Glioblastoma multiforme (GB) is the most aggressive and frequent primary malignant tumor in the central nervous system (CNS), with unsatisfactory and challenging treatment nowadays. Current standard of care includes surgical resection followed by chemotherapy and radiotherapy. However, these treatments do not much improve the overall survival of GB patients, which is still below two years (the 5-year survival rate is below 7%). Despite various approaches having been followed to increase the release of anticancer drugs into the brain, few of them demonstrated a significant success, as the blood brain barrier (BBB) still restricts its uptake, thus limiting the therapeutic options. Therefore, enormous efforts are being devoted to the development of novel nanomedicines with the ability to cross the BBB and specifically target the cancer cells. In this context, the use of nanoparticles represents a promising non-invasive route, allowing to evade BBB and reducing systemic concentration of drugs and, hence, side effects. In this review, we revise with a critical view the different families of nanoparticles and approaches followed so far with this aim.

Current therapies for treating Glioblastoma (GB), and brain tumours in general, are inefficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15–18 months. Temozolomide (TMZ) is the main chemotherapeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anticancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity (i.e., neurotoxicity), especially after long-term treatments. The objective of the current developments is to produce novel nanoformulations with improved lipophilicity and passive diffusion, promoting intracellular accumulation, while reducing toxicity and optimizing the concomitant treatment of chemo-/radiotherapy. Moreover, the blood–brain barrier (BBB) prevents the access of the drugs to the brain and accumulation in tumour cells, so it represents a key challenge for GB management. The development of novel nanomedicines with the ability to (i) encapsulate Pt-based drugs and pro-drugs, (ii) cross the BBB, and (iii) specifically target cancer cells represents a promising approach to increase the therapeutic effect of the anticancer drugs and reduce undesired side effects. In this review, a critical discussion is presented concerning different families of nanoparticles able to encapsulate platinum anticancer drugs and their application for GB treatment, emphasizing their potential for increasing the effectiveness of platinum-based drugs.

Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood–brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood–brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration.

In recent years, a great deal of effort has been undertaken with regards to treatment of pathologies at the level of the central nervous system (CNS). Here, the presence of the blood-brain barrier acts as an obstacle to the delivery of potentially effective drugs and makes accessibility to, and treatment of, the CNS one of the most significant challenges in medicine. In this Roadmap article, we present the status of the timeliest developments in the field, and identify the outstanding challenges and opportunities that exist. The format of the Roadmap, whereby experts in each discipline share their viewpoint and present their vision, reflects the dynamic and multidisciplinary nature of this research area, and is intended to generate dialogue and collaboration across traditional subject areas. It is stressed here that this article is not intended to act as a comprehensive review article, but rather an up-to-date and forward-looking summary of research methodologies pertaining to the treatment of pathologies at the level of the CNS.

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%.

Nanoparticles (NPs) are receiving increasing interest in biomedical applications. However, due to their large surface area, in physiological environments, they tend to interact with plasma proteins, inducing their agglomeration and ultimately resulting in a substantial efficiency decrease in diagnostic and therapeutic applications. To overcome such problems, NPs are typically coated with a layer of hydrophilic and biocompatible polymers, such as PEG chains. However, few examples exist in which this property could be systematically fine-tuned and combined with added properties, such as emission. Herein, we report a novel mussel-inspired catechol-based strategy to obtain biocompatible and multifunctional coatings, using a previously developed polymerization methodology based on the formation of disulfide bridges under mild oxidative conditions. Two families of NPs were selected as the proof of concept: mesoporous silica NPs (MSNPs), due to their stability and known applications, and magnetite NPs (Fe₃O₄ NPs), due to their small size (<10 nm) and magnetic properties. The PEG coating confers biocompatibility on the NPs and can be further functionalized with bioactive molecules, such as glucose units, through the end carboxylic acid moieties. Once we demonstrated the feasibility of our approach to obtaining PEG-based coatings on different families of NPs, we also obtained multifunctional coatings by incorporating fluorescein functionalities. The resulting coatings not only confer biocompatibility and excellent cell internalization, but also allow for the imaging and tracking of NPs within cells.