Interaction of ions Pt2+ and Pd2+ with transmembrane potential drug carriers

Wykorzystanie kompleksów metali o uznanej aktywności cytotoksycznej w terapii antynowotworowej obarczone jest szeregiem negatywnych skutków ubocznych wynikających przede wszystkim z niewielkiej selektywności komórkowej. Celem niniejszej pracy było zbadanie możliwości połączenia tych kompleksów ze związkami selektywnie wchłanianymi i akumulującymi się w komórkach nowotworowych. Wykazano, że takie połączenia pomiędzy Pt2+/Pd2+ a witaminą B12 posiada właściwości korzystne z punktu widzenia potencjalnego zastosowania w chemioterapii. Decydują o tym przede wszystkim względna trwałość w warunkach fizjologicznych przy równoczesnej łatwości wymuszonej dysocjacji leku. Znaczna reaktywność względem guaniny w stosunku do prostych kompleksów Pt2+ i Pd2+ może zapewniać doskonały nośnik leku do komórek nowotworowych.The use of metal complexes of the recognized cytotoxic in the antitumor therapy is encumbered with a number of adverse side effect resulting primary from very limited cellular selectivity. The aim of this study was to examine the possibilities os combining these complexes with compounds that reveal increased absorption and accumulation in the cancer cells. It has been shown that binding of Pt2+/Pd2+ to vitamin B12 has advantagegeous properties in terms of potential use in chemotherapy. They are determined primarily by the relative stability under physiological conditions while maintaining the ease of a forced dissociation of the drug. The appreciable reactivity towards guanine compared to simple Pt2+ and Pd2+ complexes, can provide additional protection of healthy cells

Synthesis and characterization of cobalamin complexes with selected bridging ligands as the basis for new carrier-drug systems.

Chemioterapia będąca wciąż podstawową metodą wspomagającą leczenie nowotworów obarczona jest wieloma skutkami ubocznymi. Wynikają one z niskiej selektywności stosowanych leków cytotoksycznych, co sprawia, że akumulują się one zarówno w komórkach nowotworowych jak i w komórkach zdrowych. Toksyczność tych leków ogranicza się poprzez użycie nośników, takich jak witamina B12¬, wykazujących zwiększone powinowactwo do komórek nowotworowych. Celem niniejszej pracy była synteza i charakterystyka kompleksów witaminy B12 z ligandami mostkowymi, mającymi ograniczyć akumulację leków w komórkach zdrowych. W toku przeprowadzonych badań otrzymano połączenia z wybranymi ligandami (etylenodiamina, imidazol, kwas glutaminowy, kwas 2,6-dipikolinowy, piperazyna). Powstałe kompleksy wykazują względną trwałość w warunkach fizjologicznych oraz obniżoną przy niskim pH, charakterystycznym dla komórek nowotworowych. Obserwacja ta może być wykorzystana przy planowaniu mechanizmu uwalniania leku wewnątrz komórki. Wyniki przeprowadzonych badań pilotażowych dotyczących łączenia z kompleksami Pt2+ jak i obliczeń teoretycznych metodą DFT stanowią przesłanki ku możliwości utworzenia funkcjonalnych połączeń nośnik-lek.Chemotherapy, which is still the basic clinical method supporting cancer treatment, has many side effects. They result from low selectivity of the cytotoxic drugs, which makes them accumulate in cancer cells and healthy cells. Toxicity of these drugs is limited by the use of carriers, such as vitamin B12, which have increased affinity for cancer cells. The aim of this work was the synthesis and characterization of B12 complexes with bridging ligands that can be used to reduce the accumulation of drugs in healthy cells. In the course of the studies we managed the complexes with selected ligands (ethylenediamine, imidazole, glutamic acid, 2,6-dipicolinic acid, piperazine) have been obtained. They exhibit relative stability under physiological conditions which decreases at low pH, characteristic of tumor cells. This can be used as a potential mechanism of drug release inside the cell. The results of preliminary experiments concerning binding with Pt2+ complexes as well as the results of theoretical calculations using the DFT method provide the premises for the possibility of obtaining the functional carrier-drug systems

The nature of parent-offspring relations amongst representatives of Homininae and Ponginae

W obrębie ssaków młode charakteryzuje się całkowitym niedostosowaniem do samodzielnego życia, oraz bezwzględną koniecznością rodzicielskiej opieki w początkowych jego fazach. Opieka rodzicielska, przede wszystkim żywienie i ochrona młodych, ma kluczowe znaczenie dla przetrwania oraz prawidłowego rozwoju zarówno fizycznego, jak i psychospołecznego młodych. Szczególnie interesująca przedstawia się wśród przedstawicieli podrodziny Homininae, biorąc pod uwagę podobieństwa z jedynym przedstawicielem gatunku człowieka (Homo sapiens).Niniejsza praca zwiera charakterystykę zachowań rodzicielskich wobec potomstwa. Analiza została oparta względem trzech rodzajów człowiekowatych.Amongst habitat of mammals, cub is totally unable to survive on their own and it demands absolute parenting in the early stages of its development.. Parenting and most of all nutrition and protection have the most crucial meaning for a cub to survive and to develop proper physical and psycho-social traits. Herein described parenting is especially interesting amongst representatives of subfamily of Homininae, considering similarities with the only one representative of human species (Homo sapiens). This paper describes the nature of parental behavior towards children. The analysis was based on respect of the three types of hominids

Ligand-tuning of the stability of Pd(II) conjugates with cyanocobalamin

Besides the well-known functions performed by vitamin B(12) (CblCN) in biochemical processes of the human body, an increasing interest has been raised by the possibility of its use as a transmembrane drug carrier, capable, among others, of enhancing the accumulation of inorganic cytostatics in cancer cells. The present study was aimed at determining the possibility of the formation of CblCN conjugates with Pd(II) complexes. A key aspect was their stability, which we attempted to tune by appropriate choice of ligands. Syntheses, spectroscopic analysis of postreaction systems and kinetic investigations of conjugate formation reactions, have been complemented by DFT modelling. The obtained results showed that ligand charge, geometry and electron affinity may have a significant impact on carrier binding and release leading to the activation of the Pd(II) complex. This provides a rationale to expect that with appropriate composition of the coordination sphere, it will be possible to extend the spectrum of less toxic inorganic chemotherapeutics

High-pressure mechanistic insight into bioinorganic NO chemistry

Pressure is one of the most important parameters controlling the kinetics of chemical reactions. The ability to combine high-pressure techniques with time-resolved spectroscopy has provided a powerful tool in the study of reaction mechanisms. This review is focused on the supporting role of high-pressure kinetic and spectroscopic methods in the exploration of nitric oxide bioinorganic chemistry. Nitric oxide and other reactive nitrogen species (RNS) are important biological mediators involved in both physiological and pathological processes. Understanding molecular mechanisms of their interactions with redox-active metal/non-metal centers in biological targets, such as cofactors, prosthetic groups, and proteins, is crucial for the improved therapy of various diseases. The present review is an attempt to demonstrate how the application of high-pressure kinetic and spectroscopic methods can add additional information, thus enabling the mechanistic interpretation of various NO bioinorganic reactions

The diverse dependence of galectin-1 and -8 on multivalency for the modulation of FGFR1 endocytosis

Abstract Fibroblast growth factor receptor 1 (FGFR1) is a N-glycosylated cell surface receptor tyrosine kinase, which upon recognition of specific extracellular ligands, fibroblast growth factors (FGFs), initiates an intracellular signaling. FGFR1 signaling ensures homeostasis of cells by fine-tuning essential cellular processes, like differentiation, division, motility and death. FGFR1 activity is coordinated at multiple steps and unbalanced FGFR1 signaling contributes to developmental diseases and cancers. One of the crucial control mechanisms over FGFR1 signaling is receptor endocytosis, which allows for rapid targeting of FGF-activated FGFR1 to lysosomes for degradation and the signal termination. We have recently demonstrated that N-glycans of FGFR1 are recognized by a precise set of extracellular galectins, secreted and intracellular multivalent lectins implicated in a plethora of cellular processes and altered in immune responses and cancers. Specific galectins trigger FGFR1 clustering, resulting in activation of the receptor and in initiation of intracellular signaling cascades that shape the cell physiology. Although some of galectin family members emerged recently as key players in the clathrin-independent endocytosis of specific cargoes, their impact on endocytosis of FGFR1 was largely unknown. Here we assessed the contribution of extracellular galectins to the cellular uptake of FGFR1. We demonstrate that only galectin-1 induces internalization of FGFR1, whereas the majority of galectins predominantly inhibit endocytosis of the receptor. We focused on three representative galectins: galectin-1, -7 and -8 and we demonstrate that although all these galectins directly activate FGFR1 by the receptor crosslinking mechanism, they exert different effects on FGFR1 endocytosis. Galectin-1-mediated internalization of FGFR1 doesn’t require galectin-1 multivalency and occurs via clathrin-mediated endocytosis, resembling in this way the uptake of FGF/FGFR1 complex. In contrast galectin-7 and -8 impede FGFR1 endocytosis, causing stabilization of the receptor on the cell surface and prolonged propagation of the signals. Furthermore, using protein engineering approaches we demonstrate that it is possible to modulate or even fully reverse the endocytic potential of galectins