Silk microneedle patch capable of on-demand multi-drug delivery to the brain for glioblastoma treatment.

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and it is associated with poor prognosis because of invasive growth. To date, surgery followed by chemotherapy and radiotherapy remains the standard treatment strategy for GBM after the exact location of the tumor has been confirmed. However, challenges still exist for many GBM patients when surgery is difficult or impossible; in many cases, surgery cannot remove the tumor completely, because the tumor tends to spread into surrounding tissues. Herein, we report the design, fabrication and application of a heterogenous silk fibroin microneedle (SMN) patch for circumventing the blood-brain barrier and releasing multiple drugs directly to the tumor site for drug combination treatment. The biocompatible and biodegradable SMN patch can dissolve slowly over time, allowing the sustained release of multiple drugs at different concentrations over an extended period of time. Furthermore, it can be triggered remotely to induce rapid drug delivery at a designated stage after implantation. In the GBM mouse models with and without tumor resection in distinct cell lines, two clinically relevant chemotherapeutic agents(thrombin and temozolomide)and targeted drug (bevacizumab) were loaded into the SMN patch at different doses and with individually controlled release profiles. The drugs were spatiotemporally and sequentially delivered to the tumor site in the mouse brain during the dissolution of the SMN patch and maintained at levels above those effective for hemostasis, anti-angiogenesis and apoptosis of tumor cells. Device application was non-toxic and resulted in both decreased tumor volume and increased survival rate in mice. The SMN patch with on-demand multi-drug delivery has potential applications for the combined administration of multiple therapeutic drugs for the clinical treatment of brain tumors when other methods are insufficient. This article is protected by copyright. All rights reserved.