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Published on: January 7, 2019
Alpha v beta 3 integrin-targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide
Ingrid Dijkgraaf1, John A W Kruijtzer, Cathelijne Frielink
1Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. I.Dijkgraaf@nucmed.umcn.nl
Abstract:
Ovarian cancer is the fourth most common cause of cancer deaths among females in the western world after cancer of the breast, colon and lung. The inability to control the disease within the peritoneal cavity is the major cause of treatment failure in patients with ovarian cancer. The majority of ovarian carcinomas express the alpha(v)beta(3) integrin. Here we studied the tumor targeting potential of an (111)In-labeled cyclic RGD peptide in athymic BALB/c mice with intraperitoneally (i.p.) growing NIH:OVCAR-3 human ovarian carcinoma tumors. The cyclic RGD peptide, c(RGDfK)E, was synthesized, conjugated with DOTA and radiolabeled with (111)In. The targeting potential of (111)In-DOTA-E-c(RGDfK) was studied in athymic mice with i.p. growing NIH:OVCAR-3 xenografts and the optimal dose of this compound was determined (0.01 microg up to 10 microg). The biodistribution at optimal peptide dose was determined at various time points (0.5 up to 72 hr). Furthermore, the therapeutic potential of (177)Lu-DOTA-E-c(RGDfK) was studied in this model. Two hours after i.p. administration, (111)In-DOTA-E-c(RGDfK) showed high and specific uptake in the i.p. growing tumors. Optimal uptake in the i.p. growing tumors was observed at a 0.03-0.1 microg dose range. Tumor uptake of (111)In-DOTA-E-c(RGDfK) peaked 4 hr p.i. [(38.8 +/- 2.7)% ID/g], gradually decreasing at later time points [(24.0 +/- 4.1)% ID/g at 48 hr p.i.]. Intraperitoneal growth of OVCAR-3 could be significantly delayed by injecting 37 MBq (177)Lu-labeled peptide i.p. Radiolabeled DOTA-E-c(RGDfK) is suitable for targeting of i.p. growing tumors and potentially can be used for peptide receptor radionuclide therapy of these tumors.
Insights
This study shows that an indium-111 labeled cyclic RGD peptide effectively targets intraperitoneal ovarian cancer tumors in mice. This radiolabeled peptide also demonstrated therapeutic potential for treating ovarian cancer via peptide receptor radionuclide therapy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Ovarian cancer is a leading cause of cancer death in women, with peritoneal cavity spread being a major treatment challenge.
- Many ovarian carcinomas overexpress the alpha(v)beta(3) integrin, a potential therapeutic target.
- Targeting intraperitoneal tumors requires agents that can effectively reach and accumulate within the peritoneal space.
Purpose of the Study:
- To evaluate the tumor-targeting capability of an indium-111 labeled cyclic RGD peptide ( (111)In-DOTA-E-c(RGDfK) ) in a mouse model of human ovarian cancer.
- To determine the optimal dosage and biodistribution of the radiolabeled peptide for intraperitoneal (i.p.) tumor targeting.
- To assess the therapeutic potential of a lutetium-177 labeled version of the peptide ( (177)Lu-DOTA-E-c(RGDfK) ) for ovarian cancer treatment.
Main Methods:
- Synthesis and radiolabeling of a cyclic RGD peptide (c(RGDfK)E) with DOTA and indium-111.
- Administration of the radiolabeled peptide to athymic mice bearing intraperitoneal NIH:OVCAR-3 human ovarian carcinoma xenografts.
- Biodistribution studies to determine optimal dose and uptake over time.
- Therapeutic efficacy studies using lutetium-177 labeled peptide administered i.p.
Main Results:
- (111)In-DOTA-E-c(RGDfK) demonstrated high and specific uptake in i.p. growing ovarian tumors within 2 hours of administration.
- Optimal tumor targeting was observed with doses ranging from 0.03 to 0.1 microg.
- Tumor uptake peaked at 4 hours post-injection, with significant accumulation persisting up to 48 hours.
- (177)Lu-DOTA-E-c(RGDfK) administration significantly delayed the growth of i.p. OVCAR-3 tumors.
Conclusions:
- Radiolabeled DOTA-E-c(RGDfK) is a promising agent for targeting intraperitoneal ovarian tumors.
- The peptide shows potential for use in peptide receptor radionuclide therapy (PRRT) for ovarian cancer.
- This approach offers a targeted strategy to manage ovarian cancer spread within the peritoneal cavity.
