Magnetic Nanoparticles with On-Site Azide and Alkyne Functionalized Polymer Coating in a Single Step through a Solvothermal Process.

Background/Objectives: Magnetic Fe3O4 nanoparticles (MNPs) are becoming more important every day. We prepared MNPs in a simple one-step reaction by following the solvothermal method, assisted by azide and alkyne functionalized polyethylene glycol (PEG400) polymers, as well as by PEG6000 and the polyol ß-cyclodextrin (ßCD), which played a crucial role as electrostatic stabilizers, providing polymeric/polyol coatings around the magnetic cores. Methods: The composition, morphology, and magnetic properties of the nanospheres were analyzed using Transmission Electron and Atomic Force Microscopies (TEM, AFM), Nuclear Magnetic Resonance (NMR), X-ray Diffraction Diffractometry (XRD), Fourier-Transform Infrared Spectroscopy (FT-IR), Matrix-Assisted Laser Desorption/Ionization (MALDI) and Vibrating Sample Magnetometry (VSM). Results: The obtained nanoparticles (@Fe3O4-PEGs and @Fe3O4-ßCD) showed diameters between 90 and 250 nm, depending on the polymer used and the Fe3O4·6H2O precursor concentration, typically, 0.13 M at 200 °C and 24 h of reaction. MNPs exhibited superparamagnetism with high saturation mass magnetization at room temperature, reaching values of 59.9 emu/g (@Fe3O4-PEG6000), and no ferromagnetism. Likewise, they showed temperature elevation after applying an alternating magnetic field (AMF), obtaining Specific Absorption Rate (SAR) values of up to 51.87 ± 2.23 W/g for @Fe3O4-PEG6000. Additionally, the formed systems are susceptible to click chemistry, as was demonstrated in the case of the cannabidiol-propargyl derivative (CBD-Pro), which was synthesized and covalently attached to the azide functionalized surface of @Fe3O4-PEG400-N3. Prepared MNPs are highly dispersible in water, PBS, and citrate buffer, remaining in suspension for over 2 weeks, and non-toxic in the T84 human colon cancer cell line, Conclusions: indicating that they are ideal candidates for biomedical applications.

Improved antitumor activity through a tyramidyl maslinic acid derivative. Design and validation as drug-loaded electrospun polymeric nanofibers.

Among the most harmful tumors detected in the human body, such as breast, colon, brain or pancreas, breast (BC) and colorectal cancer (CRC) are the first and third most frequent cancer worldwide, respectively. The current existing chemotherapeutic treatments present serious side effects due to their intravenous administration can induce cytotoxicity in healthy cells. Thus, new treatment methods based on drug-loaded polymeric nanofibers (NFs) have gained significant potential for their use in localized cancer chemotherapy. Here, a deep in vitro comparative analysis between maslinic acid (MA) and a tyramine-maslinic acid (TMA) derivative is initially performed. This analysis includes a proliferation, and a cell cycle assay, and a genotoxicity, antiangiogenic and apoptosis study. Then, the TMA derivative has been incorporated into electrospun polymeric NFs obtaining an implantable dressing material with antitumor activity. Two types of patches containing TMA-loaded polymeric NFs of poly(caprolactone) (PCL), and a mixture of polylactic acid/poly(4-vinylpyridine) (PLA/PVP) were fabricated by the electrospinning technique. The characterization of the drug-loaded NFs showed an encapsulation capacity of 0.027 mg TMA/mg PCL and 0.024 mg TMA/mg PLA/PVP. Then, the cytotoxic activity of both polymeric systems was tested in CRC (T84), BC (MCF-7) and a no tumor (L929) cell lines exposed to TMA-loaded NFs and blank NFs for 48 h. Moreover, cell cycle assay, genotoxicity, angiogenesis and apoptosis tests were carried out to study the mechanism of action of TMA. Blank NFs showed no-toxicity in all cell lines tested and both drug-loaded NFs significantly reduced cell proliferation (relative proliferation of ≈44 % and ≈25 % respectively). Therefore, TMA was less genotoxic than maslinic acid (MA), and reduced VEGFA expression in MCF-7 cells (1.32 and 2.12-fold for MA and TMA respectively). These results showed that TMA-loaded NFs could constitute a promising biocompatible and biodegradable nanoplatform for the local treatment of solid tumors such as CRC or BC.

Isolation of Mycosporine-like Amino Acids from Red Macroalgae and a Marine Lichen by High-Performance Countercurrent Chromatography: A Strategy to Obtain Biological UV-Filters.

Marine organisms have gained considerable biotechnological interest in recent years due to their wide variety of bioactive compounds with potential applications. Mycosporine-like amino acids (MAAs) are UV-absorbing secondary metabolites with antioxidant and photoprotective capacity, mainly found in organisms living under stress conditions (e.g., cyanobacteria, red algae, or lichens). In this work, five MAAs were isolated from two red macroalgae (Pyropia columbina and Gelidium corneum) and one marine lichen (Lichina pygmaea) by high-performance countercurrent chromatography (HPCCC). The selected biphasic solvent system consisted of ethanol, acetonitrile, saturated ammonium sulphate solution, and water (1:1:0.5:1; v:v:v:v). The HPCCC process for P. columbina and G. corneum consisted of eight separation cycles (1 g and 200 mg of extract per cycle, respectively), whereas three cycles were performed for of L. pygmaea (1.2 g extract per cycle). The separation process resulted in fractions enriched with palythine (2.3 mg), asterina-330 (3.3 mg), shinorine (14.8 mg), porphyra-334 (203.5 mg) and mycosporine-serinol (46.6 mg), which were subsequently desalted by using precipitation with methanol and permeation on a Sephadex G-10 column. Target molecules were identified by HPLC, MS, and NMR.

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria.

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.

Nanoscale Biocompatible Structures Generated from Fluorinated Tripodal Phenylenes on Gold Nanoprisms.

Modification of gold substrates with a stable, uniform and ultrathin layer of biocompatible materials is of tremendous interest for the development of bio-devices. We present the fabrication of hybrid systems consisting of triangular prism gold nanoparticles (Au@NTPs) covalently covered with tripod-shaped oligo(p-phenylenes) featuring trifluoromethyl groups. Their synthesis is accomplished using a biphenyl boronic ester as the key compound. Au@NTPs were prepared through a seedless procedure using 3-butenoic acid and benzyldimethyl ammonium chloride, and modified with aminothiol groups. Coverage of this amine-modified gold substrate with a self-assembled monolayer (SAM) of tripod-shaped molecules is carried out in ethanolic solution. The hybrid system avoids up to 70 % of protein corona formation, and allows unspecific attachment for bulky adsorbates, providing an optimal biosensing platform. Chemical composition and morphology are analyzed by transmission electron microscopy (TEM), UV-visible spectroscopy and field emission scanning electron microscopy (FESEM).

Bengamide Analogues Show A Potent Antitumor Activity against Colon Cancer Cells: A Preliminary Study.

The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.

10-Fold Quantum Yield Improvement of Ag2S Nanoparticles by Fine Compositional Tuning.

Ag2S semiconductor nanoparticles (NPs) are near-infrared luminescent probes with outstanding properties (good biocompatibility, optimum spectral operation range, and easy biofunctionalization) that make them ideal probes for in vivo imaging. Ag2S NPs have, indeed, made possible amazing challenges including in vivo brain imaging and advanced diagnosis of the cardiovascular system. Despite the continuous redesign of synthesis routes, the emission quantum yield (QY) of Ag2S NPs is typically below 0.2%. This leads to a low luminescent brightness that avoids their translation into the clinics. In this work, an innovative synthetic methodology that permits a 10-fold increment in the absolute QY from 0.2 up to 2.3% is presented. Such an increment in the QY is accompanied by an enlargement of photoluminescence lifetimes from 184 to 1200 ns. The optimized synthetic route presented here is based on a fine control over both the Ag core and the Ag/S ratio within the NPs. Such control reduces the density of structural defects and decreases the nonradiative pathways. In addition, we demonstrate that the superior performance of the Ag2S NPs allows for high-contrast in vivo bioimaging.

Temperature-Controlled Catalysis by Core-Shell-Satellite AuAg@pNIPAM@Ag Hybrid Microgels: A Highly Efficient Catalytic Thermoresponsive Nanoreactor.

A novel wet-chemical protocol is reported for the synthesis of "temperature-programmable" catalytic colloids consisting of bimetallic core@shell AuAg nanoparticles encapsulated into poly(N-isopropylacrylamide) (pNIPAM) microgels with silver satellites (AgSTs) incorporated within the microgel structure. Spherical AuNPs of 50 nm in diameter are initially synthesized and used for growing a pNIPAM microgel shell with temperature stimulus response. A silver shell is subsequently grown on the Au core by diffusing Ag salt through the hydrophilic pNIPAM microgel (AuAg@pNIPAM microgel). The use of allylamine as a co-monomer during pNIPAM polymerization facilitates the coordination of Ag+ with the NH2 nitrogen lone pair of electrons, which are reduced to Ag seeds (∼14 nm) using a strong reducing agent, obtaining thus AuAg@pNIPAM@Ag hybrid microgels. The two systems are tested as catalysts toward the reduction of 4-nitrophenol (4-Nip) to 4-aminophenol (4-Amp) by NaBH4. Both exhibit extremely sensitive temperature-dependent reaction rate constants, with the highest K1 value of the order of 0.6 L/m2 s, which is one of the highest values ever reported. The presence of plasmonic entities is confirmed by UV-vis spectroscopy. Dynamic light scattering proves the temperature responsiveness in all cases. Transmission electron microscopy and energy-dispersive X-ray (EDX) elemental mapping highlight the monodispersity of the synthesized hybrid nanostructured microgels, as well as their size and metallic composition. The amount of gold and silver in both systems is obtained by thermogravimetric analysis and the EDX spectrum. The reduction reaction kinetics is monitored by UV-vis spectroscopy at different temperatures for both catalytic systems, with the AuAg@pNIPAM@Ag microgels showing superior catalytic performance at all temperatures because of the synergistic effect of the AuAg core and the AgSTs. The principal novelty of this study lies in the "hierarchical" design of the metal-polymer-metal core@shell@satellite nanostructured colloids exhibiting synergistic capabilities of the plasmonic NPs for, among others, temperature-controlled catalytic applications.

Electrospun Nanofibers: Recent Applications in Drug Delivery and Cancer Therapy.

Polymeric nanofibers (NFs) have been extensively reported as a biocompatible scaffold to be specifically applied in several researching fields, including biomedical applications. The principal researching lines cover the encapsulation of antitumor drugs for controlled drug delivery applications, scaffolds structures for tissue engineering and regenerative medicine, as well as magnetic or plasmonic hyperthermia to be applied in the reduction of cancer tumors. This makes NFs useful as therapeutic implantable patches or mats to be implemented in numerous biomedical researching fields. In this context, several biocompatible polymers with excellent biocompatibility and biodegradability including poly lactic-co-glycolic acid (PLGA), poly butylcyanoacrylate (PBCA), poly ethylenglycol (PEG), poly (ε-caprolactone) (PCL) or poly lactic acid (PLA) have been widely used for the synthesis of NFs using the electrospun technique. Indeed, other types of polymers with stimuli-responsive capabilities has have recently reported for the fabrication of polymeric NFs scaffolds with relevant biomedical applications. Importantly, colloidal nanoparticles used as nanocarriers and non-biodegradable structures have been also incorporated by electrospinning into polymeric NFs for drug delivery applications and cancer treatments. In this review, we focus on the incorporation of drugs into polymeric NFs for drug delivery and cancer treatment applications. However, the principal novelty compared with previously reported publications is that we also focus on recent investigations concerning new strategies that increase drug delivery and cancer treatments efficiencies, such as the incorporation of colloidal nanoparticles into polymeric NFs, the possibility to fabricate NFs with the capability to respond to external environments, and finally, the synthesis of hybrid polymeric NFs containing carbon nanotubes, magnetic and gold nanoparticles, with magnetic and plasmonic hyperthermia applicability.

Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoquinolines and 2-substituted 1-aryl-3-tetrahydrobenzazepines.

A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date.

Seeded Growth Synthesis of Gold Nanotriangles: Size Control, SAXS Analysis, and SERS Performance.

We studied the controlled growth of triangular prismatic Au nanoparticles with different beveled sides for surface-enhanced Raman spectroscopy (SERS) applications. First, in a seedless synthesis using 3-butenoic acid (3BA) and benzyldimethylammonium chloride (BDAC), gold nanotriangles (AuNTs) were synthesized in a mixture with gold nanooctahedra (AuNOCs) and separated by depletion-induced flocculation. Here, the influence of temperature, pH, and reducing agent on the reaction kinetics was initially investigated by UV-vis and correlated to the size and yield of AuNT seeds. In a second step, the AuNT size was increased by seed-mediated overgrowth with Au. We show for the first time that preformed 3BA-synthesized AuNT seeds can be overgrown up to a final edge length of 175 nm and a thickness of 80 nm while maintaining their triangular shape and tip sharpness. The NT morphology, including edge length, thickness, and tip rounding, was precisely characterized in dispersion by small-angle X-ray scattering and in dry state by transmission electron microscopy and field-emission scanning electron microscopy. For sensor purposes, we studied the size-dependent SERS performance of AuNTs yielding analytical enhancement factors between 0.9 × 104 and 5.6 × 104 and nanomolar limit of detection (10-8-10-9 M) for 4-mercaptobenzoic acid and BDAC. These results confirm that the 3BA approach allows the fabrication of AuNTs in a whole range of sizes maintaining the NT morphology. This enables tailoring of localized surface plasmon resonances between 590 and 740 nm, even in the near-infrared window of a biological tissue, for use as colloidal SERS sensing agents or for optoelectronic applications.

Tripalmitin nanoparticle formulations significantly enhance paclitaxel antitumor activity against breast and lung cancer cells in vitro.

Paclitaxel (PTX) is one of the drugs of choice in the treatment of breast and lung cancer. However, its severe side effects, including mielosuppression, cardiotoxicity and neurotoxicity, frequently cause treatment to be discontinued. Solid lipid nanoparticles (NPs) of glyceril tripalmitate (tripalmitin) loaded with PTX (Tripalm-NPs-PTX) including modifications by the addition of hexa(ethylene glycol), ß-cyclodextrin and macelignan were developed. All NPs-PTX formulations displayed excellent hemocompatibility and significantly enhanced PTX antitumor activity in human breast (MCF7, MDAMB231, SKBR3 and T47D) and lung (A549, NCI-H520 and NCI-H460) cancer cells. Tripalm-NPs-PTX decreased PTX IC50 by as much as 40.5-fold in breast and 38.8-fold in lung cancer cells and Tripalm-NPs-PTX macelignan inhibited P-glycoprotein in resistant tumor cells. In addition, Tripalm-NPs-PTX significantly decreased the volume of breast and lung multicellular tumor spheroids that mimics in vivo tumor mass. Finally, Tripalm-NPs-PTX decreased the PTX IC50 of cancer stem cells (CSCs) derived from both lung and breast cancer cells (6.7- and 14.9-fold for MCF7 and A549 CSCs, respectively). These results offer a new PTX nanoformulation based on the use of tripalmitin which improves the antitumor activity of PTX and that may serve as an alternative PTX delivery system in breast and lung cancer treatment.

Modification of fluorous substrates with oligo(ethylene glycol) via "click" chemistry for long-term resistance of cell adhesion.

In this work perfluorinated substrates fabricated from SiO2 glass slides are modified with oligo(ethylene glycol) (OEG) units for long-term resistance of cell adhesion purposes, based on fluorous interactions and click chemistry. Specifically, fluorous substrates, prepared by treatment of glass slides with 1H, 1H, 2H, 2H-perfluorodecyltrimethoxysilane (FAS17), were coated with ethynyl-OEG-C8F17, followed by covalent attachment of an azido-OEG via copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. We demonstrate that the resultant surface avoid fibrinogen adsorption and resisted cell adhesion for over 14days. X-ray photoemission spectroscopy (XPS) analysis and contact angle goniometry measurements confirm the presence of the OEG molecules on the fluorous substrates. Bright field optical images show total absence of 3T3 fibroblast cells on the OEG modified fluorinated substrate for 1 and 5days, and a remarkably decrease of cell adhesion at 14days.

Preparation, chemical and electrical characterizations of lipid nanoparticles loaded with dihydroxybenzophenone.

Lipid nanoparticles loading the sunscreen 2,4-dihydroxybenzophenone (DHB-LNPs) have been prepared by high-pressure homogenization and ultrasound techniques. The combination of both methodologies improves the entrapment efficiency percentage reaching 95%. The morphology of the DHB-LNPs was studied with scanning electron microscopy (SEM) and atomic force microscopy (AFM), while the surface and interior chemical composition was analyzed by X-ray photoelectron spectroscopy (XPS) at different irradiation times. Conductivity of aqueous dispersions of the DHBLNPs was determined by impedance spectroscopy. A possible DHB-LNPs application related to drug release in a system simulating skin-properties is shown.

Chiral high-performance liquid chromatographic separation and circular dichroism spectra of the enantiomers of cytotoxic aristocularine alkaloids.

The HPLC enantiomeric separation of the racemic cularinoid alkaloids N-p-methoxy-1,alpha-dihydroaristoyagonine (1) and 4',5'-demethoxy-1,alpha-dihydroaristoyagonine (2) was accomplished using five chiral stationary phases (CSPs), some of them polysaccharide-derived ones. The molecular size and conjugative effect strongly affect the different enantioselectivity of the compounds 1 and 2 on the various CSPs investigated. Single enantiomers of 1 were isolated by repeated injections on an analytical HPLC column, and their circular dichroism spectra and optical rotations were measured. The cytotoxicity of the isolated enantiomers was measured on a human colon carcinoma cell line and compared with that of the racemic compound.

Protein-resistant monolayers prepared by hydrosilylation of alpha-oligo(ethylene glycol)-omega-alkenes on hydrogen-terminated silicon (111) surfaces.

Atomically flat, homogeneous, and protein-resistant monolayers can be readily prepared on H-Si(111) surfaces by photo-induced hydrosilylation of alpha-oligo(ethylene glycol)-omega-alkenes.