Vascular inflammation plays a crucial role in the progression of various pathologies, including atherosclerosis (AS), and thus it has become an attractive therapeutic target. The protocatechuic acid (PCA), one of the main metabolites of complex polyphenols, is endowed with anti-inflammatory activity, but its formulation into nanocarriers may increase its bioavailability. In this study, we developed and characterized dextran shell‒iron oxide core nanoparticles loaded with PCA (MNP-Dex/PCA) and assessed their cytotoxicity and anti-inflammatory potential on cells acting as key players in the onset and progression of AS, namely, endothelial cells (EC) and monocytes/macrophages. The results showed that MNP-Dex/PCA exert an anti-inflammatory activity at non-cytotoxic and therapeutically relevant concentrations of PCA (350 μM) as supported by the reduced levels of inflammatory molecules such as MCP-1, IL-1β, TNF-α, IL-6, and CCR2 in activated EC and M1-type macrophages and functional monocyte adhesion assay. The anti-inflammatory effect of MNP-Dex/PCA was associated with the reduction in the levels of ERK1/2 and p38-α mitogen-activated protein kinases (MAPKs) and NF-kB transcription factor. Our data support the further development of dextran shell-magnetic core nanoparticles as theranostic nanoparticles for guidance, imaging, and therapy of vascular inflammation using PCA or other anti-inflammatory compounds.

Type 2 diabetes became an alarming global health issue since the existing drugs do not prevent its progression. Herein, we aimed to synthesize and characterize a family of oxidovanadium(V) complexes with Schiff base ligands derived from L-/D-valine (val) and salicylaldehyde (sal) or o-vanillin (van) as insulin-mimetic agents and to assess their potential anti-diabetic properties. Two new oxidovanadium(V) complexes, [{V^VO(R-salval)(H₂O)}(μ₂-O){V^VO(R-salval)}] and [{V^VO(R-vanval)(CH₃OH)}₂(μ₂-O)], and their S-enantiomers were synthesized and characterized. The compounds exhibit optical activity as shown by crystallographic and spectroscopic data. The stability, the capacity to bind bovine serum albumin (BSA), the cytotoxicity against human hepatoma cell line, as well as the potential anti-diabetic activity of the four compounds are investigated. The synthesized compounds are stable for up to three hours in physiological conditions and exhibit a high capacity of binding to BSA. Furthermore, the synthesized compounds display cytocompatibility at biologically relevant concentrations, exert anti-diabetic potential and insulin-mimetic activities by inhibiting the α-amylase and protein tyrosine phosphatase activity, and a long-term increase of insulin receptor phosphorylation compared to the insulin hormone. Thus, the in vitro anti-diabetic potential and insulin-mimetic properties of the newly synthesized oxidovanadium(V) compounds, correlated with their cytocompatibility, make them promising candidates for further investigation as anti-diabetic drugs.

The cellular internalization of drug carriers occurs via different endocytic pathways that ultimately involve the endosomes and the lysosomes, organelles where the pH value drops to 6.0 and 5.0, respectively. We aimed to design and characterize pH/temperature-responsive carriers for the effective delivery of the anti-tumoral drug doxorubicin. To this purpose, poly(N-isopropylacrylamide-co-vinylimidazole) was synthesized as an attractive pH/temperature-sensitive copolymer. Microspheres made of this copolymer, loaded with doxorubicin (MS-DXR), disintegrate in monodisperse nanospheres (NS-DXR) under conditions similar to that found in the bloodstream (pH = 7.4, temperature of 36 °C) releasing a small amount of payload. However, in environments that simulate the endosomal and lysosomal conditions, nanospheres solubilize, releasing the entire amount of drug. We followed the NS-DXR internalization using two cancer cell lines, hepatic carcinoma HepG2 cells and lung adenocarcinoma A549 cells. The data showed that NS-DXR are internalized to a greater extent by HepG2 cells than A549 cells, and this correlated with increased cytotoxicity induced by NS-DXR in HepG2 cells compared with A549 cells. Moreover, NS-DXR particles do not cause hemolysis and erythrocytes aggregation. Administered in vivo, NS-DXR localized in the liver and kidneys of mice, and the loading of DXR into NS resulted in the reduced renal clearance of DXR. In conclusion, the newly developed poly(N-isopropylacrylamide-co-vinyl imidazole) particles are biocompatible and may be introduced as carriers for doxorubicin to hepatic tumors.

A wide variety of metal-based compounds have been obtained and studied for their antitumor activity since the intensely used cytostatic drugs (e.g., cisplatin) failed to accomplish their expected pharmacological properties. Thus, we aimed to develop a new vanadium-based drug and assess its antitumor properties using the human hepatocarcinoma (HepG2) cell line. The compound was synthesized from vanadyl sulfate, DL-valine, and o-vanillin and was spectrally and structurally characterized (UV-Vis, IR, CD, and single-crystal/powder-XRD). Compound stability in biological media, cell uptake, and the interaction with albumin were assessed. The mechanisms of its antitumor activity were determined compared to cisplatin by performing cytotoxicity, oxidative and mitochondrial status, DNA fragmentation, β-Tubulin synthesis investigation, and cell cycle studies. Herein, we developed a macrocyclic tetranuclear oxidovanadium(V) compound, [(V^VO)(L)(CH₃O)]₄, having coordinated four Schiff base (H₂L) ligands, 3-methoxysalicylidenvaline. We showed that [(V^VO)(L)(CH₃O)]₄: (i) has pH-dependent stability in biological media, (ii) binds to albumin in a dose-dependent manner, (iii) is taken up by cells in a time-dependent way, (iv) has a higher capacity to induce cell death compared to cisplatin (IC₅₀ = 6 μM vs. 10 μM), by altering the oxidative and mitochondrial status in HepG2 cells. Unlike cisplatin, which blocks the cell cycle in the S-phase, the new vanadium-based compound arrests it in S and G2/M-phase, whereas no differences in the induction of DNA fragmentation and reduction of β-Tubulin synthesis between the two were determined. Thus, the [(V^VO)(L)(CH₃O)]₄ antitumor mechanism involved corroboration between the generation of oxidative species, mitochondrial dysfunction, degradation of DNA, cell cycle arrest in the S and G2/M-phase, and β-Tubulin synthesis reduction. Our studies demonstrate the potent antitumor activity of [(V^VO)(L)(CH₃O)]₄ and propose it as an attractive candidate for anticancer therapy.

Two chemical motifs of interest for medicinal chemistry, silatrane as 1-(3-aminopropyl) silatrane (SIL M), and nitro group attached in position 5 to salicylaldehyde, are coupled in a new structure, 1-(3-{[(2-hydroxy-5-nitrophenyl)methylidene]amino}propyl)silatrane (SIL-BS), through an azomethine moiety, also known as a versatile pharmacophore. The high purity isolated compound was structurally characterized by an elemental, spectral, and single crystal X-ray diffraction analysis. Given the structural premises for being a biologically active compound, different specific techniques and protocols have been used to evaluate their in vitro hydrolytic stability in simulated physiological conditions, the cytotoxicity on two cancer cell lines (HepG2 and MCF7), and protein binding ability—with a major role in drug ADME (Absorption, Distribution, Metabolism and Excretion), in parallel with those of the SIL M. While the latter had a good biocompatibility, the nitro-silatrane derivative, SIL-BS, exhibited a higher cytotoxic activity on HepG2 and MCF7 cell lines, performance assigned, among others, to the known capacity of the nitro group to promote a specific cytotoxicity by a “activation by reduction” mechanism. Both compounds exhibited increased bio- and muco-adhesiveness, which can favor an optimized therapeutic effect by increased drug permeation and residence time in tumor location. Additional benefits of these compounds have been demonstrated by their antimicrobial activity on several fungi and bacteria species. Molecular docking computations on Human Serum Albumin (HSA) and M^PRO COVID-19 protease demonstrated their potential in the development of new drugs for combined therapy.

Several metal-based compounds have been synthesized and tested for their antitumor properties, as current Pt-based cytostatic drugs have not achieved the expected pharmacological outcomes. In this study, we evaluated the antitumor effects of our newly developed macrocyclic tetranuclear oxovanadium (V) compound, with the chemical formula [(VVO)(L)(CH3O)]4 (abbreviated Van), where L represents the deprotonated form of the Schiff base 3-methoxysalicylidenvaline (Turtoi M et al., 2021). We investigated the effects of Van on inducing apoptosis and pyroptosis in the human hepatocarcinoma (HepG2) cell line, as well as its potential to reduce the tumor volume in vivo. The synthesis and physicochemical characterization for Van, its stability in cell culture media, its cellular uptake, interaction with albumin, and effects on cell viability, oxidative status, DNA integrity, and cell cycle of HepG2 cells have been previously reported (Turtoi M et al., 2021). The mechanism by which Van exerts its antitumor activity was further investigated by determining the activity of caspase 3 and analyzing the protein expression levels of the anti-apoptotic protein Bcl-2, the pro-pyroptotic proteins NLRP3 and caspase 1, as well as Interleukin (IL)-1β, in comparison to cisplatin. Additionally, the ability of Van to reduce the size of solid tumors was initially evaluated through the subcutaneous injection of HepG2 cells in C57BL/6J mice. The antitumor treatment started 48 hours after tumor induction, involving three injections given either intravenously (i.v.) or intratumorally (i.t.), with each injection administered every three days. The doses were either 1 mg/kg BW Van or 1 mg/kg BW cisplatin. All animals were euthanized one-month post-anti-tumor therapy using an overdose of ketamine and xylazine. The tumors were then excised and histologically analyzed by Trichrome Masson’s staining. Our results demonstrated that Van can produce a pro-apoptotic effect by increasing caspase 3 activity and reducing the synthesis of the anti-apoptotic protein Bcl-2, similar to the effects of cisplatin. Furthermore, Van exhibited a greater ability to activate the pyroptotic signaling pathway compared to cisplatin by enhancing the expression of NLRP-1, caspase 1, and IL-1β protein expression in HepG2 cells. The preliminary in vivo results evidenced that Van effectively prevents the formation of subcutaneous solid tumors following i.v administration and reduces the tumor volume after i.t injection compared to control animals. Our findings highlight the remarkable antitumor efficacy of [(VVO)(L)(CH3O)]4, underscoring its potential as a powerful therapeutic agent.