Docetaxel and niclosamide-loaded nanofiber systems for improved chemo-therapeutic activity and resistance reversal in prostate cancer.

Abstract

Objective: The objective of the study was to tackle the recurrence of prostate cancer (PCa) post-surgery and to re-sensitize the docetaxel (DTX)-resistant PC-3 cells to chemo-therapy using NIC.

Significance: Prolonged DTX therapy leads to the emergence of chemo-resistance by overexpression of PI3K-AKT pathway in PCa along with tumor recurrence post-surgery. Suppression of this pathway could be essential in improving the anticancer activity of DTX and re-sensitizing the resistant cells.

Method: Niclosamide (NIC), an anthelmintic drug has shown tremendous anticancer potential and has re-sensitized the resistant cells to various drugs. To mitigate the post-surgical tumor recurrence, an implant-based system facilitating the sustained release of DTX and NIC could be beneficial. DTX and NIC were incorporated within a nanofiber (NF) system to prevent on-site recurrence by local release and re-sensitize the DTX-resistant cells.

Key findings: The fabricated DTX-NIC NF via electrospinning were 334 ± 96.14 nm in diameter and demonstrated sustained release profile till 6 d. Elevated mitochondrial damage, reactive oxygen species levels and apoptotic index revealed improvement in the cytotoxicity of DTX-NIC post incorporation into the NF owing to their sustained release profile. Re-sensitization of PC-3/DTX cells was observed by introduction of NIC which could be due to the suppression of p-Akt1, which was overexpressed in resistant cells.

Conclusion: From superior activity of DTX-NIC NF and re-sensitization of resistant cells, we conclude that DTX-NIC NF could be a beneficial therapeutic regimen in preventing tumor recurrence in PCa.