Water‐Soluble Carbosilane Dendrimers: Synthesis Biocompatibility and Complexation with Oligonucleotides; Evaluation for Medical Applications

Abstract

Novel amine- or ammonium-terminated carbosilane dendrimers of type nG-[Si{OCH2(C6H3)-3,5-(OCH2CH2NMe2)2}]x, nG-[Si{O(CH2)2N(Me)(CH2)2NMe2}]x and nG-[Si{(CH2)3NH2}]x or nG-[Si{OCH2(C6H3)-3,5-(OCH2CH2NMe3 +I-)2}]x, nG-[Si{O(CH2)2N(Me)(CH2)2NMe3 +I-}]x, and nG-[Si{(CH2)3NH3 +Cl-}]x have been synthesized and characterized up to the third generation by two strategies: 1) alcoholysis of Si--Cl bonds with amino alcohols and subsequent quaternization with MeI, and 2) hydrosilylation of allylamine with Si--H bonds of the dendritic systems and subsequent quaternization with HCl. Quaternized carbosilane dendrimers are soluble in water, although degradation is apparent due to hydrolysis of Si--O bonds. However, dendrimers containing Si--C bonds are water-stable. The biocompatibility of the second-generation dendrimers in primary cell cultures of peripheral blood mononuclear cells (PBMCs) and erythrocytes have been analyzed, and they show good toxicity profiles over extended periods. In addition, we describe a study on the interactions between the different carbosilane dendrimers and DNA oligodeoxynucleotides (ODNs) and plasmids along with a comparative analysis of their toxicity. They can form complexes with DNA ODNs and plasmids at biocompatible doses via electrostatic interaction. Also a preliminary transfection assay has been accomplished. These results demonstrate that the new ammonium-terminated carbosilane dendrimers are good base molecules to be considered for biomedical applications.

Novel water soluble dendrimer nanocarrier for enhanced photodynamic efficacy of protoporphyrin IX

“…Despite successful talk on drug encapsulation and the biocompatibility of dendrimers, the fate of dendrimer is to readily degrade from the body as a non-toxic product after its administration [25]. Many of the reports have been reported the problem of cytotoxicity with amine and ammonium terminated cationic dendrimers and affirmed that when compared to cationic surface functionality dendrimers, anionic (carboxyl and hydroxyl terminated) dendrimers are believed to be non-toxic on primary cell lines [26,27].…”

Changes in Gene Expression Pattern of Human Primary Macrophages Induced by Carbosilane Dendrimer 2G-NN16

“…One of these dendrimers in which we are interested-2G-NN16-is a molecule capable of binding to antisense oligonucleotides (ODNs), siRNAs, plasmids and peptides by a union that is degraded over a period of 24 h, resulting in a gradual release of the transported molecule. Moreover, the nucleic acid, when bound to the dendrimer, is protected from BSA binding, which allows higher effective concentrations of siRNA or ODNs to be maintained in the blood-stream (6).…”

“…Promising results have been obtained in vitro using 2G-NN16 carbosilane dendrimer as a vehicle for nucleic acids (6,10). In our laboratory, 2G-NN16 has been shown to be superior than commercial dendrimers, such as PAMAM (polyamidoamine) or superfect, when primary cell lines such as peripheral blood mononuclear cells (PBMCs) are transfected with siRNA.…”

“…Furthermore, the possibility to direct the drug to specific cell types by complexing the dendrimer with a specific antibody has been demonstrated (5). Another biomedical application is their use in imaging, for example (6) by monitoring the cardiovascular system, liver or kidney function and for imaging tumor vasculature (7). The mononuclear phagocytic system, principally macrophages, plays a central role in the host defence system.…”

“…In our laboratory, 2G-NN16 has been shown to be superior than commercial dendrimers, such as PAMAM (polyamidoamine) or superfect, when primary cell lines such as peripheral blood mononuclear cells (PBMCs) are transfected with siRNA. Toxicity assays (MTT, LDH, Trypan blue) in multiple primary and established cell lines have been conducted demonstrating a low effect on cellular viability at variable concentrations (6). However, toxicity assays studying how the delivery reagents affect gene expression are not routinely performed.…”