Disulfiram-loaded electrospun fibers with antimicrobial and antitumoral properties for glioblastoma treatment
Iago Gonzalez-Prada, Arthur Barcelos Ribeiro, Marine Dion, Beatríz Magariños, Clémentine Lapoujade, Audrey Rousseau, Ángel Concheiro, Emmanuel Garcion, Carmen Alvarez‐Lorenzo
Abstract
Glioblastoma (GB) is a malignant brain tumor with low survival rates and a high recurrence ratio due to limited therapeutic arsenal. The repurposed drug disulfiram (DSF), approved for alcoholism treatment, shows promising anticancer and antimicrobial activity, but its poor biopharmaceutical profile hinders its clinical use. This work aimed to develop DSF-loaded silk fibroin (SF) electrospun fibers for controlled release in the postsurgical resection cavity. Incorporating hydroxypropyl-β-cyclodextrin (HPβCD), which formed inclusion complexes with DSF, enhanced drug release rate and antimicrobial activity (>3 logCFUs reduction) against Staphylococcus aureus and Pseudomonas aeruginosa . Addition of CuCl 2 enabled in situ formation of Cu(DDC) 2 complexes, further boosting antimicrobial and in vitro antitumoral effects of the nanofibers (≤ 500 nm) while maintaining adequate mechanical properties. Selective toxicity of DSF and DSF-loaded fibers against glioblastoma cells, while sparing against astrocytes, highlights the potential of the nanofibers for targeted brain cancer therapy. Increased potency of DSF at low concentrations when combined with SF fibers, HPβCD and copper was remarkable. Thus, DSF delivery and bioavailability can be significantly optimized through electrospun nanofibers, which may also allow for more precise dosing. Combination with radiotherapy was also explored to assess the translational potential of DSF as part of a combination therapy regimen for glioblastoma. In vivo studies in a rat model simulating GB surgery confirmed the safety of selected formulations in healthy brain tissue. However, findings suggest that DSF-loaded fibers alone may be insufficient for complete tumor eradication, indicating the need for combination with existing therapies to target residual tumor cells effectively. • SF nanofibers encapsulated tunable amounts of DSF and CuCl 2 , forming chelates in the release medium. • DSF release was pH-independent, and HPβCD enhanced both the release rate and antimicrobial activity. • DSF with Cu 2+ showed selective cytotoxicity against dividing glioblastoma cells and was safe for astrocytes. • Combination with radiotherapy preserved DSF activity against glioblastoma cells. • DSF fibers were safe for brain tissue, but in vivo activity requires further investigation.