereby prolonging the survival of patients. However, the limited imaging depth and spatial resolution and the poor blood-brain barrier (BBB) permeability of most currently available luminescent probes restrict the imaging performance and surgical resection efficiency of brain tumor. Here, a brain tumor cell membrane-coated lanthanide-doped nanoparticles (CC-LnNPs) in the near-infrared-IIb window (NIR-IIb, 1500-1700 nm) is designed for brain tumor imaging and surgical navigation. The coating of brain tumor cell membrane endows CC-LnNPs with immune escape, BBB crossing, and homotypic targeting abilities, which are inherited from the source brain tumor cells. In addition, compared with clinically approved imaging agent indocyanine green, CC-LnNPs present higher temporal and spatial resolution, higher stability, and lower background signals, enabling clear visualization of the brain tumor boundary. With the guidance of NIR-IIb fluorescence, the glioma tissue (size < 3 mm, depth > 3 mm) could be clearly visualized and completely removed as a proof of concept. This study offers new insight for the future design of nanoprobe to image brain tumor and to achieve precise diagnosis and surgical navigation of brain tumor.

Loading Drugs in Natural Phospholipid Bilayers of Cell Membrane Shells to Construct Biomimetic Nanocomposites for Enhanced Tumor Therapy.

Drug-based oncotherapy is seriously challenged by insufficient drug accumulation at tumor sites, mainly resulting from low drug loading efficiency and poor tumor-targeting ability of drug carriers. We herein proposed a "one-stone, two-bird" strategy to circumvent both obstacles, utilizing the source cancer cell membrane (CM) as a dual-function carrier to simultaneously achieve sufficient drug loading and homologous tumor targeting. Combining the use of TPGS (d-α-tocopherol polyethylene glycol 1000 succinate) to inhibit the drug efflux process of drug-resistant tumor, we constructed core-shell-structured nanocomposites CMGNPs consisting of ICG (indocyanine green)/DOX (doxorubicin)-loaded, TPGS/OA (oleic acid)-stabilized upconversion nanoparticles as the core and ICG-loaded MCF7/ADR CMs as the shell, for combined chemo/phototherapy of MCF7/ADR tumor. The employment of phospholipid bilayers of CMs as natural pockets for extra drug loading while preserving the homologous targeting ability greatly enhanced drug concentration at tumor sites, endowing CMGNPs with excellent therapeutic efficacy. Our effort provides a versatile approach for facilitating drug delivery in diverse therapeutic systems.

Sensitizing the Luminescence of Lanthanide-Doped Nanoparticles over 1500 nm for High-Contrast and Deep Imaging of Brain Injury.

Real-time and in situ visualization of cerebrovascular dysfunction is significant for studying brain injury, which however, is restricted by the complex brain structure and limited imaging strategies. Luminescence imaging in NIR-IIb region (1500-1700 nm) is a promising tool owing to its merits including deep penetration, high resolution, and fast data acquisition. Unfortunately, a luminescent material in this region with sufficient brightness and biocompatibility is scarce. Herein, Ag2Se quantum dot-sensitized lanthanide-doped nanocrystals (QDs-LnNCs) with emission beyond 1500 nm were fabricated to image the cerebrovascular structure and hemodynamics in ischemic stroke and traumatic brain injury. The sensitization by QDs provided an over 100-fold enhanced brightness of LnNCs and a remarkable penetration depth of 11 mm. Dynamic information of blood perfusion and flow rates were acquired and the damage of the blood-brain barrier in the two injury models was investigated. Our results proved QDs-LnNCs as a kind of competent nanomaterial for noninvasive brain imaging.

Gold nanoclusters as a GSH activated mitochondrial targeting photosensitizer for efficient treatment of malignant tumors.

Gold nanoclusters (Au NCs), which have the characteristics of small size, near infrared (NIR) absorption and long triplet excited lifetime, have been used as a new type of photosensitizer for deep tissue photodynamic therapy (PDT). However, the therapeutic efficiency of the nano-system based on Au NCs still needs to be improved. Herein, we proposed a strategy using Mito-Au25@MnO2 nanocomposites to achieve enhanced PDT. Au25(Capt)18 - nanoclusters were applied as photosensitizers and further modified with peptides to target mitochondrial and MnO2 nanosheets to consume glutathione (GSH). In the presence of GSH, Mito-Au25@MnO2 dis-integrated and Mito-Au25 nanoparticles realized accurate mitochondrial targeting. Under the irradiation of 808 nm light, the nanocomposite ensured highly efficient PDT both in vitro and in vivo via oxidation pressure elevation and mitochondrial targeting in cancer cells.

Construction of a two-photon fluorescent probe for ratiometric imaging of hypochlorous acid in alcohol-induced liver injury.

Alcohol-induced liver injury has been a terrible threat to human health and life. The relationship between HClO and the process is unclear. Thus, a ratiometric two-photon fluorescent probe for HClO was deliberately constructed and revealed the generation of HClO in the alcohol-induced liver injury process for the first time.

Upconversion System with Quantum Dots as Sensitizer: Improved Photoluminescence and PDT Efficiency.

Upconversion nanoparticles (UCNPs) are prospective platforms for bioimaging and phototherapy, but a critical bottleneck is the limited brightness due to the faint absorptivity of lanthanide ions and the low quantum yield. To circumvent this problem, we herein propose our strategy to reconstruct the energy cascade of UCNPs using semiconductor quantum dots (QDs) as light sensitizer of Nd3+/Yb3+ codoped UCNPs. Ag2Se QDs with strong absorption at 808 nm acted as efficient antenna and transferred their energy to Yb3+ via a resonance energy transfer process, significantly enhancing the luminescence of UCNPs. This nanocomposite was then combined with Rose Bengal and applied for photodynamic therapy. Both in vitro and in vivo studies revealed the introduction of QDs improved the therapeutic performance remarkably. Our study suggests Ag2Se QDs with excellent photophysical properties can be promising agents to overcome the shortcomings of UCNPs and further strengthen their applications.

Development of a red absorbing Se-rhodamine photosensitizer and its application for bio-orthogonally activatable photodynamic therapy.

A π-extended red absorbing Se-rhodamine (Se-NR) was synthesised and characterized. By masking the amine of Se-NR as an azide, we successfully constructed a bio-orthogonally activatable photosensitizer (Se-NR-Az). Se-NR-Az was not photocytotoxic, but when activated by the Staudinger reaction, photocytotoxicity was restored.

Visualizing the Regulation of Hydroxyl Radical Level by Superoxide Dismutase via a Specific Molecular Probe.

Hydroxyl radical (·OH), as the most deleterious reactive oxygen species, is believed to be the etiological agent for many diseases and aging. An altered ·OH level has been confirmed in certain types of superoxide dismutase (SOD) mutation, but the regulation of ·OH by SOD in situ is still controversial or unclear because of the lack of effective tools to detect ·OH in the biological environment. Herein we report the first two-photon excitable molecular probe (P2) for ·OH, which is able to track the subtle fluctuation of ·OH level both in vitro and in vivo with high sensitivity and specificity. The probe was successfully applied to visualize ·OH variations in a variety of SOD1-involved biological processes, confirming that the inhibited enzymatic activity and down-regulated expression of SOD1 both lead to elevated intracellular ·OH level. This is the first report to visually reveal the relationship between SOD1 and ·OH level with a molecular tool.

A two-photon fluorescent probe for nitroreductase imaging in living cells, tissues and zebrafish under hypoxia conditions.

A two-photon fluorescent probe FNTR for nitroreductase was synthesized by using 9,9-dimethyl-2-acetyl-fluoren-7-methylamino (1) as a two-photon fluorophore and a p-nitrobenzyl carbamate group as a recognition domain for nitroreductase (NTR). The probe and the fluorophore were tested under one- and two-photon modes respectively. After reacting with nitroreductase, FNTR had a 130-fold fluorescence enhancement at 563 nm in 10 min and the maximal two-photon action cross-section value was detected as 66 GM at 750 nm. The probe showed a high sensitivity with a detection limit as low as 23.67 ng ml-1, high selectivity, low cytotoxicity and good photostability. In the presence of reduced nicotinamide adenine dinucleotide (NADH), endogenous NTR was detected in living cells, tissues and zebrafish. Cobalt chloride was used to induce chemical hypoxia to produce NTR, which generated enhanced fluorescence in cells and tumor tissues. Finally, two-photon fluorescence imaging of NTR was achieved in zebrafish at a penetration depth of up to 200 µm.