Phosphonium carbosilane dendrimers – interaction with a simple biological membrane model

Abstract

The influence of three generations of five different phosphonium carbosilane dendrimers and one ammonium carbosilane dendrimer as a reference (PMe3, PBu3, P(Et2)2(CH2)3OH, PPh3, P(MeOPh)3 and NMe3, peripheral functional groups) on dimyristoylphosphatidylcholine (DMPC) or a lipid mixture dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) of liposomes was studied by fluorescence polarization measurements and differential scanning calorimetry. All types of dendrimers interacted with neutral as well as negatively charged liposomes, but the strength and observed influence were different. Concentration, type of peripheral functional group modification and dendrimer generation were the main factors influencing the interaction. Generally, weak interactions as well as destabilization of the lipid membranes at low concentrations, regardless of liposome type, were observed in the case of DmPMe3, DmNMe3, DmPBu3 and DmP(Et2)2(CH2)3OH. Dendrimers with PPh3 and P(MeOPh)3 peripheral functional groups interacted much more strongly and increased the rigidity of liposomes. Electrostatic interactions, the hydrophobicity of substituents and charge shielding on the peripheral phosphonium group are important factors in the interaction. We suggest that, among the other types of dendrimers, the dendrimer with the P(MeOPh)3 peripheral functional group is a highly promising candidate for the design of a drug delivery system due to its positive charge, efficient interaction with lipidic membranes and low cytotoxicity.

Biodistribution and toxicity assessment of methoxyphenyl phosphonium carbosilane dendrimers in 2D and 3D cell cultures of human cancer cells and zebrafish embryos

“…The mitochondrial localization of PhO is consistent with earlier predictions based on our 2D culture assays 20 . The cationic and lipophilic nature of PhO dendrimer 21 is essential for any mitochondria-targeting molecule 44 . MTT assay IC 50 values suggested a higher toxicity of the dendrimer for the mitochondria of cancer cells compared to non-cancer cells (Fig.…”

“…The third-generation cationic carbosilane dendrimer used in this work was functionalized with the methoxyphenyl-phosphonium -P(C 6 H 4 -OMe) 3 peripheral substituents. The preparation protocols, structural features, and thorough characterization of these dendrimers were previously described in detail elsewhere 20 , 21 . For the experiments, the dried PhO powder was directly mixed into cell culture media and zebrafish embryo water, taking advantage of its excellent solubility.…”

“…The methoxyphenyl phosphonium dendrimer (PhO) emerged as a compound of interest in our previous research 20 , 21 , exhibiting attributes that highlight its potential as a promising mitochondria-targeting vector in cancer cell delivery of therapeutics. A series of experiments conducted across diverse non-cancer mammalian cell lines revealed its relatively low cytotoxicity, a feature that was consistently observed in both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and Crystal Violet (CV) assays 20 .…”

“…Our prior investigations led us to propose a mechanism that attributes the low cytotoxicity of the PhO dendrimer to a specific electronic configuration facilitated by its unique structure. The presence of three electron-donating methoxy groups in para positions appears to instigate a delocalization of the positive charge on the phosphorus atoms, thereby mitigating potentially toxic interactions with cellular structures such as the cell membrane and intracellular proteins 20 , 21 . Additionally, PhO dendrimer displayed an enhanced water solubility of more than 100 mg/mL.…”

Use of Polyamidoamine Dendrimers in Brain Diseases

“…There are many different types of dendrimers that have been synthesized with potential uses in the treatment of brain diseases. Examples include carbosilane dendrimers, polylysine dendrimers, phosphorus-containing dendrimers, and PAMAM dendrimers [ 11 , 12 , 13 ].…”