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Structure-based optimization of GRP78-binding peptides that enhances efficacy in cancer imaging and therapy

Paper ID Volume ID Publish Year Pages File Format Full-Text
5379 371 2016 14 PDF Available
Title
Structure-based optimization of GRP78-binding peptides that enhances efficacy in cancer imaging and therapy
Abstract

It is more challenging to design peptide drugs than small molecules through molecular docking and in silico analysis. Here, we developed a structure-based approach with various computational and analytical techniques to optimize cancer-targeting peptides for molecular imaging and therapy. We first utilized a peptide-binding protein database to identify GRP78, a specific cancer cell-surface marker, as a target protein for the lead, L-peptide. Subsequently, we used homologous modeling and molecular docking to identify a peptide-binding domain within GRP78 and optimized a series of peptides with a new protein-ligand scoring program, HotLig. Binding of these peptides to GRP78 was confirmed using an oriented immobilization technique for the Biacore system. We further examined the ability of the peptides to target cancer cells through in vitro binding studies with cell lines and clinical cancer specimens, and in vivo tumor imaging and targeted chemotherapeutic studies. MicroSPECT/CT imaging revealed significantly greater uptake of 188Re-liposomes linked to these peptides as compared with non-targeting 188Re-liposomes. Conjugation with these peptides also significantly increased the therapeutic efficacy of Lipo-Dox. Notably, peptide-conjugated Lipo-Dox significantly reduced stem-cell subpopulation in xenografts of breast cancer. The structure-based optimization strategy for peptides described here may be useful for developing peptide drugs for cancer imaging and therapy.

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Keywords
HotLig; GRP78; Cancer-targeting peptide; Cancer stem cells; Tumor imaging; Drug delivery
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Structure-based optimization of GRP78-binding peptides that enhances efficacy in cancer imaging and therapy
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 94, July 2016, Pages 31–44
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us