Negative Deterministic Information-Based Multiple Instance Learning for Weakly Supervised Object Detection and Segmentation.

Weakly supervised object detection (WSOD) and semantic segmentation with image-level annotations have attracted extensive attention due to their high label efficiency. Multiple instance learning (MIL) offers a feasible solution for the two tasks by treating each image as a bag with a series of instances (object regions or pixels) and identifying foreground instances that contribute to bag classification. However, conventional MIL paradigms often suffer from issues, e.g., discriminative instance domination and missing instances. In this article, we observe that negative instances usually contain valuable deterministic information, which is the key to solving the two issues. Motivated by this, we propose a novel MIL paradigm based on negative deterministic information (NDI), termed NDI-MIL, which is based on two core designs with a progressive relation: NDI collection and negative contrastive learning (NCL). In NDI collection, we identify and distill NDI from negative instances online by a dynamic feature bank. The collected NDI is then utilized in a NCL mechanism to locate and punish those discriminative regions, by which the discriminative instance domination and missing instances issues are effectively addressed, leading to improved object-and pixel-level localization accuracy and completeness. In addition, we design an NDI-guided instance selection (NGIS) strategy to further enhance the systematic performance. Experimental results on several public benchmarks, including PASCAL VOC 2007, PASCAL VOC 2012, and MS COCO, show that our method achieves satisfactory performance. The code is available at: https://github.com/GC-WSL/NDI.

H2O2-responsive polymer prodrug nanoparticles with glutathione scavenger for enhanced chemo-photodynamic synergistic cancer therapy.

The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2 to release CB and Ce6. Ce6 can effectively generate abundant 1O2 under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2 and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.

Floxuridine-chlorambucil conjugate nanodrugs for ovarian cancer combination chemotherapy.

Due to no specific symptoms and lack of early diagnosis for ovarian cancer, most diagnosed patients are often in the terminal stage resulting that tumor tissue is unable to be resected completely by operation. So postoperative chemotherapy has become an important and indispensable treatment procedure for them. Up to date, it remains a challenge to treat ovarian cancer by an effective chemotherapy strategy. Recently, the strategy of ADDC has been regarded as a highly effective chemotherapy strategy to treat various cancers without any drug carriers. Here a novel ADDC is synthesized by linking a water-soluble antitumor drug floxuridine (Fud) and a water-insoluble antitumor drug chlorambucil (Cb) through the esterification. Then the Fud-Cb conjugate can form stable nanodrugs in water with an average size around 103.0 nm through molecular self-assembly. After internalization of cells, the ester bonds in nanodrugs can be degraded to release free Fud and Cb at a fixed ratio under the intracellular acid conditions, which exhibits the high synergistic effect on ovarian cancer cells. The cytotoxicity test results show that Fud-Cb nanodrugs can efficiently inhibit the growth of ovarian cancer cells. The apoptosis data exhibit that the cell necrotic and apoptotic rate treated with Fud-Cb nanodrugs is about 73.7 % and 18.76 % within 24 h. These results suggest that Fud-Cb nanodrugs based on ADDC strategy can effectively enhance synergistic anticancer efficacy to ovarian cancer.

Amphiphilic irinotecan-melampomagnolide B conjugate nanoparticles for cancer chemotherapy.

Melampomagnolide B (MMB) is a natural sesquiterpene lactone product structurally related to parthenolide (PTL). Although MMB has been widely used to treat various types of cancers, such as glioma, leukemia and colon cancer, the effective delivery of MMB to cancer cells remains a challenge. An amphiphilic drug-drug conjugate (ADDC) strategy has been proposed and developed as a promising drug self-delivery system for cancer therapy because of its simple preparation, carrier-free nature, and high therapeutic activity. Herein, we present a new ADDC, which is synthesized by linking the hydrophilic anticancer drug irinotecan (Ir) and the hydrophobic anticancer drug MMB through a carbonate bond. The obtained amphiphilic irinotecan-melampomagnolide B conjugate (Ir-C-MMB) can self-assemble in water into stable nanoparticles with an average diameter of around 122.1 nm. After cellular uptake, the carbonate bond between the hydrophilic drug and hydrophobic drug can be cleaved to release free Ir and MMB under acidic conditions, which exhibit a synergistic effect in tumor cells. MTT results reveal that the Ir-C-MMB nanoparticles can effectively inhibit proliferation of cancer cells. The apoptosis data indicate that the apoptosis rate of cells treated with Ir-C-MMB nanoparticles is about 50% within 24 h, which is much higher than that of free Ir or MMB. Our results suggest that this ADDC strategy could be used as a drug delivery platform for MMB and its derivatives, and that it offers effective synergistic therapeutic efficacy.

Facile Synthesis of a H2O2-Responsive Alternating Copolymer Bearing Thioether Side Groups for Drug Delivery and Controlled Release.

A novel amphiphilic alternating copolymer with thioether side groups (P(MSPA-a-EG)) was synthesized through an amine-epoxy click reaction of 3-(methylthio)propylamine (MSPA) and ethylene glycol diglycidyl ether. P(MSPA-a-EG) was characterized in detail by nuclear magnetic resonance (NMR), gel permeation chromatography, Fourier transformed infrared, differential scanning calorimeter, and thermogravimetric analysis to confirm the successful synthesis. Due to its amphiphilic structure, P(MSPA-a-EG) could self-assemble into spherical micelles with an average diameter of about 151 nm. As triggered by H2O2, theses micelles could disassemble because hydrophobic thioether groups are transformed to hydrophilic sulfoxide groups in MSPA units. The oxidant disassemble process of micelles was systemically studied by dynamic light scattering, transmission electron microscopy, and 1H NMR measurements. The MTT assay against NIH/3T3 cells indicated that P(MSPA-a-EG) micelles exhibited good biocompatibility. Furthermore, they could be used as smart drug carriers to encapsulate hydrophobic anticancer drug doxorubicin (DOX) with 4.90% drug loading content and 9.81% drug loading efficiency. In vitro evaluation results indicated that the loaded DOX could be released rapidly, triggered by H2O2. Therefore, such a novel alternating copolymer was expected to be promising candidates for controlled drug delivery and release.

Stimuli-responsive nanodrug self-assembled from amphiphilic drug-inhibitor conjugate for overcoming multidrug resistance in cancer treatment.

Severe multidrug resistance (MDR) often develops in the process of chemotherapy for most small molecule anticancer drugs, which results in clinical chemotherapy failures. Methods: Here, a nanodrug is constructed through the self-assembly of amphiphilic drug-inhibitor conjugates (ADIC) containing a redox-responsive linkage for reversing the multidrug resistance (MDR) in cancer treatment. Specifically, hydrophilic anticancer irinotecan (Ir) and hydrophobic P-gp protein inhibitor quinine (Qu) are linked by a redox responsive bridge for overcoming MDR of tumors. Results: Ir-ss-Qu is able to self-assemble into nanoparticles (NPs) in water and shows the longer blood retention half-life compared with that of free Ir or Qu, which facilitates drug accumulation in tumor site. After endocytosis of Ir-ss-Qu NPs by drug-resistant tumor cells, the disulfide bond in the linkage between Ir and Qu is cleaved rapidly induced by glutathione (GSH) to release anticancer drug Ir and inhibitor Qu synchronously. The released Qu can markedly reduce the expression of P-gp in drug-resistant tumor cells and inhibits P-gp to pump Ir out of the cells. The increased concentration of intracellular Ir can effectively improve the therapeutic efficacy. Conclusions: Such redox-responsive Ir-ss-Qu NPs, as a drug delivery system, exhibit very high cytotoxicity and the most effective inhibitory to the growth of drug-resistant breast cancer compared with that of free therapeutic agents in vitro and in vivo.

Preparation, Properties, and Applications of Graphene-Based Hydrogels.

As a new carbon-based nanomaterial, graphene has exhibited unique advantages in significantly improving the combination properties of traditional polymer hydrogels. The specific properties of graphene, such as high electrical conductivity, high thermal conductivity and excellent mechanical properties, have made graphene not only a gelator to self-assemble into the graphene-based hydrogels (GBH) with extraordinary electromechanical performance, but also a filler to blend with small molecules and macromolecules for the preparation of multifunctional GBH. It fully exploits the practical applications of traditional hydrogels. This review summarizes the preparation methods, properties, and the applications of GBH. Further developments and challenges of GBH are also prospected.