title: Metal ions guided self-assembly of therapeutic proteins for controllable release: from random to ordered aggregation.
abstract: OBJECTIVE
  To make a comparative study on sustained delivery performance of rhIFN with random amorphous and spherical crystal-like ordered self-assemblies.
  
  
  METHODS
  The rhIFN self-assemblies were identified in batch crystallization mode. Physico-chemical characteristics were compared, including morphology, XRD, FTIR, CD, biological potency, the dissolution behaviors in vitro and plasma pharmacokinetics in vivo. Moreover, molecular simulation was performed to better understand their binding site and mode.
  
  
  RESULTS
  Here, we suggest that random amorphous and spherical ordered self-assemblies allow for long action without new molecular entities generation or carriers employed. By manipulating supersaturation, the ordered aggregates were self-organized at high concentration of Zn(II) (>100 mM) in pH 5.5-6.0, which was the first time that spherical semi-crystals of rhIFN can act as a depot source for the sustained delivery of biologically active proteins. The secondary structure and biological potency of rhIFN were unchanged after aggregation. Compared with that of the native rhIFN, both self-assemblies exhibited slower absorption and extended elimination profiles after s.c. administration, which were characterized as 4.75 ± 0.82 h and 10.58 ± 1.86 h of terminal half-life for random amorphous and spherical ordered self-assemblies, respectively.
  
  
  CONCLUSIONS
  The work described here demonstrates the possibility of self-assemblies of biomacromolecules for controllable release application of therapeutic proteins.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, No 103, Wenhua Road, Shenyang 110016, China. kaishi_syphu@hotmail.com
authors.forename: Kai
authors.initials: K
authors.lastname: Shi
authors.forename: Fude
authors.initials: F
authors.lastname: Cui
authors.forename: Hongshu
authors.initials: H
authors.lastname: Bi
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.forename: Tao
authors.initials: T
authors.lastname: Song
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007477:Ions / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D007477:Ions; D008670:Metals; D011994:Recombinant Proteins; D007372:Interferons