Construction of biomimetic long-circulation delivery platform encapsulated by zwitterionic polymers for enhanced penetration of blood–brain barrier

Abstract

The effective treatments for central nervous system (CNS) diseases are impeded mostly by the existence of the blood–brain barrier (BBB). The accumulation of therapeutic drugs inside the brain is far from the therapy threshold, which is closely related to the transient circulation time of drugs and their carriers. Herein, a core–shell protein-based long-circulation delivery platform was constructed. Through in situ free radical polymerization, a zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) was modified on the surface to prolong the circulation lifetime with a biomimetic structure induced by a phosphorylcholine (PC) head-group similar to the lipids in the outer membrane of living cells. A cell-penetrating peptide, HIV-1 trans-activating transcriptor (TAT) was conjugated on the surface of the protein-based nanoparticles, endowing the delivery platform with BBB-crossing ability. The BBB-permeability of the nanoparticles was investigated both in vitro and in vivo. Encapsulated with zwitterionic polymer PMPC, the nanoparticles showed a long circulation lifetime due to strong resistance to nonspecific adsorption and provided a better chance for BBB penetration. The delivery platform had enhanced permeability for BBB and a longer retention time inside the brain in a healthy mouse model. Overall, the surface modification with zwitterionic polymer PMPC and cell-penetrating peptide TAT changes the circulation modality of the nanoparticles in vivo, and provides a promising pathway for BBB crossing as a potential drug delivery platform for CNS related disease therapy.