Nanoparticles targeted to brain tumors efficiently deliver nucleic acids to malignant cells rendering them highly susceptible to chemotherapy

A team of Researchers from the Center for Neuroscience and Cell Biology (CNC) developed a nanoparticle capable of delivering therapeutic molecules to malignant brain tumors, which are generally associated with a short life expectancy after diagnosis.

The publication of the study, lead by the CNC researcher Conceição Pedroso de Lima, is the result of four years of work on the development of a new therapy for glioblastoma, a highly malignant and lethal type of brain tumor.

Pedro Costa (first author) emphasized that the study demonstrates that «nanoparticles composed of lipids (fat) coupled to a protein that recognizes tumor cells, efficiently deliver small therapeutic molecules (nucleic acids) to these cells. The intravenous delivery of the tumor-targeted nanoparticles to GBM-bearing mice, combined with chemotherapy, resulted in significant increase in tumor cell death and reduction of tumor size».

«This study shows that one of the limitations in the treatment of brain tumors – the delivery of therapeutic molecules to the tumors – can be surpassed by using delivery systems targeted to the tumor cells», explains Conceição Pedroso de Lima, which recognizes that «this is an important yet initial first step in a pathway that we expect to reach clinical trials».  

One of the main issues associated with chemotherapy are the side effects on healthy cells and tissues. The principal investigator believes that «by using targeted nanoparticles we could be able to increase chemotherapy efficacy and reduce the undesired side effects».

Authors and Affiliations:

Pedro M. Costa ^a, Ana L. Cardoso ^a*, Carlos  Custódia ^b*, Pedro Cunha ^b*, Luís Pereira de Almeida ^a,c, Maria C. Pedroso de Lima ^a,

^a CNC – Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-517 Coimbra, Portugal.

^b Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3001-401 Coimbra, Portugal.

^c Faculdade de Farmácia, Universidade de Coimbra, 3000-548 Coimbra, Portugal.

Abstract:

Malignant brain tumors, including glioblastoma (GBM), are among the most lethal human cancers, due to their tremendous invasive capacity and limited therapeutic options. Despite remarkable advances in cancer theranostics, which resulted in significant improvement of clinical outcomes, GBM relapse is very frequent and patient survival remains under one year. The elucidation of the role of abnormally-expressed miRNAs in different steps of GBM pathogenesis and in tumor resistance to therapy paved the way for the development of new miRNA-based therapeutic approaches targeting this disease, aiming at increasing specific tumor cell killing and, ultimately, cancer eradication. Here, we demonstrate that intravenously-administered chlorotoxin (CTX)-coupled (targeted) stable nucleic acid lipid particle (SNALP)-formulated anti-miR-21 oligonucleotides accumulate preferentially within brain tumors and promote efficient miR-21 silencing, which results in increased mRNA and protein levels of its target RhoB, while showing no signs of systemic immunogenicity. Decreased tumor cell proliferation and tumor size, as well as enhanced apoptosis activation and, to a lesser extent, improvement of animal survival, were also observed in GBM-bearing mice upon systemic delivery of targeted nanoparticle-formulated anti-miR-21 oligonucleotides and exposure to the tyrosine kinase inhibitor sunitinib. Overall, our results provide evidence that CTX-coupled SNALPs are a reliable and efficient system for systemic delivery of anti-miRNA oligonucleotides. Moreover, although further studies are still necessary to demonstrate a therapeutic benefit in a clinical context, our findings suggest that miRNA modulation by the targeted nanoparticles combined with anti-angiogenic chemotherapy may hold promise as an attractive approach towards GBM treatment.

Journal: Journal of Controlled Release

Link: http://www.sciencedirect.com/science/article/pii/S0168365915002205