Synthesis of a new dendritic anfiphilic polyester with pentaerythritol core and a multifunctional periphery for linking amino acids and for using in gene therapy

Dendrimers are synthetic polymers characterized by tree-like branched symmetric structure, globular shape, low polydispersity and several functions at the periphery which allow further functionalization. Their cavities can accommodate small drugs molecules protecting them from premature degradation, increasing their solubility in biological fluids, decreasing their toxicity and favoring their bioavailability. Dendrimers containing protonable nitrogen atoms can electrostatically bind nucleic acids. These reasons make dendrimers appealing materials for various biomedical applications such as drug or gene delivery non viral carriers, biosensors, bioimaging agents and theranostics. Well known polymeric systems such as bPEI or PAMAM are among the most investigated synthetic vectors with efficient transfection activity but also affected by high cytotoxicity so chemical modifications are required to reduce these drawbacks and allow a real use in gene therapy. It is known that amino acids (1, 2, 3) or peptides (4) were often used for these purposes and arginine is known to improve siRNA cellular uptake (5), efficiency of transfection and to reduce toxicity (6, 7). Hydrophobic segments in the dendrimer structure are also important in the internalization process (3) and may contribute to reduce toxicity caused by high ionic character of vectors. Looking at this background in this communication we report the step-wise protocol and NMR characterization of a new hydrolysable polyester-based dendrimer of third generation built on penthaerithritol as core and with a C-18 saturated alkyl chain as hydrophobic segment. The peripheral 24 OH groups make this anfiphilic dendritic structure fit to the esterification with selected amino acids for obtaining polycationic non viral vectors to use in gene delivery. References: 1. Navath, R. S.; Menjoge, A. R.; Wang, B.; Romero, R.; Kannan, S.; Kannan, R. M. Biomacromolecules 2010, 11, 1544-1536. 2. Park, J.; Park, H.; Park, J-S.; Choi, J. S. Macromol. Res. 2014, 22, 500-508. 3. Wang, F.; Wang, Y.; Wang, H.; Shao, N.; Chen, Y.; Cheng, Y. Biomaterials 2014, 35, 9187-9198. 4. Lam, S. J.; Sulistio, A.; Ladewig, K.; Wong, E. H. H.; Blencowe, A.; Qiao, G. G. Austr. J. Chem. 2014, 67, 592-597. 5. Liu, X.; Liu, C.; Zhou, J.; Chen, C.; Qu, F.; Rossi, J. J.; Rocchi, P.; Peng L. Nanoscale 2015, 7, 3867-3875. 6. Kim, T.; Bai, C. Z.; Nam, K.; Park, J. J. Control. Release 2009, 136, 132-139. 7. Peng, Q.; Zhu, J.; Yu, Y.; Hoffman, L.; Yang, X. J. Biomater. Sci. Polym. Ed. 2015, 26, 1163-1177