Targeted nanoparticles that deliver a sustained, specific release of Paclitaxel to irradiated tumors.
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.
Passarella
Ralph J
RJ
Department of Radiation Oncology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
Spratt
Daniel E
DE
van der Ende
Alice E
AE
Phillips
John G
JG
Wu
Hongmei
H
Sathiyakumar
Vasanth
V
Zhou
Li
L
Hallahan
Dennis E
DE
Harth
Eva
E
Diaz
Roberto
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001435:Bacteriophages / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000166:cytology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D009842:Oligopeptides; D011994:Recombinant Proteins; D017239:Paclitaxel