Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant tetrapeptides based on the model opioid YRFK motif was studied. Two tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.

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In this study the effect of oxidative modification on micellar and drug deliveryproperties of copolymers of ethylene oxide (EO) and propylene oxide (PO) wasinvestigated. Carboxylated trifunctional copolymers were synthesized in the reaction withchromium oxide (VI). We found that carboxylation significantly improved the uniformityand stability of polymeric micelles by inhibiting the microphase transition. Thecytotoxicity of copolymers was studied in relation to their aggregative state on two celltypes (cancer line vs. primary fibroblasts). The accumulation of rhodamine 123 inneuroblastoma SH-SY5Y cells was dramatically increased in the presence of the oxidizedblock copolymer with the number of PO and EO units of 83.5 and 24.2, respectively. Thecopolymer was also tested as an enhancer for topical drug delivery to the spinal cordwhen applied subdurally. The oxidized copolymer facilitated the penetration ofrhodamine 123 across spinal cord tissues and increased its intraspinal accumulation.These results show the potential of using oxidized EO/PO based polymers for noninvasivedelivery of protective drugs after spinal cord injury

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