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      Peptide-Hitchhiking for the Development of Nanosystems in Glioblastoma

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          Abstract

          Glioblastoma (GBM) remains the epitome of aggressiveness and lethality in the spectrum of brain tumors, primarily due to the blood–brain barrier (BBB) that hinders effective treatment delivery, tumor heterogeneity, and the presence of treatment-resistant stem cells that contribute to tumor recurrence. Nanoparticles (NPs) have been used to overcome these obstacles by attaching targeting ligands to enhance therapeutic efficacy. Among these ligands, peptides stand out due to their ease of synthesis and high selectivity. This article aims to review single and multiligand strategies critically. In addition, it highlights other strategies that integrate the effects of external stimuli, biomimetic approaches, and chemical approaches as nanocatalytic medicine, revealing their significant potential in treating GBM with peptide-functionalized NPs. Alternative routes of parenteral administration, specifically nose-to-brain delivery and local treatment within the resected tumor cavity, are also discussed. Finally, an overview of the significant obstacles and potential strategies to overcome them are discussed to provide a perspective on this promising field of GBM therapy.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

            Roger Stupp, Warren P Mason, Martin van den Bent … (2005)
            Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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              The biology, function, and biomedical applications of exosomes

              Raghu Kalluri, Valerie LeBleu (2020)
              The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ACS Nano
                Journal ID (iso-abbrev): ACS Nano
                Journal ID (publisher-id): nn
                Journal ID (coden): ancac3
                Title: ACS Nano
                Publisher: American Chemical Society
                ISSN (Print): 1936-0851
                ISSN (Electronic): 1936-086X
                Publication date (Electronic): 11 June 2024
                Publication date Collection: 02 July 2024
                Volume: 18
                Issue: 26
                Pages: 16359-16394
                Affiliations
                [† ]Faculty of Pharmacy, University of Coimbra , Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
                [‡ ]Coimbra Chemistry Centre, Institute of Molecular Sciences − IMS, Faculty of Sciences and Technology, University of Coimbra , 3004-535 Coimbra, Portugal
                Author notes
                Author information
                https://orcid.org/0000-0003-3424-548X
                Article
                DOI: 10.1021/acsnano.4c01790
                PMC ID: 11223498
                PubMed ID: 38861272
                SO-VID: b5abc84b-20a3-4f97-8629-d77e6b142fc0
                Copyright © © 2024 The Authors. Published by American Chemical Society
                License:

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 February 2024
                Date accepted : 23 May 2024
                Date revision received : 15 May 2024
                Funding
                Funded by: Fundação para a Ciência e a Tecnologia, doi 10.13039/501100001871;
                Award ID: NA
                Categories
                Subject: Review
                Custom metadata
                document-id-old-9 nn4c01790
                document-id-new-14 nn4c01790
                ccc-price

                ScienceOpen disciplines: Nanotechnology
                Keywords: glioblastoma,blood−brain barrier (bbb),peptide functionalization,nanoparticles,external stimuli,biomimetic approaches,extracellular vesicles,nanocatalytic medicine,nose-to-brain delivery,local treatment
                Data availability:
                ScienceOpen disciplines: Nanotechnology
                Keywords: glioblastoma, blood−brain barrier (bbb), peptide functionalization, nanoparticles, external stimuli, biomimetic approaches, extracellular vesicles, nanocatalytic medicine, nose-to-brain delivery, local treatment

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