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
Department of Radiology
Medical Subject Headings
Animals; Blood Pressure; Drug Carriers; Excipients; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Vasoactive Intestinal Peptide; dosage; Vasodilator Agents
Medicinal and Pharmaceutical Chemistry | Other Pharmacy and Pharmaceutical Sciences | Radiology
PURPOSE: 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 mug/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.
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Citation: Pharm Res. 2013 Mar;30(3):670-82. doi: 10.1007/s11095-012-0904-4. Epub 2012 Dec 7. Link to article on publisher's site
Reichstetter, Sandra; Castillo, Gerardo M.; Rubinstein, Israel; Nishimoto-Ashfield, Akiko; Lai, Manshun; Jones, Cynthia C.; Banerjee, Aryamitra A.; Lyubimov, Alex; Bloedow, Duane C.; Bogdanov, Alexei A. Jr.; and Bolotin, Elijah M., "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" (2013). Radiology Publications and Presentations. 91.