Electrochemical molecular intercalation of layered semiconducting crystals with organic cations followed by ultrasonic exfoliation has proven to be an effective approach to producing a rich family of organic/inorganic hybrid superlattices and high-quality, solution-processable 2D semiconductors. A traditional method for exfoliating 2D crystals relies on the intercalation of inorganic alkali metal cations. The organic cations (e.g., alkyl chain-substituted quaternary ammonium cations) are much larger than their inorganic counterparts, and the bulky molecular structure endows distinct intercalation and exfoliation chemistry, as well as molecular tunability. By using this protocol, many layered 2D crystals (including graphene, black phosphorus and versatile metal chalcogenides) can be electrochemically intercalated with organic quaternary alkylammonium cations. Subsequent solution-phase exfoliation of the intercalated compounds is realized by regular bath sonication for a short period (5-30 min) to produce free-standing, thin 2D nanosheets. It is also possible to graft additional ligands on the nanosheet surface. The thickness of the exfoliated nanosheets can be measured by using atomic force microscopy and Raman spectroscopy. Modifying the chemical structure and geometrical configuration of alkylammonium cations results in different exfoliation behavior and a family of versatile organic/inorganic hybrid superlattices with tunable physical/chemical properties. The whole protocol takes ~6 h for the successful production of stable, ultrathin 2D nanosheet dispersion in solution and another 11 h for depositing thin films and transferring them onto an arbitrary surface. This protocol does not require expertise beyond basic electrochemistry knowledge and conventional colloidal nanocrystal synthesis and processing.

• MeSH
• elektrochemie MeSH
• fosfor MeSH
• grafit * MeSH
• mikroskopie atomárních sil MeSH
• nanočástice * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fosfor MeSH
• grafit * MeSH

BACKGROUND: Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. METHODS: In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566. FINDINGS: In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9-9·8]) and placebo (5·1 months [3·6-7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52-1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7-9·8] vs placebo 5·1 months [2·6-10·4]; HR 0·73 [95% CI 0·42-1·28]; p=0·268) or absence (5·8 months [3·6-11·1] vs 3·6 months [2·8-7·3]; HR 0·72 [0·42-1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8-8·3] vs 10·0 months [3·6-13·0]; HR 1·07 [95% CI 0·53-2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group. INTERPRETATION: Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing. FUNDING: F Hoffmann-La Roche.

• MeSH
• antagonisté estrogenového receptoru terapeutické užití   MeSH
• chemorezistence účinky léků   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• estradiol analogy a deriváty   terapeutické užití   MeSH
• fulvestrant MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   patologie   MeSH
• míra přežití MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• následné studie MeSH
• prognóza MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny antagonisté a inhibitory   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• záchranná terapie * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté estrogenového receptoru MeSH
• estradiol MeSH
• fulvestrant MeSH
• nádorové biomarkery MeSH
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH