Hypoxia, as characterized by the low local oxygen, confers on cancer cells resistance to oxygen-consuming photodynamic therapy (PDT). The limited success reached by current approaches harnessing reoxygenation to enhance PDT outcome promotes the reconsideration of the design of the therapeutic approach. In this study, a multistage delivery system capable of reversing hypoxia is demonstrated. Unlike previous strategies that only expect to affect the peripheral tumor tissue, the size-shrinkable system allows those deeply located hypoxia regions to be treated. Specifically, therapeutics, including atovaquone and indocyanine green derivatives that are respectively responsible for oxidative phosphorylation blockage and PDT, are encapsulated in a gelatin nanoparticle, whose structure would rupture to promote deep penetration when facing matrix metallopeptidase 2 enzyme overexpression in tumor tissue. The antihypoxic performance of the platform has been evaluated using a variety of analyses including flow-cytometry assay, immunofluorescence, and micro-positron-emission tomography imaging. Tumor regression in animal models confirms the feasibility and effectiveness of conquering the PDT-resistance through abrogating the oxygen consumption. It is hopeful that such a strategy could shed light on the development of next-generation PDT-adjuvant treatment.

Cholera toxin (CT) produced by

Radiotherapy (RT) is a widely explored clinical modality to combat cancer. However, its therapeutic efficacy is not always satisfied because of the severe hypoxic microenvironment in solid tumors and the high dosage of radiation harmful to the adjacent healthy tissue. Herein, Au nanoparticle−hemoglobin complex nanoparticle loaded platelets (Au-Hb@PLT) were fabricated. These Au-Hb@PLT would be activated by tumor cells, and the formed platelet-derivate particles (PM) could deliver Au nanoparticle−hemoglobin complex deeply into tumor tissue because of their small size and tumor homing ability. Hemoglobin acts as an oxygen carrier to relieve the hypoxia and gold nanoparticles work as radiosensitizers to potentiate the sensitivity of tumor cells to Xray, thus, enhancing the in vivo therapeutic outcome even under a low-dose RT in tumor bearing mice. The enhanced antitumor effect and survival benefits endowed by the Au-Hb@PLT were confirmed in vitro and in vivo. These results demonstrate that these Au-Hb@PLT can work as an oxygen vehicle, offer a promising approach to mitigate hypoxia and improve RT efficacy with a low RT dosage.

No abstract

Protein ADP-ribosylation is a reversible posttranslational modification of uncertain significance in cancer. In this study, we evaluated the consequences for cancer susceptibility in the mouse of a genetic deletion of the enzyme responsible for removing mono-ADP–ribose moieties from arginines in cellular proteins. Specifically, we analyzed cancer susceptibility in animals lacking the ADP-ribosylarginine hydrolase (ARH1) that cleaves the ADP ribose–protein bond. ARH1−/− cells or ARH1−/− cells overexpressing an inactive mutant ARH1 protein (ARH1−/− +dm) had higher proliferation rates than either wild-type ARH1+/+ cells or ARH1−/− cells engineered to express the wild-type ARH1 enzyme. More significantly, ARH1−/− and ARH1+/− mice spontaneously developed lymphomas, adenocarcinomas, and metastases more frequently than wild-type ARH1+/+ mice. In ARH1+/− mice, we documented in all arising tumors mutation of the remaining wild-type allele (or loss of heterozygosity), illustrating the strict correlation that existed between tumor formation and absence of ARH1 gene function. Our findings show that proper control of protein ADP-ribosylation levels affected by ARH1 is essential for cancer suppression.

Treatment of liver metastasis experiences slow progress owing to the severe side effects. In this study, we demonstrate a strategy capable of eliminating metastatic cancer cells in a selective manner. Nucleus-targeting W 18 O 49 nanoparticles (WONPs) are conjugated to mitochondria-selective mesoporous silica nanoparticles (MSNs) containing photosensitizer (Ce6) through a Cathepsin B-cleavable peptide. In hepatocytes, upon the laser irradiation, the generated singlet oxygen species are consumed by WONPs, in turn leading to the loss of their photothermally heating capacity, thereby sparing hepatocyte from thermal damage induced by the laser illumination. By contrast, in cancer cells, the cleaved peptide linker allows WONPs and MSNs to respectively target nucleus and mitochondria, where the therapeutic powers could be unleashed, both photodynamically and photothermally. This ensures the energy production of cancer cells can be abolished. We further assess the underlying molecular mechanism at both gene and protein levels to better understand the therapeutic outcome.

No abstract

strength, [7] while weakening the interphase can produce additional toughness via fiber debonding and plastic deformation of the interfacial layer. [8] Therefore, engineering the interphase so as to solve the conflict between strength and toughness affords a good opportunity.Nacre, a unique microscale architecture of "brick-and -mortar" that can reform after breaking, endows it with pre-eminent mechanical strength and toughness. [9] Thus, considerable attentions have been contributed to mimic this delicate structure, aiming at gaining exceptional mechanical properties. Different inorganic materials, including graphene, [10] layered double hydroxide (LDH), [11] nanoclay, [12] man-made CaCO 3 , [13] Al 2 O 3 , [14] carbon nanotube (CNT), [15] and TiO 2 , [16] have been employed as "bricks" in fabrication of analogous nacre film materials. Observation of these nacre-like films indicates that the introduction of adequate reinforcing components and appropriate interfacial interactions over several distinct scales are keys affecting the mechanical properties. Inspired by these, whether construction of an composite interphase with nacre-like layered structure can simultaneously enhance the composites' interfacial strength and toughness?Layer-by-layer (LbL) assembly provides a good approach to fabricate such nacre-like layered structure at interphase region, since it has been proved to be a facile way for the fabrication of hierarchical nanostructured layers on various substrates via electrostatic interaction between differently charged materials. [1,6,17] To manifest the critical characteristics of natural nacre, a LDH/poly(sodium-4-styrenesulfonate) nanostructured coating over the surface of glass fiber by LbL was reported by Luca et al., [8] which increased the interfacial shear strength (IFSS) and debonding toughness by 30% and 162%. In addition, the LbL method has been employed to deposit graphene oxide (GO)/aramid nanofiber multilayers, [18] GO/SiO 2 multilayers, [19] and CNT coatings [20] on glass fiber or carbon fiber surface to improve interfacial adhesion of composites.Polydopamine (PDA) and other catechol compounds, due to their outstanding adhesive property and the role of providing platform for secondary reactions, are highly sought after being used to modify the inert surface of carbon fibers. [21][22][23][24][25] Moreover, PDA has dense aromatic structures in its molecular Interphase with nacre-like structured multilayer is constructed by alternatively depositing two polymers, respectively "rigid" polydopamine (PDA) and "flexible" polyether amine, on carbon fiber surface via the layer-by-layer (LbL) approach. The optimal interfacial strength and toughness are achieved for composites with three layers of PDA/polyether amine, respectively, 39.2% and 99.8% superior to the untreated fiber composites. The outstanding mechanical properties are mainly ascribed to the synergistic interactions of covalent bond, hydrogen bonding, and π-π stacking among fiber, multilayer, and matrix by transferring stress and bridgin...