Photosynthetic bacteria-based whole-cell inorganic-biohybrid system for multimodal enhanced tumor radiotherapy.

The whole-cell inorganic-biohybrid systems show special functions and wide potential in biomedical application owing to the exceptional interactions between microbes and inorganic materials. However, the hybrid systems are still in stage of proof of concept. Here, we report a whole-cell inorganic-biohybrid system composed of Spirulina platensis and gold nanoclusters (SP-Au), which can enhance the cancer radiotherapy through multiple pathways, including cascade photocatalysis. Such systems can first produce oxygen under light irradiation, then convert some of the oxygen to superoxide anion (•O2-), and further oxidize the glutathione (GSH) in tumor cells. With the combination of hypoxic regulation, •O2- production, GSH oxidation, and the radiotherapy sensitization of gold nanoclusters, the final radiation is effectively enhanced, which show the best antitumor efficacy than other groups in both 4T1 and A549 tumor models. Moreover, in vivo distribution experiments show that the SP-Au can accumulate in the tumor and be rapidly metabolized through biodegradation, further indicating its application potential as a new multiway enhanced radiotherapy sensitizer.

Low-dose X-ray enhanced tumor accumulation of theranostic nanoparticles for high-performance bimodal imaging-guided photothermal therapy.

BACKGROUND: Theranostic nanoparticles (NPs) have achieved rapid development owing to their capacity for personalized multimodal diagnostic imaging and antitumor therapy. However, the efficient delivery and bulk accumulation of NPs in tumors are still the decisive factors in improving therapeutic effect. It is urgent to seek other methods to alters tumor microenvironment (like vascular permeability and density) for enhancing the efficiency of nanoparticles delivery and accumulation at the tumor site. METHODS: Herein, we developed a Raman-tagged hollow gold nanoparticle (termed as HAuNP@DTTC) with surface-enhanced Raman scattering (SERS) property, which could be accumulated efficiently in tumor site with the pre-irradiation of low-dose (3 Gy) X-ray and then exerted highly antitumor effect in breast cancer model. RESULTS: The tumor growth inhibition (TGI) of HAuNP@DTTC-induced photothermal therapy (PTT) was increased from 60% for PTT only to 97%, and the lethal distant metastasis of 4T1 breast cancer (such as lung and liver) were effectively inhibited under the X-ray-assisted PTT treatment. Moreover, with the strong absorbance induced by localized surface plasmon resonance in near-infrared (NIR) region, the signals of Raman/photoacoustic (PA) imaging in tumor was also significantly enhanced after the administration of HAuNP@DTTC, indicating it could be used as the Raman/PA imaging and photothermal agent simultaneously under 808 nm laser irradiation. CONCLUSIONS: Our studied of the as-prepared HAuNP@DTTC integrated the Raman/PA imaging and PTT functions into the single platform, and showed the good prospects for clinical applications especially with the low-dose X-ray irradiation as an adjuvant, which will be a productive strategy for enhancing drug delivery and accumulation in tumor theranostics.

Metal-organic framework-edaravone nanoparticles for radiotherapy-induced brain injury treatment.

Cranial radiotherapy may cause damage to normal brain tissues and induce cognitive dysfunction, so developing an effective strategy to prevent radiotherapy-induced brain injury is essential. Metal-organic frameworks (MOFs) can be used as vectors for the delivery of neuroprotective drugs due to their high drug loading capacity and low toxicity. In this study, we synthesized MIL-53(Cr) nanoparticles, which were used to deliver edaravone, and modified the surface of the nanoparticles with polyethylene glycol and Angiopep-2 (EDA@MIL-53(Cr)-P/A) to improve their oral bioavailability and ability to cross the blood-brain barrier (BBB). We confirmed that MIL-53(Cr)-P/A nanoparticles could achieve the sustained release of edaravone and enhance its ability to cross the BBB. The results of in vitro experiments showed that EDA@MIL-53(Cr)-P/A could exert radioprotective effects on HT22 and BV2 cells. We also demonstrated that EDA@MIL-53(Cr)-P/A could alleviate brain injury and cognitive dysfunction in mice receiving whole-brain irradiation. Mechanistically, EDA@MIL-53(Cr)-P/A alleviated irradiation-induced brain damage by inhibiting oxidative stress, DNA damage, apoptosis and inflammatory reactions. This study provides a new strategy for the protection against radiotherapy-induced brain injury.

Stress and stability comparison between different systems for high tibial osteotomies.

BACKGROUND: High tibial osteotomy (HTO) with a medial opening wedge has been used to treat medial compartment osteoarthritis. However, this makes the proximal tibia a highly unstable structure and causes plate and screws to be the potentials sources for mechanical failure. Consequently, proper design and use of the fixation device are essential to the HTO especially for overweight or full weight-bearing patients. METHODS: Based on the CT-based images, a tibial finite-element model with medial opening was simulated and instrumented with one-leg and two-leg plate systems. The construct was subjected to physiological and surgical loads. Construct stresses and wedge micromotions were chosen as the comparison indices. RESULTS: The use of locking screws can stabilize the construct and decrease the implant and bone stresses. Comparatively, the two-leg design provides a wider load-sharing base to form a force-couple mechanism that effectively reduces construct stresses and wedge micromotions. However, the incision size, muscular stripping, and structural rigidity are the major concerns of using the two-leg systems. The one-leg plates behave as the fulcrum of the leverage system and make the wedge tip the zone of tension and thus have been reported to negatively affect the callus formation. CONCLUSIONS: The choice of the HTO plates involved the trade-off between surgical convenience, construct stability, and stress-shielding effect. If the stability of the medial opening is the major concern, the two-leg system is suggested for the patients with heavy load demands and greater proximal tibial size. The one-leg system with locking screws can be used for the majority of the patients without heavy bodyweight and poor bone quality.

Biocompatible Gallium Nanodots against Drug-Resistant Bacterial Pneumonia and Liver Abscess.

Resistant bacterial infection remains a severe public health threat, and conventional antibiotic drugs work poorly in effectively treating infectious diseases. Here, we developed gallium-based nanodots (Ga NDs), consisting of specific disruption of bacterial iron ability, to treat multidrug-resistant (MDR) Gram-negative bacteria-infected diseases. The Ga NDs significantly suppress the proliferation of two typical MDR bacteria strains (P. aeruginosa and ESBL E. coli) compared with clinically used antibacterial drugs, including penicillin and levofloxacin. Ga NDs could also disrupt the biofilms of these two bacterial strains. In P. aeruginosa infected pneumonia and ESBL E. coli infected acute liver abscess models, the Ga NDs enable substantial inhibition of bacterial growth and reduce the organs' inflammation that resulted in significant improvement of survival. Further, the Ga NDs demonstrated excellent biocompatibility and biosafety characteristics. Together, we believe that our gallium containing nanotherapeutics are expected to be developed into promising alternative therapies to combat drug-resistant bacterial infection.

Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP)-induced liver injury (AILI) is a common liver disease in clinical practice. Only one clinically approved drug, N-acetylcysteine (NAC), for the treatment of AILI is available in clinics, but novel treatment strategies are still needed due to the complicated pathological changes of AILI and the side effects of NAC. Here, we found that astaxanthin (ASX) can prevent AILI through the Nrf2/HO-1 pathway. After treatment with ASX, there was a positive activation of the Nrf2/HO-1 pathway in AILI models both in vivo and in vitro accompanied by enhanced autophagy and reduced ferroptosis. In APAP-challenged L02 liver cells, ASX reduced autophagy and enhanced apoptosis of the cells. Furthermore, we developed ASX-loaded hollow mesoporous silica nanoparticles (HMSN@ASX) to improve the aqueous solubility of ASX and targeted delivery of ASX to the liver and then significantly improve the therapeutic effects. Taken together, we found that ASX can protect against AILI by activating the Nrf2/HO-1 pathway, which mainly affects oxidative stress, autophagy, and ferroptosis processes, and the HMSN@ASX nanosystem can target the liver to enhance the treatment efficiency of AILI.

A Deep Learning Approach for Detecting Colorectal Cancer via Raman Spectra.

Objective and Impact Statement. Distinguishing tumors from normal tissues is vital in the intraoperative diagnosis and pathological examination. In this work, we propose to utilize Raman spectroscopy as a novel modality in surgery to detect colorectal cancer tissues. Introduction. Raman spectra can reflect the substance components of the target tissues. However, the feature peak is slight and hard to detect due to environmental noise. Collecting a high-quality Raman spectroscopy dataset and developing effective deep learning detection methods are possibly viable approaches. Methods. First, we collect a large Raman spectroscopy dataset from 26 colorectal cancer patients with the Raman shift ranging from 385 to 1545 cm -1. Second, a one-dimensional residual convolutional neural network (1D-ResNet) architecture is designed to classify the tumor tissues of colorectal cancer. Third, we visualize and interpret the fingerprint peaks found by our deep learning model. Results. Experimental results show that our deep learning method achieves 98.5% accuracy in the detection of colorectal cancer and outperforms traditional methods. Conclusion. Overall, Raman spectra are a novel modality for clinical detection of colorectal cancer. Our proposed ensemble 1D-ResNet could effectively classify the Raman spectra obtained from colorectal tumor tissues or normal tissues.

Bioinspired protein corona strategy enhanced biocompatibility of Ag-Hybrid hollow Au nanoshells for surface-enhanced Raman scattering imaging and on-demand activation tumor-phototherapy.

Silver-based hybrid nanoprobes for surface-enhanced Raman scattering (SERS) imaging show their tremendous potential for precise biological detection and mediated phototherapy. However, the severe toxicity induced by Ag to normal mammalian cells hinders its further application. Herein, we presented a versatile bioinspired protein corona strategy through assembling bovine serum albumin (BSA) protected Raman tag DTTC-conjugated Ag-hybrid hollow Au nanoshells (hollow AgAu-DTTC-BSA), which their silver ion release and reactive oxygen species (ROS) generation are significantly suppressed, enabling no damage to normal cells and tissues, but can be reactivated on-demand under laser-irradiation at the tumor site. These nanoshells could also produce strong localized surface plasmon resonance for efficient-stable photothermal effect and enhanced SERS activity under laser irradiation, approved by both theoretical and experimental calculations. Furthermore, the biocompatible hollow AgAu-DTTC-BSA could detect both primary tumor tissues and tiny liver metastases (~0.18 mm) in orthotopic/subcutaneous CT26 colon tumor-bearing mice models. We also demonstrate their excellent therapeutic efficacy for colorectal solid neoplasms by accurate SERS imaging-guided photothermal therapy, simultaneously assisted with toxic Ag ion and ROS. These results suggest that hollow AgAu-DTTC-BSA is promising imaging assisted photothermal agents for solid tumor theranostics and enhancing the potential of Ag-based nanoparticles for practical treatment.

Calcium phosphate engineered photosynthetic microalgae to combat hypoxic-tumor by in-situ modulating hypoxia and cascade radio-phototherapy.

Rationale: Hypoxia is one of the crucial restrictions in cancer radiotherapy (RT), which leads to the hypoxia-associated radioresistance of tumor cells and may result in the sharp decline in therapeutic efficacy. Methods: Herein, living photosynthetic microalgae (Chlorella vulgaris, C. vulgaris), were used as oxygenators, for in situ oxygen generation to relieve tumor hypoxia. We engineered the surface of C. vulgaris (CV) cells with calcium phosphate (CaP) shell by biomineralization, to form a biomimetic system (CV@CaP) for efficient tumor delivery and in-situ active photosynthetic oxygenation reaction in tumor. Results: After intravenous injection into tumor-bearing mice, CV@CaP could remarkably alleviate tumor hypoxia by continuous oxygen generation, thereby achieving enhanced radiotherapeutic effect. Furthermore, a cascade phototherapy could be fulfilled by the chlorophyll released from photosynthetic microalgae combined thermal effects under 650 nm laser irradiation. The feasibility of CV@CaP-mediated combinational treatment was finally validated in an orthotropic breast cancer mouse model, revealing its prominent anti-tumor and anti-metastasis efficacy in hypoxic-tumor management. More importantly, the engineered photosynthetic microalgae exhibited excellent fluorescence and photoacoustic imaging properties, allowing the self-monitoring of tumor therapy and tumor microenvironment. Conclusions: Our studies of this photosynthetic microsystem open up a new dimension for solving the radioresistance issue of hypoxic tumors.

Multistage-responsive clustered nanosystem to improve tumor accumulation and penetration for photothermal/enhanced radiation synergistic therapy.

Developing new strategies to overcome biological barriers and achieve efficient delivery of therapeutic nanoparticles (NPs) is the key to achieve positive therapeutic outcomes in nanomedicine. Herein, a multistage-responsive clustered nanosystem is designed to systematically resolve the multiple tumor biological barriers conflict between the enhanced permeability retention (EPR) effect and spatially uniform penetration of the nanoparticles. The nanosystem with desirable diameter (initial size of ~50 nm), which is favorable for long blood circulation and high propensity of extravasation through tumor vascular interstices, can accumulate effectively around the tumor tissue through the EPR effect. Then, these pH-responsive nanoparticles are conglomerated to form large-sized aggregates (~1000 nm) in the tumor under the acidic microenvironment, and demonstrated great tumor retention. Subsequently, the photothermal treatment disperses the aggregates to be ultrasmall gold nanoclusters (~5 nm), thereby improving their tumor penetration ability, and enhancing the radiotherapeutic effect by radiosensitizer. In 4T1 tumor model, this nanosystem shows great tumor accumulation and penetration, and the tumor growth and the lung/liver metastasis in particle/PTT/RT treated mice is significantly inhibited. As a photoacoustic/fluorescence imaging agent and PT/RT synergistic agent, this pH-/laser-triggered size multistage-responsive nanosystem displayes both great tumor accumulation and penetration abilities, and shows excellent potential in tumor therapy.

Biomineralized Biohybrid Algae for Tumor Hypoxia Modulation and Cascade Radio-Photodynamic Therapy.

Biomineralization of biomaterials has shown extraordinary potential in cancer treatment, but the exploration of their in vivo applications is still insufficient. Here, we report a biohybrid microalgae system using a biomineralization approach to improve their biocompatibility, while keeping their living activities for radiation and photodynamic synergistic therapy in breast cancer. The biohybrid algae (Algae@SiO2) synthesized by a one-step biomimetic silicification method could significantly enhance their cytotoxicity and tolerance, improving the living activity in the tumor area. The innate chlorophyll and unique optical property make Algae@SiO2 possess dual imaging ability, namely, photoacoustic imaging and fluorescence imaging. Algae@SiO2 accumulated in tumor sites could generate oxygen in situ by external light-mediated photosynthesis, relieve tumor hypoxia, and then enhance the efficiency of radiation therapy. As a natural photosensitizer, the released chlorophyll from Algae@SiO2 could provide reactive oxygen species to kill the cancer cells for the cascaded photodynamic therapy. The significant suppression of tumor growth in the mice bearing 4T1 tumor successfully demonstrates the promising anti-tumor effect of the Algae@SiO2-mediated synergistic therapy. Our results show that biohybrid algae, integrated with PAI/FI dual imaging, radiosensitization, and cascaded photothermal therapy, is a promising multifunctional efficient biosystem for cancer treatment.

Mild temperature photothermal assisted anti-bacterial and anti-inflammatory nanosystem for synergistic treatment of post-cataract surgery endophthalmitis.

Rationale: Endophthalmitis, which is one of the severest complications of cataract surgeries, can seriously threaten vision and even lead to irreversible blindness owing to its complicated microenvironment, including both local bacterial infection and severe inflammation. It is urgent to develop a comprehensive treatment for both anti-bacterial and anti-inflammatory effects. Methods: Herein, we developed AuAgCu2O-bromfenac sodium nanoparticles (AuAgCu2O-BS NPs), which was designed to combine anti-bacterial and anti-inflammatory effects for integrated therapy of endophthalmitis after cataract surgery. The AuAgCu2O-BS NPs could eradicate methicillin-resistant Staphylococcus aureus (MRSA) bacterial strain relied on their photodynamic effects and the release of metal ions (Ag+ and Cu+) by the hollow AuAgCu2O nanostructures mediated mild photothermal effects. The anti-inflammatory drug, bromfenac sodium, released from the nanoparticles were able to significantly reduce the local inflammation of the endophthalmitis and promote tissue rehabilitation. In vivo bacterial elimination and anti-inflammation were confirmed by a postcataract endophthalmitis rabbit model. Results: Excellent antibacterial ability of AuAgCu2O-BS NPs was verified both in vitro and in vivo. Ophthalmological clinical observation and pathologic histology analysis showed prominent treatment of inflammatory reaction. Importantly, the mild temperature photothermal effect not only promoted the release of metal ions and bromfenac sodium but also avoided the thermal damage of the surrounding tissues, which was more suitable for the practical application of ophthalmology due to the complex structure of the eyeball. Moreover, superior biocompatibility was approved by the preliminary toxicity investigations, including low cytotoxicity, negligible damage to major organs, and stable intraocular pressure. Conclusions: Our studies of nanosystem provide a promising synergic therapeutic strategy for postcataract endophthalmitis treatment with favorable prognosis and promise in clinical translations.

Gold-silver nanoshells promote wound healing from drug-resistant bacteria infection and enable monitoring via surface-enhanced Raman scattering imaging.

Chronic infections, caused by multidrug-resistant (MDR) bacteria, constitute a serious problem yet often underappreciated in clinical practice. The in situ monitoring of the bacteria-infected disease is also necessary to track and verify the therapeutic effect. Herein we present a facile approach to overcome the above challenges through a Raman tag 3,3'-diethylthiatricarbocyanine iodide (DTTC)-conjugated gold-silver nanoshells (AuAgNSs). With a strong responsive of the near-infrared laser due to surface plasmon resonance (SPR) from hybrid metallic nanoshell structure, AuAgNSs exhibits an efficient photothermal effect, and it simultaneously releases silver ions during laser irradiation to bacterial eradicate. Herein, two MDR bacteria strain, methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum ß-lactamase Escherichia coli, are chosen as models and studied both in vitro and in vivo. As a result, the AuAgNSs-DTTC substrates enable surface-enhanced Raman scattering imaging to provide a non-invasive and extremely high sensitive detection (down to 300 CFU mL-1 for MRSA) and prolonged tracking (at least 8 days) of residual bacteria. In a chronic MRSA-infected wound mouse model, the AuAgNSs gel-mediated photothermal therapy/silver-release leads to a synergistic would healing with negligible toxicity or collateral damage to vital organs. These results suggest that AuAgNSs-DTTC is a promising anti-bacterial tool for clinical translation.