Hydrophilic and amphiphilic water-soluble dendrimer formulations of a not-soluble thiocarbamate derivative with moderate anti HIV activity for biomedical applications.

The engineered technology known as Drug delivery concerns the approaches, formulations, technologies and systems for transporting therapeutics in the body and delivering them as needed. Advanced controlled Drug Delivery Systems (DDSs) able to release an effective load of drug and to maintain its concentration for long time in a limited area around the target site have been developed. These “smart” DDSs allowed to reduce dosages, administrations frequency and drugs toxicity and to improve therapeutic efficacy. Nanosized and dendritic polycationic polymers such as PAMAMs are the most exploited materials for getting advanced smart DDSs and can covalently bind or encapsulate drugs. However, the high number of protonable nitrogen atoms widespread on the whole matrix involves high cytotoxicity. The modern research is increasingly oriented towards the use of not charged dendrimer scaffolds decorated with biocompatible amino acids protonable at physiological pH. Thiocarbamate 1 (Figure 1) is a non-nucleoside HIV-1 reverse transcriptase inhibitor (EC50 = 27 µM) characterized by a free carboxylic group and endowed with poor water solubility.1 With the aim at improving both its solubility and activity, derivative 1 was physically incorporated inside not-toxic amino acid-modified core-shell hydrophilic (2,3)2 and amphiphilic (4-6)3 dendrimers. The encapsulation procedure is a straightforward protocol that involves stirring derivative 1 and the starting dendrimer at r.t. in methanol (Figure 1). The obtained dendriplexes (DPXs 7-11) showed a very good DL%, a proper particle size, an adequate buffer capacity and above all were well soluble in water. Therefore, they represent an appealing and promising crew of new smart DDSs for safe in vivo clinical administrations of 1. References: [1] A. Spallarossa, A. Ranise, et al., Eur. J. Med. Chem. 2009, 44, 1650-1663. [2] S. Alfei, S. Catena, 2018, submitted to Polym. Advan. Technol. 2018: https://doi.org/10.1002/pat.4396. [3] S. Alfei, S. Catena, 2018, submitted to Polym. Int. 2018, https://doi.org: 10.1002/pi.5680.