Design and synthesis of biologically active cationic amphiphiles built on the calix[4]arene scaffold

• Published in: International journal of pharmaceutics 2018-10, Vol.549 (1-2), p.436-445
• Main Authors: Bono, Nina, Pennetta, Chiara, Sganappa, Aurora, Giupponi, Elisa, Sansone, Francesco, Volonterio, Alessandro, Candiani, Gabriele
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Aminoglycosides; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Binding Sites; Calixarenes; Calixarenes - chemical synthesis; Calixarenes - metabolism; Calixarenes - pharmacology; DNA - chemistry; DNA - metabolism; Drug Design; Escherichia coli - drug effects; Escherichia coli - growth & development; Gene Expression Regulation; HeLa Cells; Humans; Lipoplexes; Molecular Structure; Non-viral gene delivery vectors; Nucleic Acid Conformation; Phenols - chemical synthesis; Phenols - metabolism; Phenols - pharmacology; Sarcina - drug effects; Sarcina - growth & development; Structure-Activity Relationship; Surface Properties; Surface-Active Agents - chemical synthesis; Surface-Active Agents - metabolism; Surface-Active Agents - pharmacology; Transfection; Transfection - methods
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2018.08.020

[Display omitted] A promising strategy to design safer and more effective cationic lipids for gene delivery with inherent antibacterial properties is to covalently tether a lipophilic moiety with oligomeric aminoglycosides (AGs), a large family of Gram-negative-active antibiotics. Herein, we reported the development of a new class of multicationic-head AG-based amphiphiles built on the tetramino-tetrahexyloxycalix[4]arene (4A4Hex-calix-calix[4]) scaffold. Three different conjugates, namely 4A4Hex-calix-calix[4]-neomycin, -neamine, and -paromomycin, were synthesized and characterized. Due to the inherent multivalency of AGs and the amphiphilic behaviour, every 4A4Hex-calix-calix[4]-AG exhibited greater DNA binding ability than the gold standard transfectant 25 kDa bPEI and striking DNA packing ability. DNA/4A4Hex-calix-calix[4]-AG complexes at charge ratios (CRs, +/−) used for transfections displayed good colloidal stability, with a hydrodynamic diameters of ≈150 nm and an overall surface charges of ≈+30 mV. DNA/4A4Hex-calix[4]-AGs nanoassemblies, everyone tested at the optimal CR, invariably showed good transfection efficiency in two cell lines, along with low-to-negligible cytotoxicity. Besides, DNA/4A4Hex-calix-calix[4]-AG complexes exhibited appreciable antimicrobial activity against Gram-negative bacteria, even greater than uncomplexed 4A4Hex-calix-calix[4]-AGs. Altogether, these results disclose 4A4Hex-calix[4]-AGs as promising gene delivery tools with unique antibacterial properties.