RESUMO
New pH-sensitive lipids were synthesized and utilized in formulations of liposomes suitable for controlled drug release. These liposomes contain various amounts of NaCl in the internal aqueous compartments. The release of the drug model is triggered by an application of HCl cotransporter and exogenous physiologically relevant NaCl solution. HCl cotransporter allows an uptake of HCl by liposomes to the extent of their being proportional to the transmembrane Cl(-) gradient. Therefore, each set of liposomes undergoes internal acidification, which, ultimately, leads to the hydrolysis of the pH-sensitive lipids and content release at the desired time. The developed system releases the drug model in a stepwise fashion, with the release stages separated by periods of low activity. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be nontoxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug-release model potentially suitable for in vivo applications.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Lipossomos/administração & dosagem , Cloreto de Sódio/química , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Humanos , Concentração de Íons de Hidrogênio , Lipídeos/síntese química , Lipossomos/efeitos adversos , Lipossomos/química , Simportadores de Cloreto de Sódio/administração & dosagem , Simportadores de Cloreto de Sódio/química , Soluções/administração & dosagem , Soluções/químicaRESUMO
Natural terpene quinone methides (QM) and their derivatives have been investigated as therapeutics due to their broad antifungal, antibacterial, and antitumor activities. Recently, we reported that a terpene QM was formed from the catechol precursor through the disproportionation of Cu(II)/(I) redox cycle, and extensive DNA damage was observed throughout the oxidation process. In this paper, we investigate DNA damage with a series of terpene catechols as analogues of natural QM precursors and suggest that reactive oxygen species (ROS) are responsible for the observed DNA damage in the Cu(2+)-induced oxidation despite the stereo- and structural difference of these catechol or subsequent oxidation products. In addition, the presence of NADH significantly enhanced the extent of DNA damage by oxidation of these catechols. Especially with alkene catechols 6-7, the extent of DNA damage was independent of the concentration of catechols, implying that NADH enables the continuous production of ROS through the redox cycle of catechols/quinones.