Multimodal imaging, integrating several modalities including down- and up-conversion luminescence, T₁- and T₂(T₂*)-weighted MRI, and CT contrasting in one system, is very promising for improved diagnosis of severe medical disorders. To reach the goal, it is necessary to develop suitable nanoparticles that are highly colloidally stable in biologically relevant media. Here, hydrophilic poly(N,N-dimethylacrylamide-N-acryloylglycine methyl ester)-alendronate-[P(DMA-AGME)-Ale]-coated Gd(Tb)F₃:Tb³⁺(Gd³⁺),Yb³⁺,Nd³⁺ nanoparticles were synthesized by a coprecipitation method in ethylene glycol (EG) followed by coating with the polymer. The particles were tho-roughly characterized by a dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray energy dispersive spectroscopy (EDAX), selected area electron diffraction (SAED), elemental ana-lysis and fluorescence spectroscopy. Aqueous particle dispersions exhibited excellent colloidal stability in water and physiological buffers. In vitro toxicity assessments suggested no or only mild toxicity of the surface-engineered Gd(Tb)F₃:Tb³⁺(Gd³⁺),Yb³⁺,Nd³⁺ particles in a wide range of concentrations. Internalization of the particles by several types of cells, including HeLa, HF, HepG2, and INS, was confirmed by a down- and up-conversion confocal microscopy. Newly developed particles thus proved to be an efficient contrast agent for fluorescence imaging, T₁- and T₂(T₂*)-weighted magnetic resonance imaging (MRI), and computed tomography (CT).

This report describes the design, synthesis and evaluation of tumor-targeted polymer probes to visualize epidermal growth factor receptor (EGFR)-positive malignant tumors for successful resection via fluorescence guided endoscopic surgery. Fluorescent polymer probes of various molecular weights enabling passive accumulation in tumors via enhanced permeability and retention were prepared and evaluated, showing an optimal molecular weight of 200,000 g/mol for passive tumor targeting. Moreover, poly(N-(2-hydroxypropyl)methacrylamide)-based copolymers labeled with fluorescent dyes were targeted with the EGFR-binding oligopeptide GE-11 (YHWYGYTPQNVI), human EGF or anti-EGFR monoclonal antibody cetuximab were all able to actively target the surface of EGFR-positive tumor cells. Nanoprobes targeted with GE-11 and cetuximab showed the best targeting profile but differed in their tumor accumulation kinetics. Cetuximab increased tumor accumulation after 15 min, whereas GE 11 needed at least 4 h. Interestingly, after 4 h, there were no significant differences in tumor targeting, indicating the potential of oligopeptide targeting for fluorescence-navigated surgery. In conclusion, fluorescent polymer probes targeted by oligopeptide GE-11 or whole antibody are excellent tools for surgical navigation during oncological surgery of head and neck squamous cell carcinoma, due to their relatively simple design, synthesis and cost, as well as optimal pharmacokinetics and accumulation in tumors.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma (B-NHL) with chronically relapsing clinical course. Implementation of cytarabine (araC) into induction and salvage regimen became standard of care for majority of MCL patients. In this study, tailored N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer nanotherapeutics containing covalently bound araC (araC co-polymers) were designed, synthesized and evaluated for their anti-lymphoma efficacy in vivo using a panel of six patient-derived lymphoma xenografts (PDX) derived from newly diagnosed and relapsed / refractory (R/R) MCL. While free araC led to temporary inhibition of growth of MCL tumors, araC co-polymers induced long-term disappearance of the engrafted lymphomas with no observed toxicity even in the case of PDX models derived from patients, who relapsed after high-dose araC-based treatments. The results provide sound preclinical rationale for the use of HPMA-based araC co-polymers in induction, salvage or palliative therapy of MCL patients.

Experimental infections of two South American lymnaeid populations with Fascioloides magna were carried out to determine whether these snails may sustain larval development of this digenean and, if so, to quantify their potential for cercarial production. The reference group was a French population of Galba truncatula infected and raised according to the same protocol. According to the internal transcribed sequence (ITS)-1 segment of their genomic rDNA, these South American populations were identified as Lymnaea neotropica (origin, Argentina) and Lymnaea viatrix var. ventricosa (origin, Uruguay). In the snail groups followed for cercarial shedding, longer prepatent periods and lower numbers of shed cercariae were noted in South American lymnaeids. In other snails dissected at day 65 post-exposure, the redial and cercarial burdens of F. magna found in the bodies of L. neotropica and L. v. ventricosa were significantly lower than those noted in G. truncatula. Compared to the total cercarial production noted in the dissected snails, the percentage of cercariae that exited from snails was 51.3% for G. truncatula, 32.2% for L. neotropica and 46.8% for L. v. ventricosa. The two South American species of snails can thus be considered as potential intermediate hosts of F. magna.

Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase‐separated aggregates when heated above a threshold temperature. Such polymers found many promising (bio)medical applications, including in situ thermogelling with controlled drug release, polymer‐supported radiotherapy (brachytherapy), immunotherapy, and wound dressing, among others. Yet, despite the extensive research on medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remained unknown. Thus, herein, they studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots that subsequently dissolved with a two‐phase kinetics (depot maturation, slow redissolution) with half‐lives 2 weeks to 5 months, as depot vitrification prolonged their half‐lives. Additionally, the decrease of T_CP of a polymer solution increased the density of the intramuscular depot. Moreover, they detected secondary polymer depots in the kidneys and liver; these secondary depots also followed two‐phase kinetics (depot maturation and slow dissolution), with half‐lives 8 to 38 days (kidneys) and 15 to 22 days (liver). Overall, these findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications. Their methods may become a benchmark for future studies of polymer biodistribution.

Background: Avian schistosomes, the causative agents of human cercarial dermatitis (or swimmer’s itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected withTrichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity.Methods: Inducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected byT. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluatedin vivo. The vulnerability ofT. regentischistosomula to NO and peroxynitrite was assessedin vitroby viability assays and electron microscopy. Additionally, the effect of NO on the activity ofT. regentipeptidases was tested using a fluorogenic substrate.Results: iNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord.In vitro, NO did not impair the parasites, but inhibited the activity ofT. regenticathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viabilityin vitro, but rather did not participate in parasite clearancein vivo.Conclusions: Reactive nitrogen species, specifically NO, do not directly killT. regentiin mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.