Biomimetic nanocomplex based corneal neovascularization theranostics.

Corneal neovascularization (CNV) is a major cause of blindness worldwide. However, the recent drug treatment is limited by repeated administration and low drug bioavailability. In this work, SU6668 (an inhibitor of receptor tyrosine kinases) and indocyanine green (ICG) are loaded onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and then coated with anti-VEGFR2 single chain antibody (AbVr2 scFv) genetically engineered cell membrane vesicles. The nanomedicine is delivered via eye drops, and the hyperthermia induced by laser irradiation could block the blood vessels. Meanwhile, the photothermal effect can also cause the degradation of nanomaterials and release chemotherapeutic drugs in the blocked area, thereby continuously inhibit the neovascularization. Furthermore, SU6668 could inhibit the expression of heat shock protein 70 (HSP70), promoting the cell death induced by photothermal effect. In conclusion, the combination of photothermal and chemotherapy drugs provides a novel, effective and safe approach for the treatment of CNV.

A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization.

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

Revolutionizing eye care: the game-changing applications of nano-antioxidants in ophthalmology.

Since the theory of free radical-induced aging was proposed in 1956, it has been constantly proven that reactive oxygen species (ROS) produced by oxidative stress play a vital role in the occurrence and progression of eye diseases. However, the inherent limitations of traditional drug therapy hindered the development of ophthalmic disease treatment. In recent years, great achievements have been made in the research of nanomedicine, which promotes the rapid development of safe theranostics in ophthalmology. In this review, we focus on the applications of antioxidant nanomedicine in the treatment of ophthalmology. The eye diseases were mainly classified into two categories: ocular surface diseases and posterior eye diseases. In each part, we first introduced the pathology of specific diseases about oxidative stress, and then presented the representative application examples of nano-antioxidants in eye disease therapy. Meanwhile, the nanocarriers that were used, the mechanism of function, and the therapeutic effect were also presented. Finally, we summarized the latest research progress and limitations of antioxidant nanomedicine for eye disease treatment and put forward the prospects of future development.

Soluble Nanographene C222: Synthesis and Applications for Synergistic Photodynamic/Photothermal Therapy.

Nanographene C222, which consists of a planar graphenic plane containing 222 carbon atoms, holds the record as the largest planar nanographene synthesized to date. However, its complete insolubility makes the processing of C222 difficult. Here we addressed this issue by introducing peripheral substituents perpendicular to the graphene plane, effectively disrupting the interlayer stacking and endowing C222 with good solubility. We also found that the electron-withdrawing substituents played a crucial role in the cyclodehydrogenation process, converting the dendritic polyphenylene precursor to C222. After disrupting the interlayer stacking, the introduction of only a few peripheral carboxylic groups allowed C222 to dissolve in phosphate buffer saline, reaching a concentration of up to 0.5 mg/mL. Taking advantage of the good photosensitizing and photothermal properties of the inner C222 core, the resulting water-soluble C222 emerged as a single-component agent for both photothermal and photodynamic tumor therapy, exhibiting an impressive tumor inhibition rate of 96%.

A Synergistic Therapy With Antioxidant and Anti-VEGF: Toward its Safe and Effective Elimination for Corneal Neovascularization.

Corneal neovascularization (CNV) is one of the leading causes of blindness in the world. In clinical practice; however, it remains a challenge to achieve a noninvasive and safe treatment. Herein, a biocompatible shell with excellent antioxidant and antivascularity is prepared by co-assembly of epigallocatechin gallate/gallic acid and Cu (II). After loading glucose oxidase (GOx) inside, the shell is modified with dimeric DPA-Zn for codelivering vascular endothelial growth factor (VEGF) small interfering RNA (VEGF-siRNA). Meanwhile, the Arg-Gly-Asp peptide (RGD) peptide-engineered cell membranes coating improves angiogenesis-targeting and is biocompatible for the multifunctional nanomedicine (CEGs/RGD). After eye drops administration, CEGs/RGD targets enrichment in neovascularization and CEGs NPs enter cells. Then, the inner GOx consumes glucose with a decrease in local pH, which in turn leads to the release of EGCE and VEGF-siRNA. As a result, the nanomedicines significantly reduce angiogenesis and inhibit CNV formation through synergistic effect of antioxidant and antivascular via down-regulation of cluster of differentiation 31 and VEGF. The nanomedicine represents a safe and efficient CNV treatment through the combined effect of antioxidant/gene, which provides important theoretical and clinical significance.

ICG-based laser treatments for ophthalmic diseases: Toward their safe and rapid strategy.

The eye is a very important organ, and keratitis, corneal neovascularization, floaters, age-related macular degeneration, and other vision problems have seriously affected people's quality of life. Among the ophthalmic treatments, laser photocoagulations have been proposed and have shown therapeutic effects in clinical settings. However, corneal thinning and bleeding lesions induced by laser damage have led to limit its applications. To treat the issues of traditional hyperthermia treatments, photosensitizers [e.g., indocyanine green (ICG)] have been investigated to increase the therapeutic effects of corneal neovascularization and choroidal neovascularization. In the recent study, with the help of ICG, laser-induced nanobubble was proposed to treat vitreous opacities. The developed strategies could enlarge the effect of laser irradiation and reduce the side effects, so as to expand the scope of laser treatments in clinical ophthalmic diseases.

B7H3 targeting gold nanocage pH-sensitive conjugates for precise and synergistic chemo-photothermal therapy against NSCLC.

BACKGROUND: The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). RESULTS: In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. CONCLUSION: This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.

A review on reactive oxygen species (ROS)-inducing nanoparticles activated by uni- or multi-modal dynamic treatment for oncotherapy.

Cancer seriously threatens human health. As compared to normal tissue cells, tumor cells are generally more susceptible to oxidative stress and accumulate higher concentrations of reactive oxygen species (ROS). Accordingly, nanomaterials-based therapies that boost intracellular ROS generation have recently been effective in targeting and eliminating cancer cells by causing programmed death. This review presents a comprehensive analysis of ROS-generation induced by nanoparticles and critically examines the associated therapies which can be categorized as uni-modal (chemodynamic therapy, photodynamic therapy, sonodynamic therapy) and multi-modal (uni-modal therapy + chemotherapy, uni-modal therapy + uni-modal therapy) therapies. Comparison of the relative tumor volume ratio between the experimental and initial tumor volumes shows that multi-modal therapy significantly outperformed other treatments. However, the limitations of multi-modal therapy are in the difficulties of materials preparation and sophisticated operation protocols, thus limiting its applications in clinical practice. As an emerging treatment modality, cold atmospheric plasma (CAP) is a reliable source of ROS, light, and electromagnetic fields that can be used to implement multi-modal treatments in a simple setting. Therefore, the field of tumor precision medicine is expected to increasingly benefit from these promising and rapidly emerging multi-modal therapies based on ROS-generating nanomaterials and reactive media such as CAPs.

An exploratory human study of superstable homogeneous lipiodol-indocyanine green formulation for precise surgical navigation in liver cancer.

The clinical applications of transcatheter arterial embolization (TAE) conversion therapy combined with hepatectomy have been severely restricted by ill-defined tumoral boundaries and miniscule hidden lesions. Fluorescent surgical navigation is a promising method for overcoming these barriers. However, sufficient delivery of the fluorescent probe into the tumor region after long-term TAE is challenging due to blockade of the tumor-supplying artery. Here, a super-stable homogeneous intermix formulating technology (SHIFT) to physically mix lipiodol and indocyanine green (ICG) formulation (SHIFT and ICG) for fluorescent surgical navigation after long-term TAE conversion therapy is provided. Through the retrospective study of 45 clinical liver cancer patients, it is found that SHIFT and ICG formulation have excellent tumor deposition effect and safety. During surgical resection after long-term TAE conversion therapy, SHIFT and ICG could clearly identify in real time the full tumor regions and boundaries and had a high signal-to-normal tissues ratio-even the indistinguishable satellite lesions could be identified with a strong fluorescence intensity. Meanwhile, SHIFT and ICG could improve operative, anesthetic, and postoperative variables associated with postoperative complications. This simple and effective SHIFT could provide precise fluorescent navigation for surgical resection following long-term embolization therapy in clinical practice and has great potential for a translational pipeline.

Integrated Nanorod-Mediated PD-L1 Downregulation in Combination with Oxidative-Stress Immunogene Therapy against Cancer.

It is an engaging program for tumor treatment that rationalizes the specific microenvironments, activation of suppressed immune system (immune resistance/escape reversion), and synergistic target therapy. Herein, a biomimetic nanoplatform that combines oxidative stress with genetic immunotherapy to strengthen the therapeutic efficacy is developed. Ru-TePt nanorods, small interfering RNA (PD-L1 siRNA), and biomimetic cellular membrane vesicles with the targeting ability to design a multifunctional Ru-TePt@siRNA-MVs system are rationally integrated. Notably, the Fenton-like activity significantly enhances Ru-TePt nanorods sonosensitization, thus provoking stronger oxidative stress to kill cells directly. Meanwhile, immunogenic cell death is triggered to secrete numerous cytokines and activate T cells. The effective catalase characteristics of Ru-TePt enable the in situ oxygen-producing pump to improve tumor oxygen level and coordinately strengthen the therapeutic effect of SDT followed. More importantly, anti-PD-L1-siRNA mediated immune checkpoint silence of the PD-L1 gene creates an environment conducive to activating cytotoxic T lymphocytes, synergistic with boosted reactive oxygen species-triggered antitumor immune response. The experimental results in vitro and in vivo reveal that the Ru-TePt@siRNA-MVs nanosystems can effectively activate the oxidative stress-triggered immune response and inhibit PD-1/PD-L1 axis-mediated immune resistance. Consequently, this orchestrated treatment paradigm provides valuable insights for developing potential oxidative stress and genetic immunotherapy.

Nanosensitizer-mediated unique dynamic therapy tactics for effective inhibition of deep tumors.

X-ray and ultrasound waves are widely employed for diagnostic and therapeutic purposes in clinic. Recently, they have been demonstrated to be ideal excitation sources that activate sensitizers for the dynamic therapy of deep-seated tumors due to their excellent tissue penetration. Here, we focused on the recent progress in five years in the unique dynamic therapy strategies for the effective inhibition of deep tumors that activated by X-ray and ultrasound waves. The concepts, mechanisms, and typical nanosensitizers used as energy transducers are described as well as their applications in oncology. The future developments and potential challenges are also discussed. These unique therapeutic methods are expected to be developed as depth-independent, minimally invasive, and multifunctional strategies for the clinic treatment of various deep malignancies.

m6A reader hnRNPA2B1 drives multiple myeloma osteolytic bone disease.

Rationale: Bone destruction is a hallmark of multiple myeloma (MM) and affects more than 80% of patients. Although previous works revealed the roles of N6-methyladenosine (m6A) reader hnRNPA2B1 in the development of tumors, whether hnRNPA2B1 regulates bone destruction in MM is still unknown. Methods: Alizarin red S staining, TRAP staining, ELISA and quantitative real-time PCR assays were used to evaluate osteogenesis and osteoclastogenesis in vitro. X ray and bone histomorphometric analysis were preformed to identify bone resorption and bone formation in vivo. Exosome isolation and characterization were demonstrated by transmission electron microscopy, dynamic light scattering, immunofluorescence and flow cytometry assays. The interactions between hnRNPA2B1 and primary microRNAs were examined using RNA pull-down and RIP assays. Coimmunoprecipitation assay was used to test the interaction between hnRNPA2B1 and DGCR8 proteins. Luciferase assay was established to assess miRNAs target genes. Results: Here we show that myeloma cells hnRNPA2B1 mediates microRNAs processing and upregulates miR-92a-2-5p and miR-373-3p expression. These two microRNAs are transported to recipient monocytes or mesenchymal stem cells (MSCs) through exosomes, leading to activation of osteoclastogenesis and suppression of osteoblastogenesis by inhibiting IRF8 or RUNX2. Furthermore, clinical studies revealed a highly positive correlation between the level of myeloma cells hnRNPA2B1 and the number of osteolytic bone lesions in myeloma patients. Conclusions: This study elucidates an important mechanism by which myeloma-induced bone lesions, suggesting that hnRNPA2B1 may be targeted to prevent myeloma-associated bone disease.

Ruthenium-Based Metal-Organic Nanoradiosensitizers Enhance Radiotherapy by Combining ROS Generation and CO Gas Release.

A lack of targeting accuracy and radiosensitivity severely limits clinical radiotherapy. In this study, we developed a radiosensitizer comprised of Ru-based metal-organic nanostructures (ZrRuMn-MONs@mem) to optimize irradiation by maximizing reactive oxygen species (ROS) generation and CO release in X-ray-induced dynamic therapy (XDT). The well-designed nanostructures increase the direct absorption of radiation doses (primary radiation) and promote the deposition of photons and electrons (secondary radiation). The secondary electrons were trapped and transferred in the constrained MONs where they induce a cascade of reactions to increase the therapeutic efficiency. Meanwhile, the full-length antiglypican 3 (GPC3) antibody (hGC33) expressed a cell membrane coating enabling active targeting of tumor sites with optimized biocompatibility. The ZrRuMn-MONs@mem represents a starting point for advancing an all-around radiosensitizer that operates efficiently in clinical XDT.

Metal Ion-Based Supramolecular Self-Assembly for Cancer Theranostics.

Metal-ion-based self-assembly supramolecular theranostics exhibit excellent performance in biomedical applications owing to their potential superiorities for simultaneous precise diagnosis, targeted drug delivery, and monitoring the response to therapy in real-time. Specially, the rational designed systems could achieve specific in vivo self-assembly through complexation or ionic interaction to improve tissue-specific accumulation, penetration, and cell internalization, thereby reducing toxicities of drugs in diagnostics and therapy. Furthermore, such imaging traceable nanosystems could provide real-timely information of drug accumulation and therapeutic effects in a non-invasive and safe manner. Herein, the article highlights the recent prominent applications based on the metal ions self-assembly in cancer treatment. This strategy may open up new research directions to develop novel drug delivery systems for cancer theranostics.

A clinical trial of super-stable homogeneous lipiodol-nanoICG formulation-guided precise fluorescent laparoscopic hepatocellular carcinoma resection.

BACKGROUND: Applying traditional fluorescence navigation technologies in hepatocellular carcinoma is severely restricted by high false-positive rates, variable tumor differentiation, and unstable fluorescence performance. RESULTS: In this study, a green, economical and safe nanomedicine formulation technology was developed to construct carrier-free indocyanine green nanoparticles (nanoICG) with a small uniform size and better fluorescent properties without any molecular structure changes compared to the ICG molecule. Subsequently, nanoICG dispersed into lipiodol via a super-stable homogeneous intermixed formulation technology (SHIFT&nanoICG) for transhepatic arterial embolization combined with fluorescent laparoscopic hepatectomy to eliminate the existing shortcomings. A 52-year-old liver cancer patient was recruited for the clinical trial of SHIFT&nanoICG. We demonstrate that SHIFT&nanoICG could accurately identify and mark the lesion with excellent stability, embolism, optical imaging performance, and higher tumor-to-normal tissue ratio, especially in the detection of the microsatellite lesions (0.4 × 0.3 cm), which could not be detected by preoperative imaging, to realize a complete resection of hepatocellular carcinoma under fluorescence laparoscopy in a shorter period (within 2 h) and with less intraoperative blood loss (50 mL). CONCLUSIONS: This simple and effective strategy integrates the diagnosis and treatment of hepatocellular carcinoma, and thus, it has great potential in various clinical applications.

Superior Fluorescent Nanoemulsion Illuminates Hepatocellular Carcinoma for Surgical Navigation.

Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, poses a severe threat to public health. Intraoperative fluorescence imaging provides a golden opportunity for surgeons to visualize tumor-involved margins, thereby implementing precise HCC resection with minimal damage to normal tissues. Here, a novel-acting contrast agent, which facilely bridges indocyanine green (ICG) and lipiodol using self-emulsifying nanotechnology, was developed for optical surgical navigation. Compared to clinically available ICG probe, our prepared nanoemulsion showed obviously red-shifted optical absorption and enhanced fluorescence intensity. Further benefiting from the shielding effect of lipiodol, the fluorescence stability and anti-photobleaching ability of nanoemulsion were highly improved, indicating a great capacity for long-lasting in vivo intraoperative imaging. Under the fluorescence guidance of nanoemulsion, the tumor tissues were clearly delineated with a signal-to-noise ratio above 5-fold, and then underwent a complete surgical resection from orthotopic HCC-bearing mice. Such superior fluorescence performances, ultrahigh tumor-to-liver contrast, as well as great bio-safety, warrants the great translational potential of nanoemulsion in precise HCC imaging and intraoperative navigation.

Global Burden, Incidence and Disability-Adjusted Life-Years for Dermatitis: A Systematic Analysis Combined With Socioeconomic Development Status, 1990-2019.

Background: Dermatitis is an important global health problem that not only affects social interaction and physical and mental health but also causes economic burden. Health problems or distress caused by dermatitis may be easily overlooked, and relevant epidemiological data are limited. Therefore, a better understanding of the burden of dermatitis is necessary for developing global intervention strategies. Methods: All data on dermatitis, including atopic dermatitis (AD), contact dermatitis (CD) and seborrhoeic dermatitis (SD), were obtained from the Global Burden of Disease 2019 (GBD2019) database. The extracted age-standardized incidence rates (ASIR) and disability-adjusted life-years (DALYs) rates (ASDR) data were analysed by stratification, including by sex, country or region, and sociodemographic index (SDI) indicators. Finally, we analysed the correlation between the global burden of dermatitis and socioeconomic development status. Results: According to the GBD 2019 estimate, the ASIR and ASDR for the three major types of dermatitis in 2019 were 5244.3988 (95% CI 4551.7244-5979.3176) per 100,000 person-years and 131.6711 (95% CI 77.5876-206.8796) per 100,000 person-years. The ASIR and ASDR of atopic dermatitis, contact dermatitis and seborrhoeic dermatitis are: Incidence (95%CI,per 100,000 person-years), 327.91 (312.76-343.67), 3066.04 (2405.38-3755.38), 1850.44 (1706.25- 1993.74); DALYs (95%CI, per 100,000 person-years), 99.69 (53.09-167.43), 28.06 (17.62-41.78), 3.93 (2.24-6.25). In addition, among the three dermatitis types, the greatest burden was associated with AD. According to the ASDR from 1990 to 2019, the burden of dermatitis has exhibited a slow downward trend in recent years. In 2019, the ASIR showed that the USA had the greatest burden, while the ASDR showed that Asian countries (such as Japan, Mongolia, Kazakhstan, and Uzbekistan) and some European countries (France, Estonia) had the greatest burden. According to SDI stratification and the three major dermatitis types, high ASIR and ASDR corresponded to high SDI areas (especially for AD). Conclusion: The burden of dermatitis is related to socioeconomic development status, especially for AD, which is positively correlated with the SDI. The results based on GBD2019 data are valuable for formulating policy, preventing and treating dermatitis and reducing the global burden of dermatitis.

Application of Self-Assembly Nanoparticles Based on DVDMS for Fenton-Like Ion Delivery and Enhanced Sonodynamic Therapy.

Upon harnessing low-intensity ultrasound to activate sonosensitizers, sonodynamic therapy (SDT) induces cancer cell death through the reactive oxygen species (ROS) mediated pathway. Compared with photodynamic therapy (PDT), SDT possesses numerous advantages, including deeper tissue penetration, higher accuracy, fewer side effects, and better patient compliance. Sinoporphyrin sodium (DVDMS), a sonosensitizer approved by the FDA, has drawn abundant attention in clinical research, but there are some deficiencies. In order to further improve the efficiency of DVDMS, many studies have applied self-assembly nanotechnology to modify it. Furthermore, the combined applications of SDT/chemodynamic therapy (CDT) have become a research hotspot in tumor therapy. Therefore, we explored the self-assembly of nanoparticles based on DVDMS and copper to combine SDT and CDT. A cost-effective sonosensitizer was synthesized by dropping CuCl2 into the DVDMS solution with the assistance of PVP. The results revealed that the nanostructures could exert excellent treatment effects on tumor therapy and perform well for PET imaging, indicating the potential for cancer theranostics. In vitro and in vivo experiments showed that the nanoparticles have outstanding biocompatibility, higher ROS production efficiency, and antitumor efficacy. We believe this design can represent a simple approach to combining SDT and CDT with potential applications in clinical treatment and PET imaging.