Clinical Scale Synthesis of Intrinsically Radiolabeled and Cyclic RGD Peptide Functionalized Au Nanoparticles for Targeted Cancer Therapy

Introduction: The emerging concept of intrinsically radiolabeled nanoparticles has the potential to transform the preclinical and clinical studies by improving the in vivo stability and demonstrating minimal alteration in the inherent pharmacokinetics of the nanoparticles. In this paper, a simple and efficient single-step method for clinical scale synthesis of intrinsically radiolabeled Au nanoparticles conjugated with cyclic arginine-glycine-aspartate peptide (AuNP-RGD) is reported for potential use in targeted cancer therapy.

Methods: Large radioactive doses (>37 GBq) of AuNP-RGD were synthesized by reaction of Au-HAuCl with cyclic RGD peptide. The synthesized nanoparticles were characterized by various analytical techniques. In vitro cell binding studies were carried out in B16F10 (murine melanoma) cell line. Biodistribution studies were carried out in melanoma tumor bearing C57BL/6 mice to demonstrate the tumor targeting ability of AuNP-RGD. The therapeutic efficacy of AuNP-RGD was evaluated by carrying out systematic tumor regression studies in melanoma tumor bearing mice after intravenous administration of the radioactive doses.

Results: Well dispersed and biocompatible nanoparticles (~12.5 nm diameter) could be synthesized with excellent radiochemical and colloidal stability. In vitro studies exhibited the cell binding affinity and specificity of AuNP-RGD towards melanoma cell line. A high uptake of 8.7 ± 2.1%ID/g in the tumor was observed within 4 h post-injection (p.i.). Significant decrease in tumor uptake of AuNP-RGD (2.9 ± 0.8%ID/g) at 4 h p.i. on co-injection of a blocking dose of the peptide suggested that tumor localization of the intrinsically radiolabeled nanoparticles was receptor mediated. Administration of 37.0 MBq of AuNP-RGD resulted in significant regression of tumor growth with no apparent body weight loss over a period of 15 d.

Conclusions: Overall, these promising results demonstrate the suitability of AuNP-RGD as an advanced functional nanoplatform for targeted cancer therapy.