No abstract

Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO 2 and sorafenib into HCC. We found that MnO 2 not only alleviates hypoxia by catalyzing the decomposition of H 2 O 2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn 2+ ions in the TME. Moreover, macrophages exposed to MnO 2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8 + cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.

Nitric oxide (NO), a pro-neurogenic and antineuroinflammatory gasotransmitter, features the potential to develop a translational medicine against neuropathological conditions. Despite the extensive efforts made on the controlled delivery of therapeutic NO, however, an orally active NO prodrug for a treatment of chronic neuropathy was not reported yet. Inspired by the natural dinitrosyl iron unit (DNIU) [Fe(NO) 2 ], in this study, a reversible and dynamic interaction between the biomimetic [(NO) 2 Fe(μ-SCH 2 CH 2 OH) 2 Fe(NO) 2 ] ( DNIC-1 ) and serum albumin (or gastrointestinal mucin) was explored to discover endogenous proteins as a vehicle for an oral delivery of NO to the brain after an oral administration of DNIC-1 . On the basis of the in vitro and in vivo study, a rapid binding of DNIC-1 toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of DNIC-1 . A reversible interconversion between mucin-bound DNIC and DNIC-1 facilitates the mucus-penetrating migration of DNIC-1 shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of DNIC-1 induces the transient opening of the cellular tight junction and enhances its paracellular permeability across the intestinal epithelial barrier. During circulation in the bloodstream, a stoichiometric binding of DNIC-1 to the serum albumin, as another endogenous protein vehicle, stabilizes the DNIU [Fe(NO) 2 ] for a subsequent transfer into the brain. With aging mice under a Western diet as a disease model for metabolic syndrome and cognitive impairment, an oral administration of DNIC-1 in a daily manner for 16 weeks activates the hippocampal neurogenesis and ameliorates the impaired cognitive ability. Taken together, these findings disclose the synergy between biomimetic DNIC-1 and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.

In ex-prisoners in Taiwan with a history of opiate injecting, enrollment and continued participation in methadone maintenance treatment is associated with substantially lower mortality.

Zintl-phase thermoelectric materials have garnered a lot of attention because of their intrinsic electron-crystal and phonon-glass structures. In this work, a series of ZrBeSi-type Zintlphase compounds (SrAgSb, EuAgSb, and EuCuSb) were prepared, and their band structures and thermoelectric properties were investigated. The peak ZTs of SrAgSb, EuAgSb, and EuCuSb reach ∼0.5, ∼0.35, and ∼0.3 at 773 K. The carrier concentration of Sr x AgSb was subsequently optimized by Sr self-doping. The increased Sr content suppresses the intrinsic hole concentration and leads to decreased total thermal conductivity. Together with the comparable power factor, a peak ZT of ∼0.6 was achieved at 773 K for Sr 1.01 AgSb and Sr 1.02 AgSb. The discovery of these ZrBeSi-type Zintl-phase thermoelectric materials provides a new family for exploring higher ZT.

In this paper, we demonstrate the strong influence of the regioregularity (RR) of poly-(3-hexylthiophene) (P3HT) on the optical anisotropy of hybrid P3HT/fullerene films before and after thermal annealing. We determined the conversion efficiency and characterized the optical anisotropy of P3HT/6,6-phenyl-C61-butyric acid methyl ester (PCBM) blends featuring various values of RR. Unlike grazing-incidence X-ray diffraction analysis, optical anisotropic measurement provides a clear and convenient view of the polymer orientation and the device anisotropic absorption at the same time. By calculating the in-plane and out-of-plane optical constants (extinction coefficients and refractive indices), we determined that the optical anisotropy of P3HT/PCBM films was improved in both orientations upon increasing the RR. Upon increasing the thermal annealing temperature, the main chains of high-RR P3HT were converted from an amorphous structure to an alignment parallel to the substrate, resulting in higher optical anisotropy. The degree of anisotropy of the high-RR P3HT/ PCBM blend was up to six times higher than that of the low-RR sample. This strong RR effect on optical anisotropy was also evident in the power conversion efficiency of large-area P3HT/PCBMbased organic solar cells.

Kenrad Nelson and colleagues report on the association between HIV incidence and exposure to a national harm-reduction program among people who inject drugs in Taiwan. Please see later in the article for the Editors' Summary

By means of time-resolved photoluminescence and photothermal techniques, after-effects from excited-state dynamics, energy migration, and conformational rearrangement of poly(9,9-di-n-octyl-2,7-fluorene) (PFO) and its homologues has been examined and interpreted with rotational potential maps from quantum mechanical calculations. Steady-state photoluminescence spectral changes and time-resolved photoluminescence measurements of oligofluorenes and PFO diluted in toluene suggest excited state ring torsion occurring within 30 ps of photoexitation. With all effects from internal conversion/intersystem crossing processes properly accounted for, we show that the conformational changes associated with this twisting motion can be quantitatively probed by means of photothermal methods. Results suggest mean torsion between neighboring fluorene units by ca. 40 degrees upon excitation, in agreement with the shift of rotational potential minimum from +/-40 degrees (and +/-140 degrees) in the ground state to +/-20 degrees (and +/-160 degrees) in the first excited singlet state according to results of quantum mechanical calculations.