Radiolabeled Gold Nanoseeds Decorated with Substance P Peptides: Synthesis, Characterization and In Vitro Evaluation in Glioblastoma Cellular Models.

Francisco Silva,António Paulo,Paula Raposinho,Alice D’Onofrio,Catarina Pinto,Carla Cruz,Maria Cristina Oliveira,Josué Carvalho,Maria Paula Cabral Campello,Fernanda Marques,Ana Belchior,Carolina Mendes,Salvatore Di Maria,Ana Marques

doi:10.3390/ijms23020617

Abstract

Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques, including TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.

Highlights

The work was initiated with the synthesis of the thioctic acid (TA) derivatives of Substance P peptides, to be used as NK-1 receptor targeting moieties upon attachment to the AuNP-TDOTA nanoconstructs
TDOTA coating provides versely, Auger, internal conversion (IC) and and warrants beta radiation seem to have less in increasing absorbed stability to the NPs a stable radiolabeling withimpact a variety of medical radiometdose in presence of gold. the
For to 5 nm sized AuNPs of the citrate type [14]. This this purpose, we have taken advantage of the presence of the TDOTA coating that prodifference might reflect the involvement of two Au atoms in the binding of the thioctic acid vides stability to the NPs and warrants a stable radiolabeling with a variety of medical derivatives used in this work, while the monothiolated sequence HS-PEG-substance P (SP)(5–11) binds radiometals, while still allowing the functionalization of the NPs surface with a reasonauniquely to one Au atom [14]

Summary

Introduction

Glioblastoma multiforme (GBM), classified as a grade IV brain tumor, represents the most frequent brain tumor, accounting for approximately 12–15% of all intracranial neoplasms. Current therapeutic strategies for GBM rely on open surgery, chemotherapy and radiotherapy. Despite some progress in the past 30 years, the overall survival of patients with glioblastoma remains extremely poor.

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