Abstract
To capitalize on the response of tumor cells to XRT, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to XRT. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to 3 weeks. Compared with controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P = 0.0001) in MDA-MB-231 and 12 days in GL261 (P < 0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel-encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches.
Copyright 2010 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / administration & dosage*
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Antineoplastic Agents, Phytogenic / chemistry
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Apoptosis / drug effects
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Bacteriophages / genetics
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Breast Neoplasms / radiotherapy
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Coculture Techniques
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Delayed-Action Preparations
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Drug Delivery Systems
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Endoplasmic Reticulum Chaperone BiP
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Endothelial Cells / cytology
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Glioma / drug therapy*
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Glioma / pathology
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Glioma / radiotherapy
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Heat-Shock Proteins / biosynthesis
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Nanoparticles / administration & dosage*
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Nanoparticles / chemistry
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Oligopeptides / genetics
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Oligopeptides / metabolism
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Oligopeptides / pharmacology
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Paclitaxel / administration & dosage*
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Paclitaxel / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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Delayed-Action Preparations
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Oligopeptides
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Recombinant Proteins
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Paclitaxel