Editor's Choice: «Chameleon-like glioblastoma nano-chemotherapy for brain and tumor dual targeting», by Bruno Sarmento

Glioblastoma (GBM) is the deadliest adult brain cancer. The i3S Nanomedicines and Translational Drug Delivery group coordinated a multidisciplinary team to create a chameleonic nanoparticle prototype, designed to adapt to the brain microenvironment, facilitating chemotherapeutic delivery to GBM.

Glioblastoma (GBM) is the most prevalent and lethal type of adult brain cancer, with less than 15-month median survival. Its standard of care relies on surgical resection, followed by radiotherapy and temozolomide (TMZ) chemotherapy. However, the ability of TMZ to permeate the barrier that separates blood from brain (blood-brain barrier, BBB) is far from optimal, consisting of less than 40% of the blood dose. Moreover, TMZ presents well-reported mechanisms of resistance and a poor tumoricidal potency. Altogether, this contributes to GBM recurrence rates of virtually 100%, highlighting the urgent need for more effective therapies.

In the Nanomedicines and Translational Drug Delivery group at i3S, we have established an international collaborative consortium (Portugal, UK, Belgium) with experts in pharmacology, chemistry, GBM biology and clinics, to pioneer the development of a nanoparticle (NP) prototype to sequentially target the brain and GBM. The goal is to use these nano-vehicles for a more efficient transport of a variety of anti-cancer drugs to the brain and, specifically, to GBM. To achieve this, we carefully rationalized the chemical design of the NPs surface. Specifically, we chemically grafted the Angiopep-2 peptide for BBB targeting, and L-Histidine amino acid for GBM targeting, leveraging their respective binding capabilities to key biological transporters. Importantly, we engineered the NP surface to alternate exposure between Angiopep-2 and L-Histidine as needed for BBB or GBM targeting, respectively, using a responsive chemical strategy regulated by the acidic pH of BBB endosomal vesicles. 

In our studies, we loaded these specialized nano-vehicles with the model chemotherapeutic drug docetaxel, known for its 20,000-times higher tumoricidal potency in GBM cells compared to TMZ. This led to a 12-fold enhancement in drug uptake by GBM patient cells, and a 3-fold increase in the chemotherapeutic effect. Additionally, these nano-vehicles demonstrated a 3-fold increase in blood-to-brain permeability in a laboratory model of the BBB, and in a GBM mouse model, they showed a 3-fold enhancement in brain accumulation. Administration of these nano-vehicles intratumorally or intravenously increased the median survival of the animals by up to 50%, without causing systemic toxicity.

Overall, this preclinical proof of concept holds significant clinical importance as the developed nano-vehicles greatly enhance the blood-to-brain-to-tumor transport of therapeutics, presenting an opportunity to potentially enhance outcomes for GBM patients. These nano-vehicles also hold potential for future application in the treatment of other brain oncological diseases, including brain metastasis and lower-grade gliomas. Moreover, the versatile core of these nano-vehicles opens up possibilities for future therapeutic co-delivery strategies, including of immunotherapies and gene therapies, offering a promising avenue for advancing cancer treatment approaches.

Keywords: Blood-brain barrier, drug delivery, dual-ligand functionalization, glioblastoma, nanomedicine, stimuli-responsiveness, targeting.