title: Protected graft copolymer excipient leads to a higher acute maximum tolerated dose and extends residence time of vasoactive intestinal Peptide significantly better than sterically stabilized micelles.
abstract: OBJECTIVE
  To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP).
  
  
  METHODS
  VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined.
  
  
  RESULTS
  Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1-5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP.
  
  
  CONCLUSIONS
  While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.
authors.affiliation: PharmaIN Corp., 19805 N. Creek Parkway, Bothell, Washington, 98011, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Reichstetter
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Castillo
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishimoto-Ashfield
authors.forename: Manshun
authors.initials: M
authors.lastname: Lai
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Jones
authors.forename: Aryamitra A
authors.initials: AA
authors.lastname: Banerjee
authors.forename: Aryamitra
authors.initials: A
authors.lastname: Banjeree
authors.forename: Alex
authors.initials: A
authors.lastname: Lyubimov
authors.forename: Duane C
authors.initials: DC
authors.lastname: Bloedow
authors.forename: Alexei
authors.initials: A
authors.lastname: Bogdanov
authors.forename: Elijah M
authors.initials: EM
authors.lastname: Bolotin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D005079:Excipients; D008823:Micelles; D014665:Vasodilator Agents; D014660:Vasoactive Intestinal Peptide