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Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed mice. Adult male Institute of Cancer Research (ICR) mice were exposed to a daily dose of 80 mg/kg body weight ( b.w.) Pb(II) nitrate for 14 days and subsequently treated with Sal (16 mg/kg b.w.) or DFP (19 mg/kg b.w.) for another 14 days. At the end of the experimental protocol, the brains were processed for histological and inductively coupled plasma mass spectrometry (ICP-MS) analyses. Pb exposure resulted in a 50-fold increase in Pb concentration, compared with controls. Magnesium (Mg) and phosphorus (P) were also significantly increased by 22.22% and 17.92%, respectively. The histological analysis of Pb-exposed mice revealed brain pathological changes with features of neuronal necrosis. Brain Pb level remained significantly elevated in Sal- and DFP-administered groups (37-fold and 50-fold, respectively), compared with untreated controls. Treatment with Sal significantly reduced Mg and P concentrations by 22.56% and 18.38%, respectively, compared with the Pb-exposed group. Administration of Sal and DFP ameliorated brain injury in Pb-exposed mice and improved histological features. The results suggest the potential application of Sal and DFP for treatment of Pb-induced neurotoxicity.

Lead (Pb) exposure induces severe nephrotoxic effects in humans and animals. Herein, we compare the effects of two chelating agents, salinomycin and deferiprone, on Pb-induced renal alterations in mice and in the homeostasis of essential elements. Adult male mice (Institute of Cancer Research (ICR)) were randomized into four groups: control (Ctrl)—untreated mice administered distilled water for 28 days; Pb-exposed group (Pb)—mice administered orally an average daily dose of 80 mg/kg body weight (BW) lead (II) nitrate (Pb(NO3)2) during the first two weeks of the experimental protocol followed by the administration of distilled water for another two weeks; salinomycin-treated (Pb + Sal) group—Pb-exposed mice, administered an average daily dose of 16 mg/kg BW salinomycin for two weeks; deferiprone-treated (Pb + Def) group—Pb-exposed mice, administered an average daily dose of 20 mg/kg BW deferiprone for 14 days. The exposure of mice to Pb induced significant accumulation of the toxic metal in the kidneys and elicited inflammation with leukocyte infiltrations near the glomerulus. Biochemical analysis of the sera revealed that Pb significantly altered the renal function markers. Pb-induced renal toxicity was accompanied by a significant decrease in the endogenous renal concentrations of phosphorous (P), calcium (Ca), copper (Cu) and selenium (Se). In contrast to deferiprone, salinomycin significantly improved renal morphology in Pb-treated mice and decreased the Pb content by 13.62% compared to the Pb-exposed group. There was also a mild decrease in the renal endogenous concentration of magnesium (Mg) and elevation of the renal concentration of iron (Fe) in the salinomycin-treated group compared to controls. Overall, the results demonstrated that salinomycin is a more effective chelating agent for the treatment of Pb-induced alterations in renal morphology compared to deferiprone.

Cadmium (Cd) is а hazardous multi-organ toxin. In this study, we provide the first results about the effect of oral administration of deferiprone (DFP) on Cd accumulation and on the homeostasis of essential elements in the brain of Cd-exposed mice.Adult Institute of Cancer Research (ICR) male mice were randomized into four experimental groups: untreated controls - administered distilled water for 28 days; Cd-exposed group - exposed to 18 mg/kg body weight (b.w.) Cd(II) acetate for 14 days followed by the administration of distilled water for two weeks; Cd + DFP (low dose) - Cd-intoxicated mice subsequently treated with 19 mg/kg b.w. DFP for two weeks; and Cd + DFP (high dose) - Cd-exposed mice administered high-dose DFP (135 mg/kg b.w.) for 14 days. Brains were subjected to inductively coupled plasma-mass spectrometry (ICP-MS) and histological analysis.The results revealed that exposure of mice to Cd for 14 days significantly increased Cd concentration and significantly decreased magnesium (Mg), phosphorus (P), and zinc (Zn) contents in the brain compared to untreated controls. This effect was accompanied by necrotic-degenerative changes in both the cerebrum and cerebellum. Oral administration of low-dose DFP to Cd-exposed mice decreased the concentration of the toxic metal in the brain by 16.37% and restored the concentration of the essential elements to normal control values. Histological analysis revealed substantially improved cerebral and cerebellar histoarchitectures. In contrast, oral administration of high-dose DFP increased Cd content and significantly decreased selenium (Se) concentration in the brain. Necrotic neurons and Purkinje cells were still observed in the cerebral and cerebellar cortices.The results demonstrated that oral administration of DFP at low doses has a better therapeutic potential for the treatment of Cd-induced brain damage compared to high doses.

Molecular imaging using magnetic resonance imaging (MRI) is expected to play a crucial future role in oncological diagnosis and in monitoring of therapeutic progress. Targeted nanoparticle contrast media (CM) with high relaxivities are required in order to obtain adequate signal-to-noise ratios as well as visualization of a desired pathologic area of the human body. The aims of this study were to synthesize and define certain physicochemical and enhancement properties of new doubly derivatized polylactic acid–bovine serum albumin (PLA-BSA) nanoparticles (NPs) modified by the covalent coupling of glutaraldehyde as a crosslinking agent. An additional functionalization with endothelial cells (ECs) targeting groups (tomato lectins; LEA) and signal-emitting moieties (DTPA-Gd) enables its use as a macromolecular, biodegradable contrast agent for MRI. The NPs were characterized by different spectroscopies, size exclusion chromatography, and scanning and transmission electron microscopy. In a human vein model, the dynamics of the nanoparticle interactions with the vein wall were examined in MRI, with correlative imaging in electron microscopy. In vitro studies were conducted to show endothelial binding and persistent enhancement at the apical EC surface. NPs with a diameter between 55 and 75 nm, able to carry simultaneous signal emitting, and targeting motifs on a single construct were successfully prepared. A high Gd payload and endothelial binding to blood vessel walls were observed. The binding affinity and specificity of LEA was preserved, and a strong enhancement at the endothelium was achieved. The stabilized core–shell structure of PLA-NP might allow for further encapsulation of lipophilic drugs or for attachment of other targeting molecules, such as antibodies. Graphical abstract

In this study, we compare the effects of deferiprone (Def) and tetraethylammonium salt of salinomycinic acid (Sal) on lead (Pb)-induced toxicity in testes of Pb-exposed mice. Mature male ICR mice were allocated into four groups as follows: untreated control mice (ctrl)-received distilled water for 4 weeks; Pb-exposed mice (Pb)-subjected to 14-day Pb (II) nitrate administration at dose 80 mg/kg body weight (b.w.); Pb + Def group-Pb-exposed mice, treated with 20 mg/kg b.w. Def for 2 weeks; and Pb + Sal group-Pb-intoxicated mice, treated with 16 mg/kg b.w. Sal for 14 days. The results demonstrated that Pb exposure significantly increased blood and testicular Pb concentrations, decreased testicular calcium (Ca) content, significantly elevated testicular levels of magnesium (Mg), zinc (Zn), and selenium (Se) but did not significantly affect the endogenous contents of phosphorous (P) and iron (Fe) compared with untreated controls. Pb intoxication induced disorganization of the seminiferous epithelium. Def or Sal administration reduced blood Pb and testicular Pb concentrations in Pb-exposed mice compared with the Pb-intoxicated group. Mg, Zn, and Se concentrations in testes of Pb-exposed mice, treated with Def or Sal, remained higher compared with the untreated controls. Sal significantly increased testicular P concentration compared with untreated controls and significantly elevated the testicular Ca and Fe concentrations compared with the toxic control group. Both chelating agents improved testicular morphology to a great extent. The results demonstrate the potential of both compounds as antidotes for treatment of Pb-induced impairment of male reproductive function.

Background: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. Objective: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8-quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. Method: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). Results: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer, trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. Conclusion: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga-complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents.

With the purpose to develop macromolecular magnetic resonance imaging contrast agents, we herein report three different synthetic approaches to the covalent attachment of bifunctional chelating agents to human serum albumin followed by coordination to contrast enhancing gadolinium(III). Applied methods cover active ester-mediated conjugation, linkage through glutaryl spacer, as well as the connection by the employment of glutaraldehyde. The content of gadolinium(III) was evaluated by inductively-coupled-plasma mass-spectrometry (ICP-MS) measurements and indicated reproducible amounts of conjugated contrast enhancing material. Small angle X-ray scattering (SAXS) experiments provided the size and altered shape of the gadolinium loaded proteins in comparison to unmodified albumin. Finally, the magnetic resonance properties of the protein conjugates were evaluated. The results indicated suitability of the gadolinium(III) loaded protein conjugates for use as macromolecular contrast agents in magnetic resonance imaging (MRI).

Magnetic resonance imaging (MRI) requires synthesis of contrast media bearing targeting groups and numerous gadolinium chelating groups generating high relaxivity. This paper explores the results of linking the gadolinium chelates to the targeting group, a protein molecule, via various types of linkers. Polycondensates of diethylenetriaminepentaacetic acid (DTPA) with either diols or diamines were synthesised and coupled to the targeting group, a lectin (Lycopersicon esculentum agglutinin, tomato lectin) which binds with high affinity to specific oligosaccharide configurations in the endothelial glycocalyx. The polycondensates bear up to four carboxylic groups per constitutive unit. Gd-chelate bonds are created through dative interactions with the unshared pair of electrons on each oxygen and nitrogen atom on DTPA. This is mandatory for complexation of Gd(III) and avoidance of the severe toxicity of free gadolinium ions. The polymer-DTPA compounds were characterised by (1)H NMR and mass spectrometry. The final lectin-DTPA-polycondensate conjugates were purified by fast protein liquid chromatography (FPLC). The capacity for specific binding was assessed, and the MRI properties were examined in order to evaluate the use of these oligomers as components of selective perfusional contrast agents.

Non-specific extracellular contrast agents have been on the market for more than 15 years. Here, we report on the synthesis of new selective lectin–gadolinium (Gd)-loaded chitosan nanoparticles with a prolonged clearance time and a much higher relaxivity in comparison to other preparations. Chitosan nanoparticles were prepared from 85% deacetylated chitin by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of n-hexane using sodium bis(ethylhexyl)sulfosuccinate as a surfactant. Several crucial parameters, namely, the Gd and protein content of the nanoparticles, their size and dispersity were determined. Magnetic resonance measurements were carried out by intravenous perfusion of mono-disperse suspensions of the nanoparticles into mice. Chitosan nanoparticles can be used as contrast agents in magnetic resonance imaging (MRI). They are excellent candidates for controlled delivery of bioactive compounds to molecular targets and as biospecific diagnostic tools in MRI.