Maleimide-functionalised platinum(IV) complexes as synthetic platform for targeted drug delivery

Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour targeting molecules like human serum albumi

The impact of whole human blood on the kinetic inertness of platinum(IV) prodrugs - an HPLC-ICP-MS study

The potential advantage of platinum(IV) complexes as alternative to classical platinum(II)-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow was developed to investigate the reductive biotransformation and kinetic inertness of platinum(IV) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of the platinum(IV) complexes in blood pellet and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. An analytical approach based on reversed-phase (RP)-ICP-MS was used to monitor the parent compound and the formation of metabolites using two different extraction procedures. The ligand coordination sphere of the platinum(IV) complexes had significant impact on their accumulation in red blood cells and on their degree of kinetic inertness in whole human blood. The most lipophilic platinum(IV) compound featuring equatorial chlorido ligands showed a pronounced penetration into blood cells and a rapid reductive biotransformation. In contrast, the more hydrophilic platinum(IV) complexes with a carboplatin- and oxaliplatin-core exerted kinetic inertness on a pharmacologically relevant time scale with notable amounts of the compound accumulated in the plasma fraction

Kompleksi platine sa edda (etilendiamin-N, N'-diacetat) ligandima kao potencijalni antitumorski agensi

e design of platinum based drugs is not a new field of interest. Platinum complexes are widely used as anticancer agents and currently, approximately 30 platinum(II) and platinum(IV) entered into some of the phases of clinical trials. A special place in today’s research belongs to platinum complexes with diammine ligands. A large number of edda (ethylenediamine- N, N’-diacetate)-type ligands and their corresponding metal complexes has been successfully synthesized. is article summarizes recent progress in research on edda-type-platinum complexes. Some of these agents achieves better effect compared to the gold standard (cisplatin). It has been shown that there is a possible relationship between the length of the ligand ester group carbon chain and its cytotoxic effect. In most cases the longer the ester chain is the greater is the antitumor activity. Of particular interest are the noticeable effects of some new platinum compound with edda-type ligand on cell lines that are known to have a high level of cisplatin-resistance. Exanimate complexes appear to have a diff erent mode of mechanism of action compared with cisplatin which includes apoptotic and necrotic cell death. ere are indications that further investigations of these compounds may be very useful in overcoming the problems associated global cancer statistic. © 2016, University of Kragujevac, Faculty of Science. All rights reserved.Kompleski platine koriste se kao osnova za dizajn novih lekova. Oni su u širokoj upotrebi kao antitumorski agensi i do danas je oko 30 komplesa platine(II) i platine(IV) u nekoj od faza kliničkog ispitivanja. Posebno mesto u današnjim istaživanjima zauzimaju kompleksi metala sa edda ligandima. Uspešno je sintetisan veliki broj novih edda liganda i odgovarajućih kompleksa. Neki od ovih agensa pokazuju bolju aktivnost od zlatnog standarda, cisplatine. Pokazano je da postoji moguća veza između dužine ugljovodiničnog lanca estraske grupe liganda i citotoksičnog efekta. U većini slučajeva dužina lanca direktno korelira sa antitumorskom aktivnošću. Zabeležena je efikasnija citotoksicna aktivnost određenih kompleska platine sa edda ligandima na ćelijskim linijama tumora koji pokazuju odgovarajući stepen rezistencije na cisplatinu. Ispitivani komleksi imaju različit mehanizam dejstva od cisplatine, koji uključuje elemente nekrotične i programirane ćelijske smrti. Postoje nagoveštaji da dalja istraživanja ovih agensa mogu biti značajna za prevazilaženje globalnog problema sa kojim se svet danas suočava, a koji se odnosi na stalni porast osoba obolelih od karcinoma

On guanidinium and cellular uptake.

Guanidinium-rich scaffolds facilitate cellular translocation and delivery of bioactive cargos through biological barriers. Although impressive uptake has been demonstrated for nonoligomeric and nonpept(o)idic guanidinylated scaffolds in cell cultures and animal models, the fundamental understanding of these processes is lacking. Charge pairing and hydrogen bonding with cell surface counterparts have been proposed, but their exact role remains putative. The impact of the number and spatial relationships of the guanidinium groups on delivery and organelle/organ localization is yet to be established

Cellular uptake of modified aminoglycosides.

The uptake of modified amino- and guanidino-glycosides derived from kanamycin, tobramycin and neomycin in native and mutant CHO cells is examined using confocal microscopy and flow cytometry, illustrating the significance of multivalency for mammalian cell internalization of carriers that specifically interact with cell surface heparan sulfate proteoglycans.The Journal of Antibiotics advance online publication, 1 November 2017; doi:10.1038/ja.2017.131

GNeosomes: Highly Lysosomotropic Nanoassemblies for Lysosomal Delivery.

GNeosomes, lysosomotropic lipid vesicles decorated with guanidinoneomycin, can encapsulate and facilitate the cellular internalization and lysosomal delivery of cargo ranging from small molecules to high molecular weight proteins, in a process that is exclusively dependent on cell surface glycosaminoglycans. Their cellular uptake mechanism and co-localization with lysosomes, as well as the delivery, release, and activity of internalized cargo, are quantified. GNeosomes are proposed as a universal platform for lysosomal delivery with potential as a basic research tool and a therapeutic vehicle

Cellular uptake of modified aminoglycosides.

The uptake of modified amino- and guanidino-glycosides derived from kanamycin, tobramycin and neomycin in native and mutant CHO cells is examined using confocal microscopy and flow cytometry, illustrating the significance of multivalency for mammalian cell internalization of carriers that specifically interact with cell surface heparan sulfate proteoglycans.The Journal of Antibiotics advance online publication, 1 November 2017; doi:10.1038/ja.2017.131