Efficiency Encapsulation of FK506 with New Dual Self‐Assembly Multi‐Hydrophobic‐Core Nanoparticles for Preventing Keratoplasty Rejection

Nanoparticles self‐assembled by amphiphilic copolymers for loading hydrophobic molecules are intensively investigated. However, their hydrophobic molecule‐loading capacity is low due to the limitation of hydrophobic groups in these copolymers. In this regard, new lysine oligomer‐based multi‐hydrophobic side chain polymers (MHCPs) are synthesized by polymerization of γ‐benzyl‐l glutamate N‐carboxy anhydride initiated by side‐chain primary amino groups in lysine oligomer. Each hydrophobic side chain in MHCPs can be self‐assembled by hydrophobic interaction to form multi‐hydrophobic‐core nanoparticles (MHC‐NPs) with silkworm cocoon‐, grape cluster‐, and butterfly‐like shapes (depending on hydrophobic‐side‐chains lengths). To increase their stability, MHC‐NPs are dually self‐assembled with polyethylene glycol–polyglutamic acid through charge interaction. Each hydrophobic core in MHC‐NPs serves as a carrier for hydrophobic molecules, endowing their nanostructure with high loading capacity. MHC‐NPs are employed to load tacrolimus (also known as FK506), and the loading amount is 18% and the loading efficiency is 80%, which are higher than those of previously reported nanomicelles self‐assembled by linear amphiphilic copolymers. Topical administration of FK506‐loaded nanoparticle (FK506‐NP) can significantly prolong retention of FK506 on the eye surface. FK506‐NP exhibits higher in vivo immunosuppressive effects than free FK506 and commercial FK506 eye drop, as well as a better protective effect against immunotoxicity in the corneal grafts after keratoplasty. This study reports new multi‐hydrophobic‐core nanoparticles (MHC‐NPs) with high encapsulation capacity for hydrophobic agents. MHC‐NPs achieve a maximal tacrolimus (also known as FK506)‐loading amount of 18%, which is higher than those of previously reported nanocarriers. After topical administrated, these FK506 MHC‐NPs exhibit a better protective effect against immunotoxicity in the corneal grafts after keratoplasty than free FK506 and commercial FK506 eye drop.