pH-Responsive “Supra-Amphiphilic” Nanoparticles Based on Homoarginine Polypeptides

pH-responsive “supra-amphiphiles” based on double hydrophilic, positively charged block copolypeptides such as PEG-b-poly-l-lysine together with low molecular weight stimuli-sensitive partners that contain phosphate and carboxylate groups have been widely studied. In contrast, the other widely used cationic polypeptide poly-l-arginine whose cell-penetrating properties are well-known has been much less explored for the synthesis of supra-amphiphile-based nanomaterials. It is also known that the guanidine side chain of arginine binds to carboxylate anions with binding constants that are 2.5 times higher than the corresponding amines of poly-l-lysine. Here, we demonstrate the fabrication of pH-sensitive supra-amphiphilic nanoparticles by simple mixing of PEG 2k -b-poly­(homoarginine) block copolymer and carboxylic acid containing functional low molecular weight organic compounds. A high yielding three-step methodology was developed for the synthesis of ε-N,N′-di-Boc-l-homoarginine-α-N-carboxyanhydride which was polymerized using amine-terminated PEG (2000 MW) to yield 100% guanine-functionalized polypeptide (PEG2k-b-PHR30) with controlled molecular weights and low PDIs. Incubation of PEG 2k -b-PHR30 with four different carboxylic acids (including dexamethasone a glucocorticoid receptor used in cancer therapy) in water leads to the formation of “supra-amphiphilic” nanoparticles (