Nanoparticle-induced vascular blockade in human prostate cancer.
The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth.
Agemy
Lilach
L
Vascular Mapping Laboratory, Center for Nanomedicine, Sanford-Burnham Medical Research Institute at the University of California at Santa Barbara (UCSB), Santa Barbara, CA, USA.
Sugahara
Kazuki N
KN
Kotamraju
Venkata Ramana
VR
Gujraty
Kunal
K
Girard
Olivier M
OM
Kono
Yuko
Y
Mattrey
Robert F
RF
Park
Ji-Ho
JH
Sailor
Michael J
MJ
Jimenez
Ana I
AI
Cativiela
Carlos
C
Zanuy
David
D
Sayago
Francisco J
FJ
Aleman
Carlos
C
Nussinov
Ruth
R
Ruoslahti
Erkki
E
D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D005290:Ferric Compounds; D009842:Oligopeptides; C542438:cysteinyl-arginyl-glutamyl-lysyl-alanyl; C000499:ferric oxide