Image-guided nanodelivery of Pt(IV) prodrugs to GRP-receptor positive tumors

Authors and Affiliations:

Francisco Silva^1,*, Carolina Mendes¹, Alice D’Onofrio¹, Maria Paula Cabral Campello^1,2, Fernanda Marques^1,2, Teresa Pinheiro^2,3, Kyle Gonçalves¹, Sérgio Figueiredo^4,5, Lurdes Gano^1,2, Mauro Ravera⁶, Elisabetta Gabano⁷, António Paulo^1,2

1. Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Campus Tecnológico e Nuclear, Estrada Nacional 10, Km 139.7, 2695-066 Bobadela LRS, Portugal.

2. Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Portugal.

3. iBB – Instituto de Bioengenharia e Biociências, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.

4. Institute for Systems and Robotics (ISR), LARSyS, Instituto Superior Técnico, Department of Bioengineering, Universidade de Lisboa, Portugal

5. H&TRC – Health &Technology Research Center, ESTeSL/IPL - Escola Superior de Tecnologia da Saúde de Lisboa/Instituto Politécnico de Lisboa, Portugal.

6. Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy.

7. Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Università del Piemonte Orientale, Piazza Sant’Eusebio 5, 13100 Vercelli, Italy.

Abstract:

Over the last decades, gold nanoparticles (AuNPs) have proven to be remarkable tools for drug delivery and theranostic applications in cancer treatment. On the other hand, Pt(IV) prodrugs have been employed as an interesting alternative to the more common Pt(II) complexes, such as cisplatin, for cancer chemotherapy. Searching to design an image-guided nanocarrier to deliver selectively Pt(IV) prodrugs to gastrin releasing peptide receptor (GRPR) expressing tumors, small core AuNPs carrying a thiolated macrocyclic ligand, a GRPR-targeting bombesin analog (BBN) and a Pt(IV) prodrug were synthesized. In the GRPR+ prostate cancer PC3 cells, the best performing AuNP-BBN-Pt nanoparticles displayed an IC50 value similar to cisplatin. No cytotoxic effects were found for AuNP-BBN-Pt in the non-tumoral RWPE-1 prostate cells indicating higher selective index towards cancer cells than cisplatin. The AuNPs were successfully labeled with ⁶⁷Ga and displayed high uptake and rate of internalization in PC3 cells. Biodistribution of ⁶⁷Ga-AuNP-BBN-Pt in a PC3 tumor-bearing mice after intratumoral administration showed prolonged radioactivity and Pt retention, with 20% of the injected platinum remaining in the tumor after 72 h post-injection. Moreover, microSPECT imaging studies confirmed the uptake and considerable retention of the ⁶⁷Ga-labeled AuNPs in the tumors. These results show the potential of these GRPR-targeted AuNPs loaded with Pt(IV) prodrugs for prostate cancer theranostics.

Journal: Nanotheranostics 2023, 7(1): 22-40.

Link: https://www.ntno.org/v07p0022.pdf