To develop a platform for molecular magnetic resonance imaging, we prepared gadolinium-bearing albumin-polylactic acid nanoparticles in the size range 20-40 nm diameter. Iterative cycles of design and testing upscaled the synthesis procedures to gram amounts for physicochemical characterisation and for pharmacokinetic testing. Morphological analyses showed that the nanoparticles were spheroidal with rough surfaces. Particle sizes were measured by direct transmission electron microscopical measurements from negatively contrasted preparations, and by use of photon correlation spectroscopy; the two methods each documented nanoparticle sizes less than 100 nm and generally 10-40 nm diameter, though with significant intrabatch and interbatch variability. The particles' charge sufficed to hold them in suspension. HSA retained its tertiary structure in the particles. The nanoparticles were stable against turbulent flow conditions and against heat, though not against detergents. MRI imaging of liquid columns was possible at nanoparticle concentrations below 10 mg/ml. The particles were non-cytotoxic, non-thrombogenic and non-immunogenic in a range of assay systems developed for toxicity testing of nanoparticles. They were micellar prior to lyophilisation, but loosely structured aggregated masses after lyophilisation and subsequent resuspension. These nanoparticles provide a platform for further development, based on non-toxic materials of low immunogenicity already in clinical use, not expensive, and synthesized using methods which can be upscaled for industrial production.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistanceoften due to insufficient drug deliveryis still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gramnegative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

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.

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.

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Introduction: Current imaging modalities for peripheral nerves display the nerve's structure but not its function. Based on a nerve's capacity for axonal transport, it may be visualized by targeted application of a contrast agent and assessing the distribution through radiological imaging, thus revealing a nerve's continuity. This concept has not been explored, however, may potentially guide the treatment of peripheral nerve injuries. In this experimental proof-of-concept study, we tested imaging through MRI after administering gadolinium-based contrast agents which were then retrogradely transported.Methods: We synthesized MRI contrast agents consisting of paramagnetic agents and various axonal transport facilitators (HSA-DTPA-Gd, chitosan-DTPA-Gd or PLA/HSA-DTPA-Gd). First, we measured their relaxivity values in vitro to assess their radiological suitability. Subsequently, the sciatic nerve of 24 rats was cut and labeled with one of the contrast agents to achieve retrograde distribution along the nerve. One week after surgery, the spinal cords and sciatic nerves were harvested to visualize the distribution of the respective contrast agent using 7T MRI. In vivo MRI measurements were performed using 9.4 T MRI on the 1st, 3rd, and the 7th day after surgery. Following radiological imaging, the concentration of gadolinium in the harvested samples was analyzed using inductively coupled mass spectrometry (ICP-MS).Results: All contrast agents demonstrated high relaxivity values, varying between 12.1 and 116.0 mM−1s−1. HSA-DTPA-Gd and PLA/HSA-DTPA-Gd application resulted in signal enhancement in the vertebral canal and in the sciatic nerve in ex vivo MRI. In vivo measurements revealed significant signal enhancement in the sciatic nerve on the 3rd and 7th day after HSA-DTPA-Gd and chitosan-DTPA-Gd (p < 0.05) application. Chemical evaluation showed high gadolinium concentration in the sciatic nerve for HSA-DTPA-Gd (5.218 ± 0.860 ng/mg) and chitosan-DTPA-Gd (4.291 ± 1.290 ng/mg).Discussion: In this study a novel imaging approach for the evaluation of a peripheral nerve's integrity was implemented. The findings provide radiological and chemical evidence of successful contrast agent uptake along the sciatic nerve and its distribution within the spinal canal in rats. This novel concept may assist in the diagnostic process of peripheral nerve injuries in the future.

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.

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.