Epsilon-poly-L-lysine guided improving pulmonary delivery of supramolecular self-assembled insulin nanospheres

This work presents new spherical nanoparticles that are fabricated from supramolecular self-assembly of therapeutic proteins for inhalation treatment. The formation involved self-assembly of insulin into nanospheres (INS) by a novel thermal induced phase separation method. Surface functional modification of INS with epsilon-poly-L-lysine (EPL), a homopolymerized cationic peptide, was followed to form a core-shell structure (INS@EPL). Both INS and INS@EPL were characterized as spherical particles with mean diameter size of 150-250 nm. The process of transient thermal treatment did not change their biological potency retention significantly. FTIR and CD characterizations indicated that their secondary structures and biological potencies were not changed significantly after self-assembly. The in vivo investigation after pulmonary administration, including lung deposition, alveoli distribution, pharmacological effects and serum pharmacokinetics were investigated. Compared to that of INS, intratracheal administration of INS@EPL offered a pronounced and prolonged lung distribution, as well as pharmacological effects which were indicated by the 23.4% vs 11.7% of relative bioavailability. Accordingly, the work described here demonstrates the possibility of spherical supramolecular self-assembly of therapeutic proteins in nano-scale for pulmonary delivery application. (C) 2014 Elsevier B.V. All rights reserved.