Gd- and Fe-based contrast agents reduce T
and T
relaxation times, respectively, are frequently used in MRI, providing improved cancer detection. Recently, contrast agents changing both T
/T
times, ...based on core/shell nanoparticles, have been introduced. Although advantages of the T
/T
agents were shown, MR image contrast of cancerous versus normal adjacent tissue induced by these agents has not yet been analyzed in detail as authors considered changes in cancer MR signal or signal-to-noise ratio after contrast injection rather than changes in signal differences between cancer and normal adjacent tissue. Furthermore, the potential advantages of T
/T
contrast agents using image manipulation such as subtraction or addition have not been yet discussed in detail. Therefore, we performed theoretical calculations of MR signal in a tumor model using T
-weighted, T
-weighted, and combined images for T
-, T
-, and T
/T
-targeted contrast agents. The results from the tumor model are followed by in vivo experiments using core/shell NaDyF
/NaGdF
nanoparticles as T
/T
non-targeted contrast agent in the animal model of triple negative breast cancer. The results show that subtraction of T
-weighted from T
-weighted MR images provides additional increase in the tumor contrast: over two-fold in the tumor model and 12% in the in vivo experiment.
Background
Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). ...Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure–response relationships of osimertinib in a real-life setting.
Methods
A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C
min,pred
) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.
Results
A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 – 19.1) months and 9.3 (95% CI: 7.2 – 11.1) months for patients with C
min,pred
< 166 µg/L and C
min,pred
≥ 166 µg/L, respectively (
p
= 0.03). In the multivariate analysis, a C
min,pred
< 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 – 2.01;
p
= 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08;
p
= 0.02). No relationship between exposure and toxicity was observed (
p
= 0.91).
Conclusion
In our real-life cohort, no exposure–response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non–small cell lung cancer (NSCLC) and are ...associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab.
Methods
In this single‐arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment.
Results
Thirty‐seven patients started treatment, with a median age of 65 years (range, 40–80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression‐free survival was 5.5 months (95% CI, 3.7–8.3 months) and median overall survival was 16.8 months (95% CI, 10.7–25.8 months). The most common treatment‐related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients.
Conclusions
Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction.
Combination treatment with afatinib and cetuximab in patients with non–small cell lung cancer harboring an EGFR exon 20 insertion mutation demonstrated antitumor activity with a disease control rate of 54% at 18 weeks of treatment and a 32% confirmed overall response rate.
Heteroepitaxial core–shell nanostructures have been proven advantageous in a wide variety of applications, ranging from luminescence enhancement, band gap engineering, multimodal theranostics, to ...catalysis. However, precisely tailoring the epitaxial growth is challenging, and a general understanding of the parameters that impact epitaxial growth remains unclear. Here we demonstrate the critical role of the sign of the lattice mismatch of the shell relative to the core (compressed/tensile) in generating lanthanide-based core–shell structures, a parameter conventionally not considered in heteroepitaxial design. We took advantage of the very gradual contraction of lanthanide ions along the series to control precisely both the magnitude and the sign of lattice mismatch and investigated multiple sodium lanthanide fluoride (NaLnF4) core–shell heterostructures of variable composition and size. We discovered that the tensile strained shells adapt to the core crystallite shape (i.e., conformal) and lattice structure (i.e., coherent), while under identical magnitude of mismatch, the compressively strained shells are neither conformal nor coherent to the core. This striking asymmetry between the tensile and compressively strained epitaxial growth arises from the fundamental anharmonicity of the interatomic interactions between the attractive and repulsive pairs. From a broader perspective, our findings redefine the a priori design consideration and provide a fundamental insight on the necessity to include the sign of lattice mismatch and not just its magnitude in designing heteroepitaxial core–shell nanostructures.
Ligands on the nanoparticle surface provide steric stabilization, resulting in good dispersion stability. However, because of their highly dynamic nature, they can be replaced irreversibly in buffers ...and biological medium, leading to poor colloidal stability. To overcome this, we report a simple and effective cross-linking methodology to transfer oleate-stabilized upconverting NaYF4 core/shell nanoparticles (UCNPs) from hydrophobic to aqueous phase, with long-term dispersion stability in buffers and biological medium. Amphiphilic poly(maleic anhydride-alt-1-octadecene) (PMAO) modified with and without poly(ethylene glycol) (PEG) was used to intercalate with the surface oleates, enabling the transfer of the UCNPs to water. The PMAO units on the phase transferred UCNPs were then successfully cross-linked using bis(hexamethylene)triamine (BHMT). The primary advantage of cross-linking of PMAO by BHMT is that it improves the stability of the UCNPs in water, physiological saline buffers, and biological growth media and in a wide range of pH values when compared to un-cross-linked PMAO. The cross-linked PMAO–BHMT coated UCNPs were found to be stable in water for more than 2 months and in physiological saline buffers for weeks, substantiating the effectiveness of cross-linking in providing high dispersion stability. The PMAO–BHMT cross-linked UCNPs were extensively characterized using various techniques providing supporting evidence for the cross-linking process. These UCNPs were found to be stable in serum supplemented growth medium (37 °C) for more than 2 days. Utilizing this, we demonstrate the uptake of cross-linked UCNPs by LNCaP cells (human prostate cancer cell line), showing their utility as biolabels.
Hexagonal-phase NaYF4/NaGdF4 core/shell nanocrystals were synthesized and investigated by X-ray photoelectron spectroscopy (XPS) using tunable synchrotron radiation. Based on the ratio of the Y3+ 3d ...to Gd3+ 4d core level intensities at varying photoelectron kinetic energies, we conclude that Gd3+ resides predominantly at the surface of the nanocrystals, proving a core/shell structure. These nanocrystals show potential for use as contrast agents in magnetic resonance imaging (MRI) applications and optical imaging.
The future perspective of fluorescence imaging for real in vivo application are based on novel efficient nanoparticles which is able to emit in the second biological window (1000–1400 nm). In this ...work, the potential application of Nd3+‐doped LaF3 (Nd3+:LaF3) nanoparticles is reported for fluorescence bioimaging in both the first and second biological windows based on their three main emission channels of Nd3+ ions: 4F3/2→4I9/2, 4F3/2→4I11/2 and 4F3/2→4I13/2 that lead to emissions at around 910, 1050, and 1330 nm, respectively. By systematically comparing the relative emission intensities, penetration depths and subtissue optical dispersion of each transition we propose that optimum subtissue images based on Nd3+:LaF3 nanoparticles are obtained by using the 4F3/2→4I11/2 (1050 nm) emission band (lying in the second biological window) instead of the traditionally used 4F3/2→4I9/2 (910 nm, in the first biological window). After determining the optimum emission channel, it is used to obtain both in vitro and in vivo images by the controlled incorporation of Nd3+:LaF3 nanoparticles in cancer cells and mice. Nd3+:LaF3 nanoparticles thus emerge as very promising fluorescent nanoprobes for bioimaging in the second biological window.
The future achievement of depth tissue real in vivo imaging requires the development of novel efficient infrared fluorescence nanoparticles. In this work, the potential application of Nd3+‐doped LaF3 nanoparticles is reported for fluorescence bioimaging based on their three main emission channels of Nd3+ ions (first and second biological windows). High contrast and low toxicity are obtained, both in vivo and in vitro, using 1.06 μm.
We demonstrate a novel epitaxial layer-by-layer growth on upconverting NaYF4 nanocrystals (NCs) utilizing Ostwald ripening dynamics tunable both in thickness and composition. Injection of small ...sacrificial NCs (SNCs) as shell precursors into larger core NCs results in the rapid dissolution of the SNCs and their deposition onto the larger core NCs to yield core–shell structured NCs. Exploiting this NC size dependent dissolution/growth, the shell thickness can be controlled either by manipulating the number of SNCs injected or by successive injection of SNCs. In either of these approaches, the NCs self-focus from an initial bimodal distribution to a unimodal distribution (σ <5%) of core–shell NCs. The successive injection approach facilitates layer-by-layer epitaxial growth without the need for tedious multiple reactions for generating tunable shell thickness, and does not require any control over the injection rate of the SNCs, as is the case for shell growth by precursor injection.
Photoluminescent, near-stoichiometric colloidal CuInSe2 nanocrystals are synthesized in large batches and with good colloidal quality. An organometallic method is used with a moderate reaction ...temperature (≤200 °C) to produce CuInSe2 nanocrystals with size-tunable photoluminescence spectra ranging from ∼600 to ∼850 nm. Two-dimensional photoluminescence excitation–emission maps are reported for the CuInSe2 nanocrystals, highlighting the size-tunable excitonic features. Type I heterostructured CuInSe2/ZnS nanocrystals are prepared and purified. They are found to have absolute photoluminescence quantum yields up to ∼26%. The potential to use CuInSe2/ZnS core/shell nanocrystals as a potential low toxicity active layer in light-emitting diodes is demonstrated by fabricating electroluminescent devices.
