Recent work has been published in Nanomaterials journal about the intranasal administration of catechol-based Pt(IV) nanoparticles for Glioblastoma treatment. The work includes a complete preclinical study.
New publication in Nanomaterials journal entitled “Intranasal Administration of Catechol-Based Pt(IV) Coordination Polymer Nanoparticles for Glioblastoma Therapy” by our former PhD student Xiaoman Mao as the main author led by Dr. Fernando Novio and Prof. Daniel Ruiz-Molina. The work is a result of a strong collaboration between Nanosfun and the groups of Dr. Julia Lorenzo (Protein Engineering and Nanomedicine at Institute of Biotechnology and Biomedicine, IBB-UAB) and Dr. Ana Paula Candiota (Nuclear Magnetic Resonance Biomedical Applications at IBB-UAB). The work has also had the contribution of Dr. Jordi Bruna (Neuro-Oncology Unit, Bellvitge University Hospital-ICO, IDIBELL) and Dr. Victor Yuste (Institut de Neurociències – INc-UAB).
Glioblastoma (GB) is one of the most common and lethal malignant brain tumors. The median survival after diagnosis is 12–18 months, and the five-year survival rate is less than 5%. Standard treatment includes surgical resection followed by radiotherapy and concomitant and adjuvant chemotherapy with temozolomide (TMZ). Unfortunately, only a small fraction of the administered TMZ reaches the brain tissue, mostly due to the low permeability of the blood-brain barrier (BBB), even in cases with compromised BBB such as GB. Recently, several strategies have been investigated to overcome this challenge by increasing BBB permeability, allowing drug delivery within biodegradable polymer implants in the tumor bed, or mediated by simple diffusion using a reservoir-catheter system or positive pressure bulk flow via convection-enhanced delivery (CED). However, most of these approaches require a neurosurgical intervention at the relapsing tumor scenario or device placement with the consequent problems both in neuroimaging response and surgical complications risk. Therefore, there is an urgent need to develop new opportunities for pharmaceutical applications beyond oral, intravenous, or alternative administration routes. As an alternative to TMZ second-line treatments based on nitrosourea-based drugs, anti-angiogenic agents, topoisomerase inhibitors or even platinum complexes have been used. Unfortunately, some of these developments do not improve half-life and toxicity or require the use of therapeutic concentrations well over the tolerated dose-limiting toxicity. Additionally, the nose-to-brain or intranasal (IN) route has emerged as a non-invasive and easily accessible approach that has been explored in the clinical phase within the last decade.
In this work, the authors reported the formation of nanostructured coordination polymers (NCPs) containing Pt(IV) prodrugs as constitutive building blocks (Figure 1).
Figure 1. Scheme of the Pt-Fe NCPs synthesis upon polymerization of complex 1 with iron ions as metal nodes in open to air conditions, and analysis of their therapeutic effect in vitro (GL261 cell line) and in vivo murine models (C57BL/6J mice bearing orthotopic GL261 GB tumors)
These nanoparticles have been analyzed to determine the Pt(IV) encapsulation yields and subsequent controlled release, together with the study of their in vitro therapeutic efficacy in comparison with cisplatin when tested in murine GB cells. On top of that, in vivo tolerability and therapeutic activity have been determined for the evaluation of Pt-Fe NCPs as efficient IN nanoformulations for treating GB.
ABSTRACT: Cisplatin has been described as a potent anticancer agent for decades. However, in the case of glioblastomas, it is only considered a rescue treatment applied after the failure of second-line treatments. Herein, based on the versatility offered by coordination chemistry, we engineered nanoparticles by reaction of a platinum (IV) prodrug and iron metal ions showing in vitro dual pH- and redox-sensitivity, controlled release and comparable cytotoxicity to cisplatin against HeLa and GL261 cells. In vivo intranasal administration in orthotopic preclinical GL261 glioblastoma tumor-bearing mice demonstrated increased accumulation of platinum in tumors, leading in some cases to complete cure and prolonged survival of the tested cohort. This was corroborated by a magnetic resonance imaging follow-up, thus opening new opportunities for intranasal glioblastoma therapies while minimizing side effects. The findings derived from this research showed the potentiality of this approach as a novel therapy for glioblastoma treatment.
Funding: This work was supported by grant RTI2018-098027-B-C21, RTI2018-098027-B-C22 and PID2020-113058GB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe. With the support from “Metalfármacos multifuncionales para el diagnóstico y la terapia” with grant RED2018-102471-T funded by MCIN/AEI/10.13039/501100011033. The ICN2 is funded by the CERCA programme/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, grant SEV-2017-0706 funded by MCIN/AEI/10.13039/501100011033. COST is kindly acknowledged for stimulating scientific discussion and financial support via the Cost Action CA 17140 “Cancer nanomedicine from the bench to the bedside”. A.P.C. received funding from the ATTRACT project funded by the EC under Grant Agreement 777222. Work also supported by Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN [http://www.ciber-bbn.es/en, accessed on 24 March 2022], CB06/01/0010), an initiative of the Instituto de Salud Carlos III (Spain). The PhD program of X.M. was supported by the La Caixa-Severo Ochoa International PhD Fellowship. We acknowledge the UAB Predoctoral training program (14ª Convocatoria PIF-19612, predoctoral fellowships for P.C.-P).