Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer.
OBJECTIVE
Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model.


METHODS
To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of (3)H-RGD2-PTX was compared with that of (3)H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, (18)F-FDG/PET, (18)F-FLT/PET, and postmortem histopathology.


RESULTS
By comparing the biodistribution of (3)H-RGD2-PTX and (3)H-PTX, we found that (3)H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than (3)H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo (18)F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, (18)F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining.


CONCLUSIONS
Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing.
Cao
Qizhen
Q
Molecular Imaging Program at Stanford, Department of Radiology, Biophysics, and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, Stanford P095, CA 94305-5484, USA.
Li
Zi-Bo
ZB
Chen
Kai
K
Wu
Zhanhong
Z
He
Lina
L
Neamati
Nouri
N
Chen
Xiaoyuan
X
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D009928:Organ Specificity; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D017239:Paclitaxel