Highly Efficient, Nonpeptidic Oligoguanidinium Vectors that Selectively Internalize into Mitochondria

Abstract

Oligoguanidinium-based cell delivery systems have gained broad interest in the drug delivery field since one decade ago. Thus, arginine-containing peptides as Tat or Antp, oligoarginine peptides, and derived peptoids have been described as shuttles for delivering nonpermeant drugs inside cancer cells. Herein we report a new family of tetraguanidinium cell penetrating vectors efficiently internalized in human tumor cells. Their high internalization, studied by confocal microscopy and flow cytometry, as well as their specific accumulation in mitochondria makes these new vectors likely vehicles for the targeted delivery of anticancer drugs to mitochondria.

Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90

“…These data suggest that the cytosolic transfer of Shepherdin may be long enough to mediate inhibition of Hsp90 activity in the cytosol followed by mitochondrial accumulation. Conversely, 2 structurally unrelated small molecule moieties, TPP-OH (28) or tandem repeats of cyclic guanidinium (27), mediated fast mitochondrial targeting of Gamitrinibs, which prevented inhibition of cytosolic Hsp90. These data have important practical implications for drug delivery in vivo.…”

The design of guanidinium-rich transporters and their internalization mechanisms

“…Multiple phosphate-modified deoxynucleic guanidines (39) in which negative phosphodiester linkages of DNA are replaced with guanidinium groups have been reported by Bruice and coworkers. In addition to being highly nuclease resistant, these compounds also have high binding affinities and specificities for various duplex formations [45,46,47].…”

“…Mendoza and coworkers recently reported a new family of tetraguanidinium compounds 35, in which bicyclic guanidinium subunits are linked by thioether spacers [39]. The cellpenetrating ability of the conjugates was studied in HeLa cells by confocal microscopy (both in living and fixed cells) and FACS analysis after a 1-hour incubation.…”

Mitochondrial Affinity of Guanidine-rich Molecular Transporters Built on myo- and scyllo-Inositol Scaffolds: Stereochemistry Dependency

“…In efforts to improve upon these limitations, several different types of synthetic molecular transporters (MTs), e.g. peptoids, 6 oligocarbamates, 7 β-peptides, 8 peptide nucleic acids, 9 and others [10][11][12][13] have been investigated. Recently we have explored novel classes of synthetic molecular transporters, in which multiple units of the guanidine functionality are attached through linear or branched chain carboxylate linkers to various scaffolds such as inositol dimers, sorbitol, lactose, and sucrose.…”