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Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

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ABSTRACT

Purpose

To design a binding-induced conformation change drug delivery system for integrin-targeted delivery of methotrexate and prove the feasibility of using hairpin peptide structure for binding triggered drug delivery.

Methods

Methotrexate prodrugs were synthesized using solid phase peptide synthesis techniques by conjugating methotrexate to Arg-Gly-Asp (RGD) or a hairpin peptide, RWQYVDPGKFTVQRGD (hairpin-RGD). Levels of integrin αVβ3 in HUVEC were up-regulated using adenoviral system and knocked down using siRNA. Stability of prodrugs and methotrexate release from prodrugs were evaluated in plasma, in presence or absence of integrin αVβ3-expressing cells. Molecular modeling was performed to support experimental results using MOE.

Results

Prodrugs recognized and bound to integrin αVβ3-expressing cells in integrin αVβ3 expression level-dependent manner. Prodrug with hairpin peptide could resist Streptomyces griseus-derived glutamic acid-specific endopeptidase (SGPE) and plasma enzyme hydrolysis. Drug release was triggered in presence of HUVEC cells and SGPE. Analysis of conformation energy supported that conformational change in MTX-hairpin-RGD led to exposure of labile link upon binding to integrin αVβ3-expressing cells.

Conclusions

Binding-induced conformation change of hairpin peptide can be used to design integrin-targeted drug delivery system.

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ACKNOWLEDGMENTS & DISCLOSURES

The authors would like to thank Dr. William Chan and Dr. Shiladitya Bhattacharya for their contributions and supports for the development of AdEasy viral vector.

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Author notes

  1. Phanidhara Kotamraj

    Present address: Abon Pharmaceuticals, Northvale, New Jersey, USA

Authors and Affiliations

  1. Department of Pharmaceutics & Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California, 95211, USA

    Phanidhara Kotamraj, Wade A. Russu, Bhaskara Jasti & Xiaoling Li

  2. VM Discovery, Fremont, California, USA

    Jay Wu

Authors
  1. Phanidhara Kotamraj
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  2. Wade A. Russu
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  3. Bhaskara Jasti
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  4. Jay Wu
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  5. Xiaoling Li
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Corresponding author

Correspondence to Xiaoling Li.

ELECTRONIC SUPPLEMENTARY MATERIAL

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Kotamraj, P., Russu, W.A., Jasti, B. et al. Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate. Pharm Res 28, 3208–3219 (2011). https://doi.org/10.1007/s11095-011-0495-5

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  • DOI: https://doi.org/10.1007/s11095-011-0495-5

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