Bombesin ligand functionalized gold nanoparticles containing five different linker moieties for pancreatic tumor targeting

Objectives Bombesin (BBN) peptides have demonstrated high affinity toward gastrin-releasing peptide (GRP) receptors in vivo that are expressed in pancreas and over-expressed in prostate, breast, and small-cell lung carcinoma. The goal of this study was to evaluate and compare the pharmacokinetic profiles of different linker modifiers. Specifically, we have synthesized BBN peptides conjugated gold nanoparticles containing five different linker moieties (99mTc-BBN(7-14)-X-TP-Au@NP, x = ethylenediamine, butanediamine, hexandiamine, octanediamine, amoniethylbenzenediamine).

Methods Briefly, tiopronin (TP)-protected AuNPs were synthesized and five linkers were introduced to tiopronin terminal of AuNPs by EDC/NHS reaction, respectively. And then, succinimidyl-BBN peptide introduced to five amine terminals. Finally, AuNPs surface was fully coated with cellobiose. After each step, the product purification was carried by dialysis (Mw=12-14 k). The particle diameter was determined TEM and checked 1H-NMR, FT-IR, and TGA, respectively. All AuNPs derivatives were labeled with Tc-99m and i.p. injected into the mice and identified in vivo distribution, respectively.

Results All derivatives were well made and characterized. In both biodistribution and planar gamma imaging studies in normal mice, longer hydrocarbon linker moieties typically exhibited higher pancreas retention than short linker or aromatic linker. All AuNPs derivatives were i.p. injected into PC3 xenografted tumor mice, AuNPs derivatives showed mainly RES organ uptake with decrease in uptake at tumor targets.

Conclusions These results showed the linking groups have influence on in vivo pancreas uptake, retention, and clearance of the AuNP-BBN peptide analogs. However, effective tumor uptake was not occurred. Future designs will focus on optimizing the pharmacokinetic profile of the AuNP-BBN based on linking groups for pancreas uptake.