Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment

Abstract

Simple Summary Glioblastoma (GB) is a type of brain cancer with a poor prognosis and few improvements in its treatment. One of the greatest difficulties in GB therapy lies in the fact that most of the drugs with high anticancer potential do not reach the brain and exert high therapeutic activity while minimizing side effects. To overcome these limitations, we focused on a catechol-based Pt(IV) prodrug (able to reverse cisplatin in a cellular environment) with the intention of repurposing Pt-based drugs as GB chemotherapeutic agents. Our in vitro results have corroborated the therapeutic effect of the synthesized complexes as comparable to cisplatin, and in vivo studies have demonstrated the potential of nose-to-brain delivery of this Pt(IV) prodrug for GB treatment. Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood-brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood-brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration.