A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity

JOURNAL OF CONTROLLED RELEASE

卷:175

Article

Pang, Hong-Bo¹  Braun, Gary B.¹  She, Zhi-Gang¹  Kotamraju, Venkata R.¹  Sugahara, Kazuki N.^1,2  Teesalu, Tambet^1,3  Ruoslahti, Erkki^1,4,5 

[1] Sanford Burnham Med Res Inst, Canc Res Ctr, La Jolla, CA 92037 USA

[2] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA

[3] Univ Tartu, Inst Biomedicine & Translat Med, Ctr Excellence Translat Med, Canc Biol Lab, EE-50411 Tartu, Estonia

[4] Univ Calif Santa Barbara, Ctr Nanomed, Santa Barbara, CA 93106 USA

[5] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA

关键词: iRGD;    Extra cysteine;    Half-life;    Tumor extravasation;    Bystander activity;    Albumin;   

DOI  :  10.1016/j.jconrel.2013.12.006

来源: Elsevier

【 摘 要 】

The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

Free