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Background Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site became a new standard in novel anticancer methods Anticancer photodynamic therapy also takes benefit from using nanoparticles by means of increasing targeting efficiency and decreased side effect. With this in mind, the silica-based nanoparticles, as drug delivery systems for the second-generation photosensitizer 5,10,15,20-tetrakis( m -hydroxyphenyl) chlorin (temoporfin) were developed. Methods In order to determine the stability and therapeutic performance of the selected nanomaterials in physiological fluids, their physicochemical properties (i.e. size, polydispersity, zeta potential) were measured by dynamic light scattering technique and the diameter and the morphology of the individual particles were visualized by a transmission electron microscopy. Their efficacy was compared with commercial temoporfin formulation in terms of in vitro phototoxicity in 4T1 (murine mammary carcinoma) and of in vivo anticancer effect in Nu/Nu mice bearing MDA-MB-231 tumors. Results and conclusions The two types of silica nanoparticles, porous and non-porous and with different surface chemical modification, were involved and critically compared within the study. Their efficacy was successfully demonstrated and was shown to be superior in comparison with commercial temoporfin formulation in terms of in vitro phototoxicity and cellular uptake as well as in terms of in vivo anticancer effect on human breast cancer model. Temoporfin-loaded silica nanoparticles also passed through the blood-brain barrier showing potential for the treatment of brain metastases. [ABSTRACT FROM AUTHOR]

A new generator of two successive shock waves focused to a common focal point has been developed. Cylindrical pressure waves created by multichannel electrical discharges on two cylindrical composite anodes are focused by a metallic parabolic reflector - cathode, and near the focus they are transformed to strong shock waves. Schlieren photos of the focal region have demonstrated that mutual interaction of the two waves results in generation of a large number of secondary short-wavelength shocks. Interaction of the focused shockwaves with liver tissues and cancer cell suspensions was investigated. Localized injury of rabbit liver induced by the shock waves was demonstrated by magnetic resonance imaging. Histological analysis of liver samples taken from the injured region revealed that the transition between the injured and the healthy tissues is sharp. Suspension of melanoma B16 cells was exposed and the number of the surviving cells rapidly decreased with increasing number of shocks and only 8 % of cells survived 350 shocks. Photographs of cells demonstrate that even small number of shocks results in perforation of cell membranes. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has the potential to cure pancreatic cancer with minimal side effects. Visible wavelengths are primarily used to activate hydrophobic photosensitizers, but in clinical practice, these wavelengths do not sufficiently penetrate deeper localized tumor cells. In this work, NaYF 4 :Yb 3+ ,Er 3+ ,Fe 2+ upconversion nanoparticles (UCNPs) were coated with polymer and labeled with meta -tetra(hydroxyphenyl)chlorin (mTHPC; temoporfin) to enable near-infrared light (NIR)-triggered PDT of pancreatic cancer. The coating consisted of alendronate-terminated poly[ N , N -dimethylacrylamide- co -2-aminoethylacrylamide]- graft -poly(ethylene glycol) [P(DMA-AEM)-PEG-Ale] to ensure the chemical and colloidal stability of the particles in aqueous physiological fluids, thereby also improving the therapeutic efficacy. The designed particles were well tolerated by the human pancreatic adenocarcinoma cell lines CAPAN-2, PANC-1, and PA-TU-8902. After intratumoral injection of mTHPC-conjugated polymer-coated UCNPs and subsequent exposure to 980 nm NIR light, excellent PDT efficacy was achieved in tumor-bearing mice.

Hydrogels based on natural and modified polysaccharides represent growing group of suitable matrices for the construction of effective wound healing materials. Bioactive tripeptide glycyl-l-histidyl-l-lysine and amino acid α-l-arginine are known to accelerate wound healing and skin repair. In this study, hydrogels based on low-methoxyl amidated citrus pectin or flaxseed gum were prepared and used for the transport of these healing agents to the experimental cutting wounds affected by extensive skin damage. Fourier-transform infrared spectroscopy, rheology, differential scanning calorimetry, scanning electron microscopy, swelling and release tests confirmed that these hydrogels differed in structure and physical properties. The cationic tripeptide was found to bind to carboxylic groups in LMA pectin, and the C3OH hydroxyl and ring oxygen O5 are involved in this interaction. The pectin hydrogel showed high viscosity and strong elastic properties, while the flaxseed gum hydrogel was characterised as a viscoelastic system of much lower viscosity. The former hydrogel released the drugs very slowly, while the latter hydrogel demonstrated zero order releasing kinetics optimal for drug delivery. In the in vivo wound healing testing on rats, both polysaccharide hydrogels improved the healing process mediated by the mentioned biomolecules. The tripeptide applied in the hydrogels showed significantly higher healing degree and lower healing time than in the control animals without treatment and when it was applied in an aqueous solution. Despite the absence of a synergistic effect, the mixture of the tripeptide and α-l-arginine in the hydrogels was also quite effective in wound healing. According to histological analysis, complete healing was achieved only when using the tripeptide in the flaxseed gum hydrogel. These observations might have an important prospect in clinical application of polysaccharide hydrogels., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Photodynamic therapy (PDT) has garnered immense attention as a minimally invasive clinical treatment modality for malignant cancers. However, its low penetration depth and photodamage of living tissues by UV and visible light, which activate a photosensitizer, limit the application of PDT. In this study, monodisperse NaYF 4 :Yb 3+ /Er 3+ nanospheres 20 nm in diameter, that serve as near-infrared (NIR)-to-visible light converters and activators of a photosensitizer, were synthesized by high-temperature co-precipitation of lanthanide chlorides in a high-boiling organic solvent (octadec-1-ene). The nanoparticles were coated with a thin shell (≈3 nm) of homogenous silica via the hydrolysis and condensation of tetramethyl orthosilicate. The NaYF 4 :Yb 3+ /Er 3+ @SiO 2 particles were further functionalized by methacrylate-terminated groups via 3-(trimethoxysilyl)propyl methacrylate. To introduce a large number of reactive amino groups on the particle surface, methacrylate-terminated NaYF 4 :Yb 3+ /Er 3+ @SiO 2 nanospheres were modified with a branched polyethyleneimine (PEI) via Michael addition. Aluminum carboxyphthalocyanine (Al Pc-COOH) was then conjugated to NaYF 4 :Yb 3+ /Er 3+ @SiO 2 -PEI nanospheres via carbodiimide chemistry. The resulting NaYF 4 :Yb 3+ /Er 3+ @SiO 2 -PEI-Pc particles were finally modified with succinimidyl ester of poly(ethylene glycol) (PEG) in order to alleviate their future uptake by the reticuloendothelial system. Upon 980 nm irradiation, the intensive red emission of NaYF 4 :Yb 3+ /Er 3+ @SiO 2 -PEI-Pc-PEG nanoparticles completely vanished, indicating efficient energy transfer from the nanoparticles to Al Pc-COOH, which generates singlet oxygen ( 1 O 2 ). Last but not least, NaYF 4 :Yb 3+ /Er 3+ @SiO 2 -PEI-Pc-PEG nanospheres were intratumorally administered into mammary carcinoma MDA-MB-231 growing subcutaneously in athymic nude mice. Extensive necrosis developed at the tumor site of all mice 24-48 h after irradiation by laser at 980 nm wavelength. The results demonstrate that the NaYF 4 :Yb 3+ /Er 3+ @SiO 2 -PEI-Pc-PEG nanospheres have great potential as a novel NIR-triggered PDT nanoplatform for deep-tissue cancer therapy., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, we studied indolium and benzothiazolium pentamethine salts 1-3 as novel type of receptors for the recognition of sulphated signalling molecules (sulphated steroids: oestrone, pregnenolone and cholesterol sulphate). A recognition study was performed in an aqueous medium (1mM phosphate buffer (H2O:MeOH; 99:1 (v/v))) at pH 7.34. The tested salts displayed a high affinity for these sulphated analytes, mainly for cholesterol sulphate. However, no interaction between the salts and control, non-sulphated sterol analytes (cholesterol and bile acid) was observed. The highest affinity for the sulphated steroids was observed for benzothiazole salt 1. This salt also displayed different spectral behaviour from that observed for carbocyanine salts 2 and 3. In this presence of cholesterol sulphate, benzothiazole salt 1 displayed significant spectral changes depending on the medium used: a blue shift in the aqueous medium and a red shift in the methanolic one (H2O:MeOH; 2:1 (v/v)). Subsequently preliminary in vivo study showed that, salt 1 significantly inhibits a growth of breast carcinoma on Nu/nu mice model., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Proteinase-activated receptor 2 (PAR-2) is a ubiquitous surface molecule. It belongs to the family of G protein-coupled receptors activated by site-specific proteolysis by trypsin. Altered function of PAR-2 has been described in different malignant tumours, both in vivo and in vitro. In the present study, we investigated differences of metastatic spread of B16 melanoma in knock-out animals compared with C57Bl6 mice. Knock-out mice B6.Cg-F2rl1(tm1Mslb)/J (PAR2-/-) and C57Bl6 controls were subcutaneously inoculated with the B16 melanoma tissue cell line. Fourteen days after inoculation, all primary tumours were removed and histopathologically analysed. After one month, animals in both group started to die. Autopsy showed metastatic spread of the melanoma to various organs in both groups. Our experiment confirmed growth and metastatic spread in both groups of mice. Excised tumours differed in volume and weight; average weight (0.62 g in PAR2-/- and 0.4 g in control animals). Metastatic spread was observed in both groups and reached 80 % in PAR2-/- and 50 % in control animals. While in control mice only lung metastases were observed, local tumour recurrence, renal and lung metastases were observed in PAR2-/- mice. The absence of functional PAR-2 could be an important factor influencing the growth and spread of melanoma in vivo, probably associated with tumour cell migration, invasiveness and metastasis formation.

A general method for the synthesis of a novel porphyrin with pentamethine periphery substitution is described. The combination of two chromophoric systems, a porphyrin macrocycle and a polymethine moiety was achieved by transformation of tetrapyridyl porphyrin. The synthetic strategy included conversion of the tetrapyridyl porphyrin to its corresponding 2,4-dinitrophenylpyridinuim salt, which was subsequently converted to tetrakis(meso-pentamethinium salt) on the porphyrin core. This novel porphyrin exhibited PDT properties as manifested by the induction of apoptosis in the myeloid cell line HL-60 and the effective reduction of amelanotic melanoma in nude mice., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We present here a general system for the coordination attachment of therapeutic proteins to a drug delivery system and its application in combined therapy. Proof of concept is demonstrated by the synthesis and testing of the targeted drug delivery system for cytostatics, which is based on a combination of the drug carrier Zn-porphyrin-cyclodextrin conjugates and their supramolecular coordination complexes with immunoglobulins. This system can be as readily used for a variety of therapeutic and targeting proteins including PAs, MAs, lectins, and HSA. Moreover, it allows combined photodynamic therapy, cell targeted chemotherapy and immunotherapy. When tested in a mouse model with human C32 carcinoma, the therapeutic superiority of the coordination assembly nanosystem was shown in comparison with the efficacy of building blocks used for the construction of the system., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Biochemical and structural properties of three recombinant (R), highly homologous, plant bifunctional nucleases from tomato (R-TBN1), hop (R-HBN1) and Arabis brassica (R-ABN1) were determined. These nucleases cleave single- and double-stranded substrates, as well as both RNA and DNA with nearly the same efficiency. In addition, they are able to cleave several artificial substrates and highly stable viroid RNA. They also possess 3'-nucleotidase activity; therefore, they can be classified as nuclease I family members. Interestingly, poly(G) is resistant to cleavage and moreover it inhibits dsDNase, ssDNase and RNase activity of the studied nucleases. All three nucleases exhibit zinc-dependence and a strong stimulatory effect of Zn²+ for dsDNA cleavage. 3-D models, predicted on the basis of experimental structure of P1 nuclease, show nine amino acid residues responsible for interactions with zinc atoms, located in the same positions as in P1 nuclease. It was also shown that R-TBN1, R-HBN1, and R-ABN1 are all N-glycosylated. Oligosaccharidic chains constitute about 16% of their MW. In addition, an anticancer potential of the R-ABN1 is compared in this work with previously tested R-TBN1, and R-HBN1. R-ABN1 injected intravenously showed 70% inhibitory effect on growth of human prostate carcinoma in athymic mice., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Shock waves, pressure waves manifested as a sharp increase in positive pressure followed by a decrease and the negative part of the wave, are not only used to treat concrements in medicine. Recently, research has been focused on the possibility of their use for damaging the tumour tissue. In contrast to concrements, which are different from the surrounding tissue by their acoustic impedance, the tumour tissue has the same acoustic impedance as the surrounding soft tissue. Therefore, we have developed a new source of shock waves, which is based on the principle of multichannel discharge. This new source generates two successive shock waves (tandem shock waves). The first shock creates acoustic non-homogeneity and cavitations in the tissue, and the second shock is damped in it. In this work we demonstrated the effect of tandem shock waves on the muscle tissue in depth. The damage is shown on the images from the magnetic resonance imaging and histological sections. In the further part of the experiment, we investigated the in vivo effects of tandem shock waves in combination with Photosan and cisplatin on the tumour tissue. The application of tandem shock waves resulted in the inhibition of tumour growth, compared with controls, in both parts of the experiment. The largest inhibition effect was observed in the groups of tandem shock waves combined with Photosan and in the second part with cisplatin.