Interrogating the Role of Receptor-Mediated Mechanisms: Biological Fate of Peptide-Functionalized Radiolabeled Gold Nanoparticles in Tumor Mice

Abstract

To get a better insight on the transport mechanism of peptide-conjugated nanoparticles to tumors, we performed in vivo biological studies of bombesin (BBN) peptide functionalized gold nanoparticles (AuNPs) in human prostate tumor bearing mice. Initially, we sought to compare AuNPs with thiol derivatives of acyclic and macrocyclic chelators of DTPA and DOTA types. The DTPA derivatives were unable to provide a stable coordination of (67)Ga, and therefore, the functionalization with the BBN analogues was pursued for the DOTA-containing AuNPs. The DOTA-coated AuNPs were functionalized with BBN[7-14] using a unidentate cysteine group or a bidentate thioctic group to attach the peptide. AuNPs functionalized with thioctic-BBN displayed the highest in vitro cellular internalization (≈ 25%, 15 min) in gastrin releasing peptide (GRP) receptor expressing cancer cells. However, these results fail to translate to in vivo tumor uptake. Biodistribution studies following intravenous (IV) and intraperitoneal (IP) administration of nanoconjugates in tumor bearing mice indicated that the presence of BBN influences to some degree the biological profile of the nanoconstructs. For IV administration, the receptor-mediated pathway appears to be outweighed by the EPR effect. By contrast, in IP administration, it is reasoned that the GRPr-mediated mechanism plays a role in pancreas uptake.

Dual Imaging Gold Nanoplatforms for Targeted Radiotheranostics

“…These studies proved that the DOTA-containing AuNPs functionalized with a BBN thioctic derivative are the most promising ones, allowing for a fast complexation of trivalent radiometals (e.g. 67 Ga 3+ ) and showing high in vitro/in vivo stability, along with a favorable cellular internalization in GRPr-positive cells and significant tumor uptake [52,53]. Herein, we describe our efforts to assess the capacity of these BBN-containing AuNPs to anchor, at the same time, trivalent metal ions adequate for MRI (e.g., Gd 3+ ) and for radioimaging (e.g., 67 Ga 3+ ), taking advantage of the favorable coordination properties of the DOTA-based chelator towards Gd 3+ and Ga 3+ , yielding a bimodal MRI/nuclear imaging reporter.…”

“…Anhydrous GdCl 3 was obtained from Alfa Aesar. AuNP-TDOTA and thioctic acid terminated bombesin peptide (TA-BBN) were synthesized according to previously published methods [53]. 67 GaCl 3 was prepared from 67 Ga-citrate (acquired from Mallinckrodt) following a protocol previously described [54].…”

“…AuNPs were synthesized according to our previously described method [53]. Briefly, TDOTA•2TFA (68 mg, 0.10 mmol) was dissolved in 10 mL of a MeOH/H 2 O solution (7:3), and added to 4.5 mL of a solution of HAuCl 4 •3H 2 O (1 mM) in MeOH.…”

Enhanced and selective permeability of gold nanoparticles functionalized with cell penetrating peptide derived from maurocalcine animal toxin

“…Functionalized GNPs can be used for drug delivery, transfection, bio‐imaging, single molecule tracking, biosensing, and diagnostic . Recently, to obtain more insight on the role of surface bound biomolecules in tumor targeting, peptide‐functionalized radiolabeled gold nanoparticles characteristics have been studied . Moreover, a highly sensitive colorimetric aptasensor has been developed based on GNPs aggregation …”

“…17 Recently, to obtain more insight on the role of surface bound biomolecules in tumor targeting, peptide-functionalized radiolabeled gold nanoparticles characteristics have been studied. 18 Moreover, a highly sensitive colorimetric aptasensor has been developed based on GNPs aggregation. 19 Among functionalized GNPs, peptide-conjugated GNPs have been routinely used for more effective cell penetration.…”