A multi-scale pooling convolutional neural network for accurate steel surface defects classification.

Surface defect detection is an important technique to realize product quality inspection. In this study, we develop an innovative multi-scale pooling convolutional neural network to accomplish high-accuracy steel surface defect classification. The model was built based on SqueezeNet, and experiments were carried out on the NEU noise-free and noisy testing set. Class activation map visualization proves that the multi-scale pooling model can accurately capture the defect location at multiple scales, and the defect feature information at different scales can complement and reinforce each other to obtain more robust results. Through T-SNE visualization analysis, it is found that the classification results of this model have large inter-class distance and small intra-class distance, indicating that this model has high reliability and strong generalization ability. In addition, the model is small in size (3MB) and runs at up to 130FPS on an NVIDIA 1080Ti GPU, making it suitable for applications with high real-time requirements.

Erythrocyte membrane bioengineered nanoprobes via indocyanine green-directed assembly for single NIR laser-induced efficient photodynamic/photothermal theranostics.

Traditional combinational photodynamic therapy (PDT) and photothermal therapy (PTT) were limited in clinical therapy of cancer due to exceptionally low drug payload and activation by light with separate wavelengths. We have accidentally discovered that zinc phthalocyanine (ZNPC, a typical hydrophobic photosensitizer) and indocyanine green (ICG, a clinically approved fluorescence probe) could be co-assembled into carrier-free nanodrugs (almost 100 wt%) for single NIR laser-induced efficient PDT/PTT. Interestingly, ICG could act as "transformers" for modulating the geometric shape of ZNPC/ICG co-assembling structures from needle-like/spindle-like structure via cubic structure finally to spherical structure. Unfortunately, the nanodrugs suffered from rapid immune clearance. The ZNPC-ICG nanoprobes were further embedded into the erythrocyte membrane (RBC)-camouflaged framework. The designed ZNPC-ICG@RBC could be efficiently accumulated within the tumor sites (continue for ~60 h) and rapidly internalized into cancer cells upon laser irradiation rather than macrophage RAW264.7 cells. Compared with the free ZnPC or ICG, the biomimetic ZNPC-ICG@RBC nanoprobes exhibited amplified therapeutic effects by simultaneously producing ROS and hyperthermia, thereby synergistically improving antitumor efficiency and eliminating the tumors without any regrowth under the guidance of fluorescence imaging. The co-delivery of ZnPC and ICG via a biomimetic carrier-free system might be a promising strategy for bimodal phototherapy of cancer.

Self-Distinguishing and Stimulus-Responsive Carrier-Free Theranostic Nanoagents for Imaging-Guided Chemo-Photothermal Therapy in Small-Cell Lung Cancer.

Lack of tumor targeting and low drug payload severely impedes various nanoagents further employed in small-cell lung cancer (SCLC). Therefore, how to develop a new targeting ligand and enhance drug payload has been an urgent need for SCLC therapy. Herein, we first sift and verify that capreomycin (Cm) has a high affinity toward CD56 receptors overexpressed on SCLC cells. Motivated by the concept of self-targeted drug delivery, Cm is selected as the specific targeting ligand toward CD56 receptors and chemodrug doxorubicin (Dox) is adopted to be covalently linked via the redox-responsive disulfide linkage. The synthesized self-distinguishing prodrug (Dox-ss-Cm) and FDA-approved photosensitizer indocyanine green (ICG) as structural motifs can be self-assembled into theranostic nanoagents (ICG@Dox-ss-Cm NPs) within an aqueous solution. Such carrier-free nanoagents with high drug payload can exert targeted on-demand drug release under multiple stimuli of intracellular lysosomal acidity, glutathione (GSH), and an external near-infrared (NIR) laser. Besides, our nanoagents can be specifically self-targeted to SCLC sites in vivo and self-distinguishing via SCLC cells in vitro; thus, they decrease the undesirable effects on normal tissues and organs. Further in vitro and in vivo studies uniformly confirm that such nanoagents show highly synergistic effects for SCLC chemo-photothermal therapy (PTT) under the precise guidance of NIR fluorescence (NIRF)/photoacoustic (PA) imaging. Taken together, our work can provide a novel and promising strategy for the targeted treatment of SCLC.

Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy.

Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.

Tumor-Specific Endogenous FeII-Activated, MRI-Guided Self-Targeting Gadolinium-Coordinated Theranostic Nanoplatforms for Amplification of ROS and Enhanced Chemodynamic Chemotherapy.

Low drug payload and lack of tumor-targeting for chemodynamic therapy (CDT) result in an insufficient reactive oxygen species (ROS) generation, which seriously hinders its further clinical application. Therefore, how to improve the drug payload and tumor targeting for amplification of ROS and combine it with chemotherapy has been a huge challenge in CDT. Herein, methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) were used as theranostic building blocks to be coordinately assembled into tumor-specific endogenous FeII-activated and magnetic resonance imaging (MRI)-guided self-targeting carrier-free nanoplatforms (NPs) for amplification of ROS and enhanced chemodynamic chemotherapy. The obtained ASA-MTX-GdIII NPs exhibited extremely high drug payload (∼96 wt %), excellent physiological stability, long circulating ability (half-time: ∼12 h), and outstanding tumor accumulation. Moreover, ASA-MTX-GdIII NPs could be specifically uptaken by tumor cells via folate (FA) receptors and subsequently be disassembled via lysosomal acidity-induced coordination breakage, resulting in drug burst release. Most strikingly, the produced ASA could be catalyzed by tumor-specific overexpressed endogenous FeII ions to generate sufficient ROS for enhancing the main chemodynamic efficacy, which could exert a synergistic effect with the assistant chemotherapy of MTX. Interestingly, ASA-MTX-GdIII NPs caused a lower ROS generation and toxicity on normal cell lines that seldom expressed endogenous FeII ions. Under MRI guidance with assistance of self-targeting, significantly superior synergistic tumor therapy was performed on FA receptor-overexpressed tumor-bearing mice with a higher ROS generation and an almost complete elimination of tumor. This work highlights ASA-MTX-GdIII NPs as an efficient chemodynamic-chemotherapeutic agent for MRI imaging and tumor theranostics.

Redox-Responsive and Dual-Targeting Hyaluronic Acid-Methotrexate Prodrug Self-Assembling Nanoparticles for Enhancing Intracellular Drug Self-Delivery.

The clinical translation of methotrexate (MTX) is limited because of low aqueous solubility, poor bioavailability, low uptake efficiency, and toxicity concerns. Herein, dual-acting MTX (not only targeting folate receptors but also killing cells via inhibition of intracellular folate metabolism) and hyaluronic acid (HA, targeting CD44 receptors) were selected to be covalently linked by the redox-responsive disulfide bond. The synthesized prodrug (HA-SS-MTX) as a molecular structural motif could self-assemble into simple yet multifunctional nanoparticles (HA-SS-MTX NPs) in aqueous solution. The HA-SS-MTX NPs displayed an average diameter of ∼110 nm with a uniformly spherical shape and maintained stability in different physiological media. Moreover, the HA-SS-MTX NPs could exhibit a sharp redox-dependent response for rapid structure disassembly and sequential MTX release compared to the redox-irresponsive group (HA-ADH-MTX NPs). Furthermore, the results of confocal microscopy and flow cytometry verified that the nanosystems were selectively uptaken by cancer cells via folate and CD44 receptor-mediated internalization through the dual-active targeting mechanism. In addition, HA-SS-MTX NPs could accumulate within tumor sites for a longer period. Notably, in vitro and in vivo antitumor results demonstrated that HA-SS-MTX NPs significantly promoted the death of cancer cells and enhanced the inhibition of tumor growth while reducing the toxicity as compared to MTX and HA-ADH-MTX NPs. Therefore, the smart HA-SS-MTX NPs as the simple and efficient platform have great potential in tumor-targeting drug delivery and therapy.

Small Molecular Theranostic Assemblies Functionalized by Doxorubicin-Hyaluronic Acid-Methotrexate Prodrug for Multiple Tumor Targeting and Imaging-Guided Combined Chemo-Photothermal Therapy.

Because of high drug payload and minimized burden of foreign materials in the course of metabolism and excretion, carrier-free nanomedicine based on self-assembly of small-molecule therapeutic agents has attracted considerable attention in cancer therapy. However, obstacles still remained, such as lack of targeting efficiency, poor physiological stability, and serious drug burst release. Herein, we developed a self-dual-targeting prodrug conjugate by coupling methotrexate (MTX) and doxorubicin (DOX) to a hyaluronic acid (HA) backbone which enveloped the small molecular drug coassemblies of DOX and indocyanine green for specific targeting and imaging-guided chemo-photothermal therapy (PTT). The constructed nanosystems exhibited a diameter of ∼200 nm, superior physiological stability, and improved photothermal effect. Taking advantage of functionality of MTX-HA-DOX conjugate, the nanosystems remarkably enhanced the accumulation in the tumor regions by enhanced penetration and retention effect and CD44/folate receptor-mediated endocytosis. Upon the stimuli of acid, the nanosystems showed the rapid disassembly followed by the accelerated drug release. Consequently, the nanosystems demonstrated highly efficient apoptosis in cancer cells and remarkable tumor ablation by synergy between chemotherapy and PTT upon the irradiation of near-infrared laser. The multifunctional nanosystems based on small molecular theranostic assemblies could provide a promising potential in developing dual-targeting drug delivery and imaging-guided combinational therapy.

Light/pH-Triggered Biomimetic Red Blood Cell Membranes Camouflaged Small Molecular Drug Assemblies for Imaging-Guided Combinational Chemo-Photothermal Therapy.

Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core-shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.

Tumor Microenvironment-Activated and Viral-Mimicking Nanodrugs Driven by Molecular Precise Recognition for dNTP Inhibition-Induced Synergistic Cancer Therapy.

The medical application of nanotechnology is promising for cancer chemotherapy. However, most of the small-molecule drug assemblies still have such disadvantages as serious drug leakage and nonideal synergistic mechanisms, resulting in undesired therapeutic effect. Both nucleoside analogue-based clofarabine (CA) and methotrexate (MTX) were used as the first-line anticancer medication. However, a single-agent chemotherapy still faced many challenges including low bioavailability and toxic side effects to normal tissues due to nonspecific biodistribution of drugs. Herein, we designed and fabricated novel viral-mimicking and carry-free nanodrugs (CA-MTX NPs) via molecular recognition-driven precise self-assembly between CA and MTX. After introduction of mild acid-responsive PEG-lipid on the surface of CA-MTX NPs, the synthetic nanodrugs with a diameter of ∼150 nm exhibited tumor microenvironment-activated characteristics and self-targeting property. The results suggested that our nanodrugs could achieve superior tumor accumulation and synergistically promote the tumor suppression by collaboratively inhibiting dNTP pools. We foresaw that the well-designed smart nanodrugs delivery system would open a new avenue in synergistic cancer therapeutics.