Dual-stimuli responsive smart nanoprobe for precise diagnosis and synergistic multi-modalities therapy of superficial squamous cell carcinoma.

BACKGROUND: Although the promising advancements of current therapeutic approaches is available for the squamous cell carcinoma (SCC) patients, the clinical treatment of SCC still faces many difficulties. The surgical irreparable disfigurement and the postoperative wound infection largely hamper the recovery, and the chemo/radiotherapy leads to toxic side effects. RESULTS: Herein, a novel pH/Hyaluronidase (HAase) dual-stimuli triggered smart nanoprobe FeIIITA@HA has been designed through the biomineralization of Fe3+ and polyphenol tannic acid (TA) under the control of hyaluronic acid (HA) matrix. With the HA residues on the outer surface, FeIIITA@HA nanoprobes can specifically target the SCC cells through the over-expressed CD44, and accumulate in the carcinoma region after intravenously administration. The abundant HAase in carcinoma microenvironment will trigger the degradation of HA molecules, thereby exposing the FeIIITA complex. After ingesting by tumor cells via CD44 mediated endocytosis, the acidic lysosomal condition will further trigger the protonation of TA molecules, finally leading to the Fe3+ release of nanoprobe, and inducing a hybrid ferroptosis/apoptosis of tumor cells through peroxidase activity and glutathione depletion. In addition, Owing to the outstanding T1 magnetic resonance imaging (MRI) performance and phototermal conversion efficiency of nanoprobes, the MRI-guided photothermal therapy (PTT) can be also combined to complement the Fe3+-induced cancer therapy. Meanwhile, it was also found that the nanoprobes can promote the recruitment of CD4+ and CD8+ T cells to inhibit the tumor growth through the cytokines secretion. In addition, the FeIIITA@HA nanoprobes can be eliminated from the body and no obvious adverse side effect can be found in histological analysis, which confirmed the biosafety of them. CONCLUSION: The current FeIIITA@HA nanoprobe has huge potential in clinical translation in the field of precise diagnosis and intelligent synergistic therapy of superficial SCC. This strategy will promisingly avoid the surgical defects, and reduce the systemic side effect of traditional chemotherapy, paving a new way for the future SCC treatment.

Glutathione-sensitive mesoporous nanoparticles loaded with cinnamaldehyde for chemodynamic and immunological therapy of cancer.

Chemodynamic therapy as a novel type of chemotherapy can damage the DNA structures and induce cell apoptosis and immunogenic cell death (ICD) through generating reactive oxygen species (ROS) to aggravate oxidative stress. Nonetheless, as an intrinsic antioxidative response of tumor cells, the expression of glutathione (GSH) can be upregulated to maintain the cellular redox balance and protect the tumor cells from ROS-mediated damage. In this context, it is feasible to simultaneously boost ROS generation and GSH depletion in tumor cells; however, the precise delivery and release of GSH scavengers at specific subcellular sites is of great importance. Herein, we propose a GSH-responsive mesoporous organosilica nanoparticle (MON)-based nanomedicine MON-CA-TPP@HA through sequentially covalently attaching triphenylphosphine (TPP) and electrostatically coating hyaluronic acid (HA) onto the surface of cinnamaldehyde (CA)-loaded MONs, known as MON-CA-TPP@HA, which has been demonstrated to be an extremely effective therapeutic strategy for cancer treatment through inducing ICD and apoptosis of breast cancer cells. Systematic in vitro experimental results clearly revealed that the nanomedicine can actively target the tumor cells with the help of HA, subsequently enter the tumor cells, and precisely bind with the mitochondria through TPP residues. Upon cleavaging the disulfide bond in the MONs triggered by over-expressed GSH within tumors, the CA molecules can be released inducing the excessive ROS in situ surrounding the mitochondria to activate oxidative stress to induce apoptosis and ICD of breast cancer cells. The results of the in vivo experiments confirm that the MON-CA-TPP@HA nanomedicine can effectively promote dendritic cell (DC) maturation and CD 8+ T cell activation and regulate the ratio of M1/M2 macrophages, which improve tumor immunosuppressive microenvironment. It is thus believed that the current nanomedicine has paved a new way for future cancer therapy.

Polydopamine Nanoparticle-Reinforced Near-Infrared Light-Triggered Shape Memory Polycaprolactone-Polydopamine Polyurethane for Biomedical Implant Applications.

Near-infrared (NIR) light-triggered shape memory polymers are expected to have a more promising prospect in biomedical applications compared with traditional heat-triggered shape memory polymers. In this work, a new kind of polyurethane with NIR light-triggered shape memory property was prepared by using polycaprolactone (PCL), polydopamine nanoparticles (PDANPs), hexamethylene diisocyanate (HDI), and 1,4-butanediol (BDO). The synthesized PCL-PDA polyurethanes, especially when the weight content of PDANPs was 0.17%, showed excellent mechanical properties because the PDANPs were well-dispersed in polyurethanes by the chain extension reaction. Moreover, it also showed an NIR light-triggered rapid shape recovery because of the photothermal effect of polydopamine. The in vitro and in vivo tests showed that the PCL-PDA polyurethane would not inhibit cell proliferation nor induce a strong host inflammatory response, revealing the non-cytotoxicity and good biocompatibility of the material. In addition, the PCL-PDA polyurethane exhibited excellent in vivo NIR light-triggered shape memory performance under an 808 nm laser with low intensity (0.33 W cm-2), which was harmless to the human skin. These results demonstrated the potential of the PCL-PDA polyurethane in biomedical implant applications.

Red Blood Cell Membrane-Coated Ultrasmall NaGdF4 Nanoprobes for High-Resolution 3D Magnetic Resonance Angiography.

Enhanced angiography based on magnetic resonance imaging (MRI) has emerged as a noninvasive, robust, and high-resolution imaging technique for the clinical evaluation of vascular diseases. However, the effects of clinical Gd-chelating contrast agents are unsatisfactory for MRI contrast enhancement owing to their short blood half-life caused by rapid vascular extravasation, especially in microvessels. To address these issues, nanoprobes based on red blood cell membrane-coated ultrasmall NaGdF4 nanoparticles that exhibit much higher longitudinal molar relaxivity (r1) than the clinically used contrast agent gadolinium diethylenetriaminepentaacetic acid have been developed. Furthermore, the appropriate hydrodynamic diameter and stealth nature aid the nanoprobes to reside longer within the blood vessels without extravasation, thereby increasing the contrast between the blood vessels and surrounding tissues. Through probe-enhanced three-dimensional (3D) dynamic contrast-enhanced MR angiography, the main arteries and veins of the mouse were readily discernible, and even tiny vessels with sub-millimeter diameters could be clearly depicted. With this level of outstanding MR angiography performance, the embolization and recanalization processes of the carotid artery can be serially monitored with high imaging resolution using only a single injection. Additionally, the results of clearance studies and the toxicity tests further highlight the safety features of the nanoprobe. To summarize, the nanoprobes used in this study exhibit less extravascular leakage and a longer blood half-life, thus successfully overcoming the defects of the conventional low-molecular-weight Gd-based contrast agents and demonstrating their potential usefulness in enhanced MR angiography.

Bright, Magnetic NIR-II Quantum Dot Probe for Sensitive Dual-Modality Imaging and Intensive Combination Therapy of Cancer.

Improving the effectiveness of cancer therapy will require tools that enable more specific cancer targeting and improved tumor visualization. Theranostics have the potential for improving cancer care because of their ability to serve as both diagnostics and therapeutics; however, their diagnostic potential is often limited by tissue-associated light absorption and scattering. Herein, we develop CuInSe2@ZnS:Mn quantum dots (QDs) with intrinsic multifunctionality that both enable the accurate localization of small metastases and act as potent tumor ablation agents. By leveraging the growth kinetics of a ZnS shell on a biocompatible CuInSe2 core, Mn doping, and folic acid functionalization, we produce biocompatible QDs with high near-infrared (NIR)-II fluorescence efficiency up to 31.2%, high contrast on magnetic resonance imaging (MRI), and preferential distribution in 4T1 breast cancer tumors. MRI-enabled contrast of these nanoprobes is sufficient to timely identify small metastases in the lungs, which is critically important for preventing cancer spreading and recurrence. Further, exciting tumor-resident QDs with NIR light produces both fluorescence for tumor visualization through radiative recombination pathways as well as heat and radicals through nonradiative recombination pathways that kill cancer cells and initiate an anticancer immune response, which eliminates tumor and prevents tumor regrowth in 80% of mice.

The influence of surface charge on the tumor-targeting behavior of Fe3O4 nanoparticles for MRI.

Nanomedicine-based tumor-targeted therapy has emerged as a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. "Passive" targeting caused by the tumor EPR effect and "active" targeting endowed by the tumor-targeting moieties provide promising biomedical utilities and cancer therapy strategies for nanomedicine. However, as the nanoparticles are exposed to biological fluids, a large number of protein molecules will be adsorbed on their surface, known as protein corona, which may alter the targeting ability of the nanoparticles. The impact of different protein corona on the "passive" and "active" targeting behaviors is still ambiguous. Herein, three kinds of aqueous soluble Fe3O4 nanoparticles with different surface modifications were synthesized and applied to explore the correlation between their protein corona and passive/active tumor-targeting abilities. In the in vitro and in vivo studies, the protein corona exhibited completely different effects on the active and passive cancer-targeting capability of the particles. The particles presented active cancer-targeting ability if there was enough interaction time between the particles and cells. This was mainly due to the dynamic evolution of the protein corona, the proteins of which may be outcompeted by the cancer cell membrane and determine the targeting abilities. Unfortunately, the protein corona also inevitably accelerated RES/MPS uptake after the particles were injected into the body, which almost completely disabled the active targeting abilities of the particles. We believe that this in-depth understanding of protein corona will provide new ideas on the tumor-targeting mechanisms of nanoparticles and present a feasible approach to designing targeted drugs in the future.

An inflammation-targeted nanoparticle with bacteria forced release of polymyxin B for pneumonia therapy.

The epidemic of multidrug-resistant Gram-negative bacteria is an ever-growing global concern. Polymyxin B (PMB), a kind of "old fashioned" antibiotic, has been revived in clinical practice and mainly used as last-line antibiotics for otherwise untreatable serious infections because the incidence of the resistance to PMB is currently relatively low in comparison with other antibiotics in vivo owing to the unique bactericidal mechanism of PMB. However, serious adverse side effects, including nephrotoxicity and neurotoxicity, hamper its clinical application. Herein, we describe the development of a nanoparticle that can target sites of inflammation and forcedly release PMB specifically in the area of Gram-negative bacteria. This particle was constructed through the electrostatic self-assembly of hyaluronic acid (HA) and PMB molecules in order to realize the safe and effective treatment of pneumonia. After systemic administration, PMB-HA nanoparticles were found to actively accumulate in the lungs, precisely target the CD44 receptors over-expressed on the membrane of activated endothelial cells in inflammatory sites, and then come into contact with the bacteria resident in the damaged alveolar-capillary membrane. Due to the electrostatic and hydrophobic interactions between PMB and the lipopolysaccharide (LPS) in the outer membranes of bacteria, the PMB molecules in the PMB-HA nanoparticles are expected to escape from the nanoparticles to insert into the bacteria via competitive binding with LPS. Through shielding the cationic nature of PMB, PMB-HA nanoparticles also possess outstanding biosafety performance in comparison to free PMB. It is thus believed that this smart delivery system may pave a new way for the resurrection of PMB in the future clinical treatment of bacterial inflammatory diseases.

Visualizing the Potential Impairment of Polymyxin B to Central Nervous System Through MR Susceptibility-Weighted Imaging.

Polymyxin B (PMB) exert bactericidal effects on the cell wall of Gram-negative bacteria, leading to changes in the permeability of the cytoplasmic membrane and resulting in cell death, which is sensitive to the multi-resistant Gram-negative bacteria. However, the severe toxicity and adverse side effects largely hamper the clinical application of PMB. Although the molecular pathology of PMB neurotoxicity has been adequately studied at the cellular and molecular level. However, the impact of PMB on the physiological states of central nervous system in vivo may be quite different from that in vitro, which need to be further studied. Therefore, in the current study, the biocompatible ultra-uniform Fe3O4 nanoparticles were employed for noninvasively in vivo visualizing the potential impairment of PMB to the central nervous system. Systematic studies clearly reveal that the prepared Fe3O4 nanoparticles can serve as an appropriate magnetic resonance contrast agent with high transverse relaxivity and outstanding biosafety, which thus enables the following in vivo susceptibility-weighted imaging (SWI) studies on the PMB-treated mice models. As a result, it is first found that the blood-brain barrier (BBB) of mice may be impaired by successive PMB administration, displaying by the discrete punctate SWI signals distributed asymmetrically across brain regions in brain parenchyma. This result may pave a noninvasive approach for in-depth studies of PMB medication strategy, monitoring the BBB changes during PMB treatment, and even assessing the risk after PMB successive medication in multidrug-resistant Gram-negative bacterial infected patients from the perspective of medical imaging.

Enhanced Bioavailability of Dihydrotanshinone I-Bovine Serum Albumin Nanoparticles for Stroke Therapy.

Dihydrotanshinone I (DHT) is a natural component in Salvia miltiorrhiza and has been widely researched for its multiple bioactivities. However, poor solubility and biocompatibility of DHT limit its desirable application for clinical purposes. Herein, DHT was encapsulated with bovine serum albumin (BSA) to enhance bioavailability. Compared to free DHT, DHT-BSA NPs (nanoparticles) showed an improved solubility in normal saline and increased protection against hydrogen peroxide-induced oxidative damage in PC12 cells. In addition, DHT-BSA NPs administered by intravenous injection displayed a significant efficacy in the middle cerebral artery occlusion/reperfusion models, without any impact on the cerebral blood flow. In summary, DHT-BSA NPs show an enhanced bioavailability compared with free DHT and a successful penetration into the central nervous system for stroke therapy, demonstrating their application potential in cardio-cerebrovascular diseases.

Activable Multi-Modal Nanoprobes for Imaging Diagnosis and Therapy of Tumors.

Malignant tumors have become one of the major causes of human death, but there remains a lack of effective methods for tiny tumor diagnosis, metastasis warning, clinical efficacy prediction, and effective treatment. In this context, localizing tiny tumors via imaging and non-invasively extracting molecular information related to tumor proliferation, invasion, metastasis, and drug resistance from the tumor microenvironment have become the most fundamental tasks faced by cancer researchers. Tumor-associated microenvironmental physiological parameters, such as hypoxia, acidic extracellular pH, protease, reducing conditions, and so forth, have much to do with prognostic indicators for cancer progression, and impact therapeutic administrations. By combining with various novel nanoparticle-based activatable probes, molecular imaging technologies can provide a feasible approach to visualize tumor-associated microenvironment parameters noninvasively and realize accurate treatment of tumors. This review focuses on the recent achievements in the design of "smart" nanomedicine responding to the tumor microenvironment-related features and highlights state-of- the-art technology in tumor imaging diagnosis and therapy.