α_vβ₃ Integrin‐targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide

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 αvβ3 integrin. Here we studied the tumor targeting potential of an 111In‐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 111In. The targeting potential of 111In‐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 μg up to 10 μg). The biodistribution at optimal peptide dose was determined at various time points (0.5 up to 72 hr). Furthermore, the therapeutic potential of 177Lu‐DOTA‐E‐c(RGDfK) was studied in this model. Two hours after i.p. administration, 111In‐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 μg dose range. Tumor uptake of 111In‐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 177Lu‐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. © 2006 Wiley‐Liss, Inc.

Follicle-Stimulating Hormone Peptide Can Facilitate Paclitaxel Nanoparticles to Target Ovarian Carcinoma In vivo

“…This kind of endocytosis results in efficient internalization of ligand-modified carriers in receptor-expressing cells (39)(40)(41). Our results are similar to other studies showing receptor-targeted therapy for ovarian cancer (42)(43)(44). A common chemotherapeutic drug in ovarian cancer, PTX, was incorporated into nanoparticle carriers.…”

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…Efforts to antagonize a5b1-integrin interactions were implemented in phase II clinical trials, using a chimeric antibody, Volociximab (Table 1), in patients with platinum-resistant advanced EOC, although clinical efficacy was not accomplished (65). Moreover, targeting of a v b 3 with antibodies and radiolabeled nucleotides in xenografts has opened up new avenues and opportunities for therapeutic intervention (66)(67)(68).…”

Isolation of targeting nanobodies against co-opted tumor vasculature

“…Targeting of newly formed vessels with agents directed against such molecules has already been shown to result in potent anti-tumor effects in preclinical models of subcutaneous xenografts. [33][34][35][36] However, these results cannot be translated directly to clinically relevant situations: in subcutaneous xenografts the vasculature is more or less synchronized and will be homogeneously susceptible to targeting of angiogenic vessels. In contrast, the vasculature of clinical tumors is composed of a heterogeneous population of vessels, 12 which requires that clinically relevant anti-vascular therapies combine targeting of newly formed vessels with targeting of more mature or co-opted vessels.…”