Acid and Glutathione Dual-Responsive, Injectable and Self-Healing Hydrogels for Controlled Drug Delivery.

Considering the complexity of physiological microenvironments and the risks of surgical infection, there still remains critical demand to develop a hydrogel as a drug release platform with multifunctional properties, including good neutral stability and sensitive multiple stimuli-responsive behaviors, as well as injectable and self-healing properties. Herein, we present a facile preparation of injectable, self-healing hydrogels with acid and glutathione (GSH) dual-responsiveness for controlled drug delivery. Initially, the anticancer drug camptothecin (CPT) was premodified with disulfide bonds and attached to poly(ethylenimine) (PEI) via the Schiff base reaction, resulting in PEI-CPT. Subsequently, OSA-IR780 was synthesized through the Schiff base reaction involving IR780 with amine groups (IR780-NH2) and oxidized sodium alginate with aldehyde groups (OSA). The formation of PEI-CPT/OSA-IR780 hydrogels with various solid contents occurred rapidly within 40 s through a simple mixing process of the aqueous solution of PEI-CPT and OSA-IR780. These hydrogels exhibited remarkable stability under neutral conditions and controlled release of CPT upon exposure to simulated tumor environments characterized by acidic conditions and elevated GSH concentrations. Furthermore, they had significant injectable and self-healing properties due to the dynamically imine-cross-linked networks. In addition, the prepared hydrogels exhibited long-term biodegradability and biocompatibility. Collectively, these features indicate the great potential of PEI-CPT/OSA-IR780 hydrogels as therapeutic delivery vehicles.

Deformable and Disintegrable Multifunctional Integrated Polyprodrug Amphiphiles for Synergistic Phototherapy and Chemotherapy.

Multimodal collaborative therapy has been recognized as one of the more effective means to eliminate tumors in the current biomedicine research field as compared with monotherapy. Among them, by taking advantage of its high-precision and controllability, phototherapy has become a mainstay of treatment. However, physical encapsulation of free photosensitive units within nanocarriers was one of the main implementations, which might inevitably result in the photosensitizer leakage and side effect. For this purpose, a kind of multifunctional integrated polyprodrug amphiphiles, P(PFO-IG-CPT)-PEG, were prepared by reversible addition-fragmentation chain transfer polymerization from polymerizable pentadecafluorooctan monomers, indocyanine green monomers, reduction-responsive camptothecin monomers, and acid-responsive PEG based methacrylate monomers (GMA(-OH/-PEG)). The resultant copolymers could self-assemble into spherical nanoparticles in water, performing size-deformability in acidic conditions and subsequent disintegration in reduction environment as demonstrated by in vitro experiments. Furthermore, an enhanced CPT release ratio and rate from nanoparticles could be achieved by a NIR irradiation due to the hyperthermia induced by the covalently linked IG moieties. Not only that, because of the sufficient O2 content brought by PFO, the NIR light-triggered generation of 1O2 was also detected in cells. With the combination of CPT-guided chemotherapy as well as NIR light-guided photo-thermal and photodynamic therapies, fatal and irreversible damage to cancer cells was observed by cell experiments; the implanted tumor size in the mouse model was obviously shrunk upon receiving multimodal collaborative therapy. We speculate that such fabricated nanodiagnosis and treatment systems could meet the growing emergency for effective drug delivery, programmed and on-demand drug release, and multimodal integrated therapy.

Ethylene Activates the EIN2-EIN3/EIL1 Signaling Pathway in Tapetum and Disturbs Anther Development in Arabidopsis.

Ethylene was previously reported to repress stamen development in both cucumber and Arabidopsis. Here, we performed a detailed analysis of the effect of ethylene on anther development. After ethylene treatment, stamens but not pistils display obvious developmental defects which lead to sterility. Both tapetum and microspores (or microsporocytes) degenerated after ethylene treatment. In ein2-1 and ein3-1 eil1-1 mutants, ethylene treatment did not affect their fertility, indicating the effects of ethylene on anther development are mediated by EIN2 and EIN3/EIL1 in vivo. The transcription of EIN2 and EIN3 are activated by ethylene in the tapetum layer. However, ectopic expression of EIN3 in tapetum did not induce significant anther defects, implying that the expression of EIN3 are regulated post transcriptional level. Consistently, ethylene treatment induced the accumulation of EIN3 in the tapetal cells. Thus, ethylene not only activates the transcription of EIN2 and EIN3, but also stabilizes of EIN3 in the tapetum to disturb its development. The expression of several ethylene related genes was significantly increased, and the expression of the five key transcription factors required for tapetum development was decreased after ethylene treatment. Our results thus point out that ethylene inhibits anther development through the EIN2-EIN3/EIL1 signaling pathway. The activation of this signaling pathway in anther wall, especially in the tapetum, induces the degeneration of the tapetum and leads to pollen abortion.