Encapsulation of a small-molecule drug based on substituted 2-aminothiophenes in calcium carbonate carriers for therapy of melanoma.

Although small molecule drugs are widely used in chemotherapy, their low bioavailability, low-concentrated dose in the tumor zone, systemic toxicity, and chemoresistance can significantly limit the therapeutic outcome. These drawbacks can be overcome by two main strategies: (i) development of novel therapeutic molecules with more significant antitumor activity than currently available drugs and (ii) loading chemotherapeutic agents into drug delivery systems. In this study, we aimed to encapsulate a highly prospective small molecule drug based on substituted 2-aminothiophene (2-AT) into calcium carbonate (CaCO3) microparticles (MPs) for the treatment of melanoma tumors. In particular, we have optimized the encapsulation of 2-AT into MPs (2-AT@MPs), studied drug release efficiency, investigated cellular uptake, and evaluated in vivo biodistribution and tumor inhibition efficiency. In vitro results revealed that 2-AT@MPs were able to penetrate into tumor spheroids, leading to prolonged release of 2-AT. By performing intratumoral injection of 2-AT@MPs we observed significant melanoma suppressions in murine models: ∼0.084 cm3 for 2-AT@MPs at a dose of 0.4 g kg-1versus ∼1.370 cm3 for untreated mice. In addition, the 2-AT@MPs showed negligible in vivo toxicity towards major organs such as heart, lung, liver, kidney, and spleen. Thus, this work provided an efficient strategy for the improved chemotherapy of solid tumors by using an encapsulated form of small molecule drugs.

Comparison of passive targeted delivery of inorganic and organic nanocarriers among different types of tumors.

In this study, we have considered four types of nanoparticles (NPs): polylactic acid (PLA), gold (Au), calcium carbonate (CaCO3), and silica (SiO2) with similar sizes (TEM: 50-110 nm and DLS: 110-140 nm) to examine their passive accumulation in three different tumors: colon (CT26), melanoma (B16-F10), and breast (4T1) cancers. Our results demonstrate that each tumor model showed a different accumulation of NPs, in the following order: CT26 > B16-F10 > 4T1. The Au and PLA NPs were evidently characterized by a higher delivery efficiency in case of CT26 tumors compared to CaCO3 and SiO2 NPs. The Au NPs demonstrated the highest accumulation in B16-F10 cells compared to other NPs. These results were verified using SPECT, ex vivo fluorescence bioimaging, direct radiometry and histological analysis. Thus, this work contributes to new knowledge in passive tumor targeting of NPs and can be used for the development of new strategies for delivery of bioactive compounds.

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies.

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

Controllable synthesis of barium carbonate nano- and microparticles for SPECT and CT imaging.

The design and synthesis of nano- and microcarriers for preclinical and clinical imaging are highly attractive due to their unique features, for example, multimodal properties. However, broad translation of these carriers into clinical practice is postponed due to the unknown biological reactivity of the new components used for their synthesis. Here, we have developed microcarriers (∼2-3 µm) and  nanocarriers (<200 nm) made of barium carbonate (BaCO3) for multiple imaging applications in vivo. In general, barium in the developed carriers can be used for X-ray computed tomography, and the introduction of a diagnostic isotope (99mTc) into the BaCO3 structure enables in vivo visualization using single-photon emission computed tomography. The bioimaging has shown that the radiolabeled BaCO3 nano- and microcarriers had different biodistribution profiles and tumor accumulation efficiencies after intratumoral and intravenous injections. In particular, in the case of intratumoral injection, all the types of used carriers mostly remained in the tumors (>97%). For intravenous injection, BaCO3 microcarriers were mainly localized in the lung tissues. However, BaCO3 NPs were mainly accumulated in the liver. These results were supported by ex vivo fluorescence imaging, direct radiometry, and histological analysis. The BaCO3-based micro- and nanocarriers showed negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys, and spleen. This study provides a simple strategy for the design and fabrication of the BaCO3-based carriers for the development of dual bioimaging.

Application of DUT-4 MOF structure switching for optical and electrical humidity sensing.

The threshold structural transformation of the DUT-4 metal-organic framework (MOF) from an ordered to distorted phase during exposure to ambient conditions has been revealed. The in situ X-ray diffraction analysis, in situ Raman and FTIR spectroscopy, scanning electron microscopy and synchronous thermal analysis have been used for investigation. The reversible effect of exposure time and humidity on such a phase transition has been confirmed. We also demonstrated that the observed phase transition correlated well with changes in the optical and electronic properties of DUT-4, paving the way to a new family of MOF-based phase change materials for optoelectronic applications.

FeAu mixing for high-temperature control of light scattering at the nanometer scale.

Control of the optical properties of a nanoparticle (NP) through its structural changes underlies optical data processing, dynamic coloring, and smart sensing at the nanometer scale. Here, we report on the concept of controlling the light scattering by a NP through mixing of weakly miscible chemical elements (Fe and Au), supporting a thermal-induced phase transformation. The transformation corresponds to the transition from a homogeneous metastable solid solution phase of the (Fe,Au) NP towards an equilibrium biphasic Janus-type NP. We demonstrate that the phase transformation is thermally activated by laser heating up to a threshold of 800 °C (for NPs with a size of hundreds of nm), leading to the associated changes in the light scattering and color of the NP. The results thereby pave the way for the implementation of optical sensors triggered by a high temperature at the nanometer scale via NPs based on metal alloys.

Size-dependent therapeutic efficiency of 223Ra-labeled calcium carbonate carriers for internal radionuclide therapy of breast cancer.

The size of drug carriers strongly affects their biodistribution, tissue penetration, and cellular uptake in vivo. As a result, when such carriers are loaded with therapeutic compounds, their size can influence the treatment outcomes. For internal α-radionuclide therapy, the carrier size is particularly important, because short-range α-emitters should be delivered to tumor volumes at a high dose rate without any side effects, i.e. off-target irradiation and toxicity. In this work, we aim to evaluate and compare the therapeutic efficiency of calcium carbonate (CaCO3) microparticles (MPs, >2 µm) and nanoparticles (NPs, <100 nm) labeled with radium-223 (223Ra) for internal α-radionuclide therapy against 4T1 breast cancer. To do this, we comprehensively study the internalization and penetration efficiency of these MPs and NPs, using 2D and 3D cell cultures. For further therapeutic tests, we develop and modify a chelator-free method for radiolabeling of CaCO3 MPs and NPs with 223Ra, improving their radiolabeling efficiency (>97%) and radiochemical stability (>97%). After intratumoral injection of 223Ra-labeled MPs and NPs, we demonstrate their different therapeutic efficiencies against a 4T1 tumor. In particular, 223Ra-labeled NPs show a tumor inhibition of approximately 85%, which is higher compared to 60% for 223Ra-labeled MPs. As a result, we can conclude that 223Ra-labeled NPs have a more suitable biodistribution within 4T1 tumors compared to 223Ra-labeled MPs. Thus, our study reveals that 223Ra-labeled CaCO3 NPs are highly promising for internal α-radionuclide therapy.

Green and Red Emissive N,O-Doped Chiral Carbon Dots Functionalized with l-Cysteine.

Although chirality plays an important role in the natural world, it has also attracted much scientific attention in nanotechnology, in particular, spintronics and bioapplications. Chiral carbon dots (CDs) are promising nanoparticles for sensing and bioimaging since they are biocompatible, ecofriendly, and free from toxic elements. Herein, green and red emissive chiral CDs are fabricated via surface modification treatment of achiral CDs at room temperature. After modification with l-cysteine molecules, the treated CDs demonstrate an intense chiral signal in the region of 200-300 nm with a dissymmetry factor up to 2.3 × 10-4 and high photoluminescence quantum yields of 19% and 15% for green and red emission bands, respectively. These CDs preserve their chiral signal in different ion systems, such as those with pH changes or in the presence of metal ions, along with remarkably low cytotoxicity, making them potential candidates for use as photoluminescent labels for biological objects.

Exfoliation of 2D Metal-Organic Frameworks: toward Advanced Scalable Materials for Optical Sensing.

Two-dimensional metal-organic frameworks (MOFs) occupy a special place among the large family of functional 2D materials. Even at a monolayer level, 2D MOFs exhibit unique sensing, separation, catalytic, electronic, and conductive properties due to the combination of porosity and organo-inorganic nature. However, lab-to-fab transfer for 2D MOF layers faces the challenge of their scalability, limited by weak interactions between the organic and inorganic building blocks. Here, comparing three top-down approaches to fabricate 2D MOF layers (sonication, freeze-thaw, and mechanical exfoliation), The technological criteria have established for creation of the layers of the thickness up to 1 nm with a record aspect ratio up to 2*10^4:1. The freezing-thaw and mechanical exfoliation are the most optimal approaches; wherein the rate and manufacturability of the mechanical exfoliation rivaling the greatest scalability of 2D MOF layers obtained by freezing-thaw (21300:1 vs 1330:1 aspect ratio), leaving the sonication approach behind (with a record 900:1 aspect ratio) have discovered. The high quality 2D MOF layers with a record aspect ratio demonstrate unique optical sensitivity to solvents of a varied polarity, which opens the way to fabricate scalable and freestanding 2D MOF-based atomically thin chemo-optical sensors by industry-oriented approach.

Laser-Assisted Design of MOF-Derivative Platforms from Nano- to Centimeter Scales for Photonic and Catalytic Applications.

Laser conversion of metal-organic frameworks (MOFs) has recently emerged as a fast and low-energy consumptive approach to create scalable MOF derivatives for catalysis, energy, and optics. However, due to the virtually unlimited MOF structures and tunable laser parameters, the results of their interaction are unpredictable and poorly controlled. Here, we experimentally base a general approach to create nano- to centimeter-scale MOF derivatives with the desired nonlinear optical and catalytic properties. Five three- and two-dimensional MOFs, differing in chemical composition, topology, and thermal resistance, have been selected as precursors. Tuning the laser parameters (i.e., pulse duration from fs to ns and repetition rate from kHz to MHz), we switch between ultrafast nonthermal destruction and thermal decomposition of MOFs. We have established that regardless of the chemical composition and MOF topology, the tuning of the laser parameters allows obtaining a series of structurally different derivatives, and the transition from femtosecond to nanosecond laser regimes ensures the scaling of the derivatives from nano- to centimeter scales. Herein, the thermal resistance of MOFs affects the structure and chemical composition of the resulting derivatives. Finally, we outline the "laser parameters versus MOF structure" space, in which one can create the desired and scalable platforms with nonlinear optical properties from photoluminescence to light control and enhanced catalytic activity.

Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma.

The design and synthesis of new promising compounds based on thienopyrimidine scaffold containing 2-aminothiophene fragments with good safety and favorable drug-like properties are highly relevant for chemotherapy. In this study, a series of 14 variants of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives (11aa-oa) and their precursors (31 compounds) containing 2-aminothiophenes fragments (9aa-mb, 10aa-oa) were synthesized and screened for their cytotoxicity against B16-F10 melanoma cells. The selectivity of the developed compounds was assessed by determining the cytotoxicity using normal mouse embryonic fibroblasts (MEF NF2 cells). The lead compounds 9cb, 10ic and 11jc with the most significant antitumor activity and minimum cytotoxicity on normal non-cancerous cells were chosen for further in vivo experiments. Additional in vitro experiments with compounds 9cb, 10ic and 11jc showed that apoptosis was the predominant mechanism of death in B16-F10 melanoma cells. With support from in vivo studies, compounds 9cb, 10ic and 11jc demonstrated the biosafety to healthy mice and significant inhibition of the metastatic nodules in pulmonary metastatic melanoma mouse model. Histological analysis detected no abnormal changes in the main organs (the liver, spleen, kidneys, and heart) after the therapy. Thus, the developed compounds 9cb, 10ic and 11jc demonstrate high efficiency in the treatment of pulmonary metastatic melanoma and can be recommended for further preclinical investigation of the melanoma treatment.

Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy.

Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional "all-in-one" carriers, but also contributes to the development of combined PTT in clinical practice.

Light-Induced Color Switching of Single Metal-Organic Framework Nanocrystals.

Photoinduced modulation of the optical parameters of nanomaterials underlies the operating principles of all-optical nanodevices. Here, we demonstrate the laser-induced 10% modulation of the refractive index and 16-fold modulation of the extinction coefficient of the dynamic metal-organic framework (HKUST-1) nanocrystals within the whole visible range. Using the laser-induced water sorption/desorption process inside HKUST-1, we have achieved size-dependent reversible tuning of brightness and color of its nanocrystals over the different spatial directions and color palette. The numerical analysis also confirmed the detected optical tuning through the evolution of optical spectra and directivity of the scattered light. The results of the work demonstrate the promising nature of the dynamic metal-organic frameworks for nonlinear optics and expand the library of chemically synthesized hybrid materials with light-controlled optical properties.

A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting (p)ppGpp synthetases.

Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of tuberculosis. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches - ΔrelMsm and ΔrelZ gene knockout mutations versus relMsm and relZ overexpression technique - we showed that both RelMsm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro, DMNP inhibited (p)ppGpp-synthesizing activity of purified RelMsm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by RelMsm, RelZ, and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs.

One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors.

A new, efficient, and versatile one-pot cascade reaction of diverse Gewald's aminothiophenes, 2-hydroxy-4-oxobut-2-enoic acid, and derivatives of cyanoacetic acid catalyzed by Et3N is presented. It enables direct synthesis of diverse 1-(2-oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine in good to excellent yields. The reaction exhibits a broad substrate scope and also presents an opportunity for further modification of the structure. The method offers a convenient practical alternative to the known procedures. The synthesized thieno[3,2-e]pyrrolo[1,2-a]pyrimidine scaffold is an important structural motif of new poly(ADP-ribose) polymerase (PARP) inhibitors, playing a useful role in multiple pharmacological applications.

Stereoselective Synthesis of Atropisomeric Bipyridine N,N'-Dioxides by Oxidative Coupling.

Bipyridine N,N'-dioxide is a structural fragment found in many bioactive compounds. Furthermore, chiral analogues secured their place as powerful Lewis base catalysts. The scope of the existing methods for the synthesis of atropisomeric bipyridine N,N'-dioxides is limited. Herein, we present a practical, highly chemo- and stereoselective method for oxidative dimerization of chiral pyridine N-oxides using O2 as a terminal oxidant. A series of 13 axially chiral bipyridine N,N'-dioxides were synthesized in up to 75% yield.

Dehydration of Amides to Nitriles under Conditions of a Catalytic Appel Reaction.

A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed that employs oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only a 1 mol % catalyst loading. The reaction scope includes aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids.

Oxidative Dehomologation of Aldehydes with Oxygen as a Terminal Oxidant.

A mild, efficient protocol for oxidative cleavage of C-C bonds in aldehydes has been developed that employs alkali metal hydrides as reagents and oxygen from air as a terminal oxidant. The method is applicable to a broad substrate range.

Asymmetric Total Synthesis of (-)-Erogorgiaene and Its C-11 Epimer and Investigation of Their Antimycobacterial Activity.

A short, nine-step, highly enantioselective synthesis of (-)-erogorgiaene and its C-11 epimer is reported. The key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy-Cope rearrangement and cationic cyclisation. (-)-Erogorgiaene exhibited promising antitubercular activity against multidrug-resistant strains of Mycobacterium tuberculosis.