Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

Abstract

The imaging of molecular markers associated with disease offers the possibility for earlier detection and improved treatment monitoring. Receptors for gastrin-releasing peptide are overexpressed on prostate cancer cells offering a promising imaging target, and analogs of bombesin, an amphibian tetradecapeptide have been previously demonstrated to target these receptors. Therefore, the pan-bombesin analog [β-Ala11, Phe13, Nle14]bombesin-(7-14) was conjugated through a linker to dye-functionalized superparamagnetic iron oxide nanoparticles for the development of a new potential magnetic resonance imaging probe. The peptide was conjugated via click chemistry, demonstrating a complementary alternative methodology to CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript conventional peptide-nanoparticle conjugation strategies. The peptide-functionalized nanoparticles were then demonstrated to be selectively taken up by PC-3 prostate cancer cells relative to unfunctionalized nanoparticles and this uptake was inhibited by the presence of free peptide, confirming the specificity of the interaction. This study suggests that these nanoparticles have the potential to serve as magnetic resonance imaging probes for the detection of prostate cancer.

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…These include: coupling to fluorescent-probes to be used for optical-imaging[66–68]; coupling to gold-nanorods coated with PEG which can be used for photoacoustical imaging for use particularly in breast-cancers idenfication[69]; conjugation to superparamagnetic iron oxide nanoparticles[70,71] or to other contrast agents[Gd-TTDA-NP, a protein based contrast agent, ProCA1] enhances detection by MRI; magnetofluorescent polymeric nanoparticles coupled to BnR-agonists improve the localization of the nanoparticles in PC-3 bearing mice compared to nanoparticles without coupling to a Bn-agonist, suggesting this approach could be useful for prostate-cancer imaging[72]; and the use of radiolabeled-monoclonal antibodies to proGRP to image tumors(gastric, lung) overexpressing Bn-related peptides.…”

Novel delivery approaches for cancer therapeutics

“…Targeting ligands conjugated to MNP was exploited for theranostics purposes ranging from small molecule nutrient transporters such folate [241–243] to macromolecules like Trastuzumab [244–246], single-chain anti-epidermal growth factor antibody [247], anti-epidermal growth factor receptor antibody [248], anti-vascular endothelial growth factor antibody (VEGF) [249, 250] and aptamers [251], [252]. A number of small molecular weight peptide have also been investigated including arginylglycylaspartic acid (RGD) [243, 253], bombesin [254, 255], and luteinizing hormone releasing hormone [256, 257]; highly cationic peptides like CPP [258], myristoylated poly-arginine peptide (MPAP) [259, 260] and HIV-TAT [261]. Multifunctional MNP have also been developed where nanocomposites are surface modified with fluorescent probes enabling both fluorescence and MR imaging for enhanced in vivo tracking.…”

Synthetic routes to magnetic nanoparticles for MPI

“…SPIO nanoparticles up to approximately 100 nm in hydrodynamic size should be applicable for magnetic tumor labeling [50,56]. In addition, different tracers can be specifically functionalized for active targeting [48,55,65,66]. This is accomplished by coupling various biomolecules to the particle surfaces via functional groups of the coating.…”