The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound 1 retained high antiproliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile. Cancer Res; 77(24); 6963-74. Ó2017 AACR.

Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally into invasive adenocarcinoma. The cellular heterogeneity and molecular events underlying this stepwise progression remain unclear. In this study, we perform single-cell RNA sequencing of 268,471 cells collected from 25 patients in four histologic stages of LUAD and compare them to normal cell types. We detect a group of cells closely resembling alveolar type 2 cells (AT2) that emerged during atypical adenomatous hyperplasia and whose transcriptional profile began to diverge from that of AT2 cells as LUAD progressed, taking on feature characteristic of stem-like cells. We identify genes related to energy metabolism and ribosome synthesis that are upregulated in early stages of LUAD and may promote progression. MDK and TIMP1 could be potential biomarkers for understanding LUAD pathogenesis. Our work shed light on the underlying transcriptional signatures of distinct histologic stages of LUAD progression and our findings may facilitate early diagnosis.

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The ability to impart Pt-based catalysts with high catalytic activity and low cost is essential for advancing fuel cell technologies. This report describes the synthesis of composition-tunable PtCu alloy nanowires (NWs) of ultrathin diameters (ca. 1 nm) to create synergistic catalytic sites along the nanowire surfaces. The bimetallic NWs exhibit composition-tunable fcc-type alloy phase. The electrocatalytic properties of the PtCu alloy NWs for methanol oxidation reaction were shown to display an intriguing composition-dependent catalytic synergy. The maximum mass activity for Pt32Cu68 NWs was about 2 times higher than that of Pt NWs. It also exhibited the highest stability and tolerance to CO poisoning. The enhanced activity and stability were attributed to a bifunctional synergy whereby the alloyed Cu atoms in the Pt lattice provides CO-maneuvering sites for reducing the poisoning effect of CO intermediate species on the active surface sites of the NWs.

The design and synthesis of effective and recyclable oxidative desulfurization catalysts is of great importance in view of environmental protection and human health. Herein, a family of polyoxomolybdate-based inorganic–organic hybrid materials, namely, [Mn­(TMR4A)­(H2O)4]­[Mo6O19]·0.5CH3CH2OH·H2O (1), [Ni­(TMR4A)­(H2O)4]­[Mo6O19]·0.5CH3CH2OH·H2O (2), [Zn­(TMR4A)­(H2O)4]­[Mo6O19]·0.5CH3CH2OH·H2O (3), and [Co2(TMR4A)2(H2O)4(β-Mo8O26)]·CH3CN·12H2O (4), were assembled by the functionalized resorcin[4]­arene ligand (TMR4A) with polyoxomolybdate and metal ions under solvothermal conditions. In isostructural 1–3, the [M­(TMR4A)­(H2O)4]2+ species (M = MnII, NiII, ZnII) and [Mo6O19]2– anions are held together via C–H···O hydrogen bonds to give a 3D supramolecular architecture. In 4, two [Co­(TMR4A)­(H2O)2]2+ cations were linked by one [β-Mo8O26]4– anion to produce an attractive molecular dimer. Remarkably, 1–4, as recyclable heterogeneous catalysts, exhibit efficient catalytic oxidation desulfurization activities toward thioethers. Particularly, 1, as a representative example, features selective catalytic oxidation for sulfur mustard simulant. Moreover, their electrochemical properties were also studied.

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Here we report a novel mechanism for triggering drug release in the polydopamine (PDA)-coated magnetic CuCo2S4 core–shell nanostructure by glutathione (GSH) triggered degradation of PDA for release.

Two remarkable polyoxometalate-bridged Cu(I)-and Ag(I)thiacalix[4]arene dimers, namely, [Cu 4 (SiW 12 O 40 )(L) 2 (DMF) 2 ]•2EtOH•DMF (1-Cu) and [Ag 4 (PMo 12 O 40 )(L) 2 ]•OH (1-Ag), were prepared by using a new thiacalix[4]arene, metal cation and polyoxometalate (L = tetra[2-(ethylthio)-1methyl-1H-imidazole]-thiacalix[4]arene). In 1-Cu and 1-Ag, two thiacalix[4]arenes were linked together by one [SiW 12 O 40 ] 4− or [PMo 12O 40 ] 3− anion via two metal cations to give a molecular dimer. Further, adjacent dimers were extended into a high-dimensional supramolecular architecture through hydrogen bonds. Markedly, these molecular dimers are exceedingly stable in organic solvents and then were employed as efficient catalysts for catalytic oxidation desulfurization as well as the azide−alkyne "click" reaction.