Synthesis of cationic carbosilane dendrimers via click chemistry and their use as effective carriers for DNA transfection into cancerous cells.

New amine-terminated carbosilane dendrimers have been prepared by a Huisgen cycloaddition ("click chemistry" reaction) of azide-terminated carbosilane dendrimers with two different propargyl amines. The corresponding cationic derivatives with peripheral ammonium groups were obtained by subsequent addition of MeI. Quaternized dendrimers are soluble and stable in water or other protic solvents for long time periods, and have been studied as nonviral vectors for the transfection of DNA to cancer cells. In this study DNA-dendrimeric nanoparticles (dendriplexes) formulated with two different families of cationic carbosilane dendrimers (family 1 (G1, G2 and G3) and family 2 (G1, G2)) were characterized and evaluated for their ability to transfect cells in vitro and in vivo. Dendriplex derived from second generation dendrimer of family 1 (F1G2 5/1 (+/-)) increased the efficiency of plasmid-mediated gene transfer in HepG2 cells as compared to naked DNA and the commercial control dendrimer. Also, intravenously administered dendriplex F1G3 20/1 (+/-) is superior in terms of gene transfer efficiency in vivo.

Synergistic activity of carbosilane dendrimers in combination with maraviroc against HIV in vitro.

OBJECTIVE: Dendrimers have been shown as effective and safe anti-HIV compounds with great potential as topical microbicides. Currently, the most advanced microbicides are based on antiretrovirals. However, nowadays none of them has shown any success in clinical trials. DESIGN: Antiviral activity and combinatorial profile of different combinations between CCR5 co-receptor antagonist, maraviroc (MRV), and polyanionic carbosilane dendrimers against HIV-1 strains were evaluated. METHODS: Cellular in-vitro models were used to evaluate the antiviral action of combinations of carbosilane dendrimers/MRV against CCR5 and dual tropic viral strains in TZM.bl cells and peripheral blood mononuclear cells. Combinatorial analysis was performed using Calcusyn software. RESULTS: In the majority of combinations tested, dendrimers showed synergistic profile with MRV against CCR5 and dual tropic HIV-1. CONCLUSION: The evaluated two-drug combinations increase their antiviral potency supporting further clinical investigations to develop combinatorial formulated topical microbicides to fight against the worldwide HIV spread.

Development of sulphated and naphthylsulphonated carbosilane dendrimers as topical microbicides to prevent HIV-1 sexual transmission.

OBJECTIVES: For the last 20 years, the idea of alternative prevention strategies based on the use of topical vaginally products to inhibit HIV-1 infection in women has been established. The concept of a 'microbicide' product has been born out of the unavailability of a vaccine against HIV-1 and the problems of women in negotiating the use of preventive prophylaxis by their partners, especially in developing countries. DESIGN: We have developed and evaluated polyanionic carbosilane dendrimers G3-S16 and G2-NF16 with sulphated and naphthylsulphonated end groups as nonspecific microbicides. METHODS: Cellular in-vitro or in-vivo models were used to evaluate the safety, biocompatibility and anti-HIV ability of two polyanionic carbosilane dendrimers. RESULTS: Both dendrimers showed high biosafety in human epithelial cell lines derived from uterus and vagina and in primary blood human cells (PBMC). These dendrimers not only have a partial capacity to block the entry of different X4 and R5 HIV-1 isolates inside epithelial cells but protect the epithelial monolayer from cell disruption and also reduce HIV-1 infection of activated PBMC. Additionally, treatment of epithelial cells with G3-S16 or G2-NF16 dendrimers did not produce changes in proinflammatory cytokines profile, in proliferation of PBMC, on microbiota or sperm survival. Finally, no irritation or vaginal lesions were detected in female CD1(ICR) mice after dendrimers vaginal administration. CONCLUSION: These interesting results suggest that G3-S16 or G2-NF16 could be effective to inhibit HIV infection and transmission within genital mucosa as well as the spread of HIV transmission to human PBMC.