Multi-ligand functionalized blood-to-tumor sequential targeting strategies in the field of glioblastoma nanomedicine

Glioblastoma (GBM) is an unmet clinical need characterized by a standard of care (SOC) 5-year survival rate of only 5%, and a treatment mostly palliative. Significant hurdles in GBM therapies include an effective penetration of therapeutics through the brain protective barrier, namely the blood-brain barrier (BBB), and a successful therapeutic delivery to brain-invading tumor cells post-BBB crossing. These hurdles, along with the poor prognosis and critical heterogeneity of the disease, have shifted attention to treatment modalities with capacity to precisely and sequentially target (i) BBB cells, inducing blood-to-brain transport, and (ii) GBM cells, leading to a higher therapeutic accumulation at the tumor site. This sequential targeting allows therapeutic molecules to reach the brain parenchyma and compromise molecular processes that support tumor cell invasion. Besides improving formulation and pharmacokinetics constraints of drugs, nanomedicines offer the possibility of being surface functionalized with multiple possibilities of targeting ligands, while delivering the desired therapeutic cargos to the biological sites of interest. Targeting ligands exploit the site-specific expression or overexpression of specific molecules on BBB and GBM cells, triggering brain plus tumor transport. Since the efficacy of single-ligand functionalized nanomedicines is limited due to the GBM anatomical site (brain) and disease complexity, this review presents an overview of multi-ligand functionalized, BBB and GBM sequentially- and dual-targeted nanomedicines reported in literature over the last 10 years. The role of the BBB in GBM progression, treatment options, and the multiple possibilities of currently available targeting ligands will be summarized.This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Automated summary

Glioblastoma (GBM) is a challenging disease with limited treatment options and poor prognosis. The blood-brain barrier (BBB) presents a major obstacle to drug delivery to the brain, and targeting brain-invading tumor cells is crucial for effective therapy. Nanomedicines with multiple ligands have emerged as a promising approach to sequentially target BBB cells and GBM cells, improving therapeutic accumulation at the tumor site. This review provides an overview of the development of multi-ligand functionalized nanomedicines for BBB and GBM dual targeting over the past decade.