Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery

Abstract

In order to find new efficient and safe agents for gene delivery, we have designed and synthesized nine novel single- and double-charged amphiphiles on the base of 1,4-dihydropyridine (1,4-DHP) ring. Some biophysical properties of the amphiphilic dihydropyridines and their complexes with DNA were examined. We investigated the transfer of beta-galactosidase gene into fibroblasts (CV1-P) and retinal pigment epithelial (D 4O7) cell lines in vitro. The structure-property relationships of the compounds were investigated in various ways. The net surface charges of 1,4-DHP liposomes were highly positive (25-49 mV). The double-charged compounds condensed DNA more efficiently than single-charged and the condensation increases with the increasing +/- charge ratio between the carrier and DNA. Double-charged compounds showed also buffering properties at endosomal pH and these compounds were more efficient in transfecting the cells, but transfection efficiency of amphiphiles was cell type-dependent. The length of alkyl chains in double-charged compounds affected the transfection efficacy. The most active amphiphile (compound VI) was double-charged and had two C(12) alkyl chains. At optimal charge ratio (+/- 4), it was 2.5 times more effective than PEI 25 and 10 times better than DOTAP, known efficient polymeric and liposomal transfection agents. Formulation of amphiphiles with DOPE did not change their activities. Our data demonstrate some important effects of amphiphile structure on biophysics and activity. The data also suggest that cationic amphiphilic 1,4-DHP derivatives may find use as DNA delivery system.

Neural retina limits the nonviral gene transfer to retinal pigment epithelium in an in vitro bovine eye model

“…Dividing, nondifferentiated primary 21,22 and secondary RPE cells (D407) 30,31 can be transfected successfully with many liposomal and polymeric vectors but the efficacy of in vivo transfection of rat retina and RPE cells is very low after intravitreal administration (L.P., unpublished data, 2000). Understanding of the limiting barriers should Figure 4.…”

A QSAR‐modeling perspective on cationic transfection lipids. 1. Predicting efficiency and understanding mechanisms

“…However, a conservative approach was used since no widely applicable, firstprinciples comparisons between cationic lipids are possible, given the wide variations of experimental protocols. Representative papers noting the additional effective cationic lipids are those of [18], [22][23][24][25], [27], and [36][37][38][39][40][41][42][43][44][45][46][47][48].…”

“…[21]) have focused on the influence of a variety of structural motifs. These include the optimal chain length of alkyl chains [22], the number [23] or presence [24] of unsaturated bonds in these chains, the number of cationic groups [25] and their pH sensitivity [26], and the presence of hydroxy substituents [27], in the hydrophilic headgroup. Whilst such motifs correlate with transfection efficacy within limited groups of compounds, no widely applicable rules have emerged distinguishing effective from ineffective cationic lipids.…”

Molecular basis of applying antimutagens as anticarcinogens

“…Кроме того, установлены иммунно протекторные и нейромодулиру ющие эффекты препаратов нового поколения (глутапи рона, цереброкраста) [82,93]; цереброкраст также про являет противовоспалительную активность [81]. Кро ме того, новые производные 1,4 ДГП могут служить средствами доставки ДНК [71].…”