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      Nanocarrier-based drug combination therapy for glioblastoma

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          Abstract

          The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms. Drug combination therapies have shown increasing benefits against those challenges. With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents. In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics. We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies. The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM.

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          Current state of immunotherapy for glioblastoma

          Chetan Bettegowda, Michael Lim, Yuanxuan Xia … (2018)
          Article 0 comments Cited 523 times – based on 0 reviews     Review now
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            Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers.

            Rakesh Jain (2013)
            For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
            Article 0 comments Cited 403 times – based on 0 reviews     Review now
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              To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

              F Danhier (2016)
              Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.
              Article 0 comments Cited 387 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2020
                Publication date (Electronic): 1 January 2020
                Volume: 10
                Issue: 3
                Pages: 1355-1372
                Affiliations
                [1 ]Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier, 73, B1 73.12, 1200 Brussels, Belgium
                [2 ]Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
                [3 ]Department of Neurosurgery, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
                Author notes
                ✉ Corresponding authors: Véronique Préat, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier, 73, B1 73.12, 1200 Brussels, Belgium. veronique.preat@ 123456uclouvain.be OR Raymond M. Schiffelers, Clinical Chemistry and Haematology, University Medical Center Utrecht, G03.550, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. r.schiffelers@ 123456umcutrecht.nl

                *Shared coauthorship

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov10p1355
                DOI: 10.7150/thno.38147
                PMC ID: 6956816
                PubMed ID: 31938069
                SO-VID: ff479624-d45d-456a-8c0c-e9785adc63ef
                Copyright © © The author(s)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 4 July 2019
                Date accepted : 4 November 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: glioblastoma,nanomedicine,nanoparticles,local delivery,systemic delivery,epr effect,theranostics
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: glioblastoma, nanomedicine, nanoparticles, local delivery, systemic delivery, epr effect, theranostics

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