Nek1-inhibitor and temozolomide-loaded microfibers as a co-therapy strategy for glioblastoma treatment

Luiza Steffens Reinhardt; Ana Moira Morás; Jeferson Gustavo Henn; Pablo Ricardo Arantes; Matheus Bernardes Ferro; Elizandra Braganhol; Priscila Oliveira de Souza; Josias de Oliveira Merib; Gabriela Ramos Borges; Carolina Silveira Dalanhol; Mabilly Cox Holanda de Barros Dias; Michael Nugent; Dinara Jaqueline Moura

doi:10.1016/j.ijpharm.2022.121584

Nek1-inhibitor and temozolomide-loaded microfibers as a co-therapy strategy for glioblastoma treatment

Int J Pharm. 2022 Apr 5:617:121584. doi: 10.1016/j.ijpharm.2022.121584. Epub 2022 Feb 22.

Authors

Affiliations

¹ Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil; Biosciences Graduation Course, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: luizasteffens@live.com.
² Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil; Biosciences Graduation Course, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: anamoiramoras@gmail.com.
³ Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil; Biosciences Graduation Course, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: jefersonghenn@gmail.com.
⁴ Department of Bioengineering, University of California, Riverside, USA. Electronic address: pabloa@ucr.edu.
⁵ Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: matheusbf@ufcspa.edu.br.
⁶ Biosciences Graduation Course, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: ebraganhol@ufcspa.edu.br.
⁷ Biosciences Graduation Course, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: priscilaoliveira2@hotmail.com.
⁸ Analytical Center, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: josias@ufcspa.edu.br.
⁹ Analytical Center, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: gabriela@ufcspa.edu.br.
¹⁰ Analytical Center, UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: mdbdias@research.ait.ie.
¹¹ Bioscience Research Institute, Technological University of the Shannon, Midlands Midwest (TUS), Athlone, Co. Westmeath, Ireland. Electronic address: cdalanhol@gmail.com.
¹² Materials Research Institute, TUS, Athlone, Co. Westmeath, Ireland. Electronic address: michael.nugent@tus.ie.
¹³ Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil. Electronic address: dinaram@ufcspa.edu.br.

PMID: 35202726
DOI: 10.1016/j.ijpharm.2022.121584

Abstract

Malignant glioblastoma (GB) is the predominant primary brain tumour in adults, but despite the efforts towards novel therapies, the median survival of GB patients has not significantly improved in the last decades. Therefore, localised approaches that treat GB straight into the tumour site provide an alternative to enhance chemotherapy bioavailability and efficacy, reducing systemic toxicity. Likewise, the discovery of protein targets, such as the NIMA-related kinase 1 (Nek1), which was previously shown to be associated with temozolomide (TMZ) resistance in GB, has stimulated the clinical development of target therapy approaches to treat GB patients. In this study, we report an electrospun polyvinyl alcohol (PVA) microfiber (MF) brain-implant prepared for the controlled release of Nek1 protein inhibitor (iNek1) and TMZ or TMZ-loaded nanoparticles. The formulations revealed adequate stability and drug loading, which prolonged the drugs' release allowing a sustained exposure of the GB cells to the treatment and enhancing the drugs' therapeutic effects. TMZ-loaded MF provided the highest concentration of TMZ within the brain of tumour-bearing rats, and it was statistically significant when compared to TMZ via intraperitoneal (IP). All animals treated with either co-therapy formulation (TMZ + iNek1 MF or TMZ nanoparticles + iNek1 MF) survived until the endpoint (60 days), whereas the Blank MF (drug-unloaded), TMZ MF and TMZ IP-treated rats' median survival was found to be 16, 31 and 25 days, respectively. The tumour/brain area ratio of the rats implanted with either MF co-therapy was found to be reduced by 5-fold when compared to Blank MF-implanted rats. Taken together, our results strongly suggest that Nek1 is an important GB oncotarget and the inhibition of Nek1's activity significantly decreases GB cells' viability and tumour size when combined with TMZ treatment.

Keywords: Drug delivery systems; Electrospinning; Glioblastoma; Microfibers; NIMA-related kinase 1; Polyvinyl alcohol; Temozolomide.

MeSH terms

Animals
Antineoplastic Agents, Alkylating
Brain Neoplasms* / drug therapy
Brain Neoplasms* / metabolism
Cell Line, Tumor
Cell Survival
Glioblastoma* / metabolism
Humans
NIMA-Related Kinase 1
Nanoparticles*
Rats
Temozolomide / pharmacology

Substances

Antineoplastic Agents, Alkylating
NEK1 protein, human
NIMA-Related Kinase 1
Temozolomide