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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

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An Erratum to this article was published on 09 May 2013

ABSTRACT

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 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.

Pharmacokinetics of VIP after SC injection of 100 μg/kg in BALB/c mice (n = 5). (a) Overview of entire 72 h sampling period, (b) the first 6 h shown in detail. VIP quantitation in serum samples was by competitive ELISA. LOD: level of detection.

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Abbreviations

MRT:

mean residence time

MTD:

maximum tolerated dose

PGC:

protected graft copolymer

PK:

pharmacokinetics

SSM:

sterically stabilized micelles

VIP:

vasoactive intestinal peptide

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ACKNOWLEDGMENTS AND DISCLOSURES

The work described in this paper was supported, in part, by NIH SBIR grant 1R43AI082723 and by VA Merit Review.

The NIH had no influence on our decision about study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication.

DCB and AB are consultants to, and ANA, CCJ, GMC, SR, and EMB are employees of PharmaIN Corp.

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Authors and Affiliations

  1. PharmaIN Corp., 19805 N. Creek Parkway, Bothell, Washington, 98011, USA

    Sandra Reichstetter, Gerardo M. Castillo, Akiko Nishimoto-Ashfield, ManShun Lai, Cynthia C. Jones & Elijah M. Bolotin

  2. College of Medicine, The University of Illinois, 840 S. Wood St. (M/C 719) 920-N CSB, Chicago, Illinois, 60612, USA

    Israel Rubinstein

  3. Jesse Brown VA Medical Center, Chicago, Illinois, 60612, USA

    Israel Rubinstein

  4. College of Medicine, The University of Illinois, 808 S. Wood Street, Rm. 1306, Chicago, Illinois, 60612, USA

    Aryamitra Banjeree & Alex Lyubimov

  5. School of Pharmacy, The University of Washington, H-272, Box 357610, Seattle, Washington, 98195-7631, USA

    Duane C. Bloedow

  6. University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Alexei Bogdanov Jr.

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  1. Sandra Reichstetter
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  2. Gerardo M. Castillo
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  3. Israel Rubinstein
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  11. Elijah M. Bolotin
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Correspondence to Elijah M. Bolotin.

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Reichstetter, S., Castillo, G.M., Rubinstein, I. et al. 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. Pharm Res 30, 670–682 (2013). https://doi.org/10.1007/s11095-012-0904-4

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