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WIREs Nanomed Nanobiotechnol
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Nanotherapeutic systems for local treatment of brain tumors

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Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle‐based DDSs aiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an in‐depth review of nanotherapeutic systems that are intended to bypass the blood–brain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner.

A summary of the current standards of treatments for brain tumor patients. (a) (I) Intraoperative surgical view of part of the right frontotemporal region, the number tag identifying the eloquent brain area (motor area—see arrow). (II) The surgical cavity after removing the lesion with preservation of the eloquent brain function. (III) Preoperative axial magnetic resonance image (MRI) showing a heterogeneous enhancing mass involving the right putamen and globus pallidus. (IV) Postoperative MRI shows complete resection of the lesion with normal postsurgical changes in this view. (b) (I) Axial MRI shows postsurgical changes of resected glioma, with nodular enhancement along the resection cavity. (II) Postradiotherapy axial MRI shows resolution of the postsurgical changes along the resection cavity with no signs of recurrence or residual lesion. (III) Three years postradiotherapy shows normal expected postsurgical changes with no signs of recurrence or residual. (c) Image showing the placement of carmustine wafers along the tumor cavity walls. The typical dimensions of a wafer cylinder each containing 7.7 mg of carmustine are also shown. (Reprinted with permission from Ref 19. Copyright 2012 Elsevier) (d) Illustration of a systemically administered drug passing through the blood–brain barrier into the adjacent tumor cells: a similar mechanism to that of the drugs Avastin® and Temodar®.
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The blood–brain barrier (BBB) is a highly selective filtration system to mediate mass transport between the circulating blood and the brain's extracellular fluid. In the context of targeted drug delivery for brain tumor treatment, it represents a major hurdle for effective delivery of therapeutic agents within the circulating blood system into the brain tumor area.
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Illustration showing the overall process developed in the Green lab to identify the optimal formulations for in vivo studies of poly(β‐amine esters) (PBAEs)/DNA nanoparticles, screening a library of PBAE/DNA nanoparticles against fetal neural progenitor cells. (Adapted with permission from Ref 166)
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Summary of different methods being investigated for the local treatment of brain tumors. Convection‐enhanced delivery allows the administration of a drug system to the target site using an external device. Cell encapsulation delivers encapsulated cells within alginate or other particles that could naturally produce a therapeutic agent capable of targeting and killing cancer cells. Nanoparticles can be modified in many ways, including the type of material used to form the particle shell, the molecule encapsulated within these nanoparticles to provide a specific method of treatment or any surface modifications to allow specific targeting. Hydrogels and microchips/microdevices can serve as large depots that can store and release drugs to provide a longer treatment duration.
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(a) Schematic illustrations of the design and assembly of drug‐based hydrogelators. A typical drug amphiphile (DA) contains an anticancer drug, a biodegradable linker, and a short peptide. DAs are designed to self‐assemble into filamentous nanostructures in water that could further form a hydrogel under physiological condition. (b) Transmission electron microscopy (TEM) characterization of long filaments formed by self‐assembly of a camptothecin (CPT) DA. (c) Cryo‐TEM image of these ultra‐long filamentous nanostructures. (d) A photograph to illustrate the hydrogel form of CPT DAs.
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Brain tumor imaging and treatment using drug‐loaded magnetic nanoparticles delivered by convection‐enhanced delivery. The tumor area could be clearly visualized through T2‐weighted magnetic resonance image (MRI) instantly or 48 h after the injection of the magnetic nanoparticles. When in the tumor, the magnetic nanoparticles decorated with chlorotoxin could recognize brain tumor cells, be dePEGylated by glutathione, and release O6 ‐benzylguanine to inactivate O6 ‐methylguanine‐DNA methyltransferase (MGMT). (Adapted with permission from Ref 189)
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The anticancer efficacy of poly(d,l‐lactic‐co‐glycolic acid) (PLGA) nanoparticles loaded with camptothecin (CPT). The PLGA nanoparticles were around 100 nm in diameter (a), and when delivered into the brain tumor through convection‐enhanced delivery technology, could significantly prolong the survival of model animals with an intracranial brain tumor (b). Crystal violet staining revealed that CPT–PLGA nanoparticles could eradicate the cancer cells when injected into the center of the tumor (c), or partially inhibit the growth of tumor if injected in the margin of the tumor (d). Free CPT (e) and blank nanoparticles (f) showed no antitumor efficacy. (Reprinted with permission from Ref 185. Copyright 2011 Springer)
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Schematic illustration of the tissue penetration of non‐PEGylated and PEGylated poly(d,l‐lactic‐co‐glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and labeled with fluorescent dyes after the intratumoral injection. (Adapted with permission from Ref 117)
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The process used to produce these labeled, magnetized, and carmustine‐loaded nanoparticles. (Reprinted with permission from Ref 146. Copyright 2016 Elsevier)
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The microdevice made of poly(l‐lactic acid) (PLLA) and liquid crystal polymer (LCP) (a) (Reprinted with permission from Ref 120. Copyright 2011 Elsevier) and polysulphone (b). The drug release from the polysulphone‐based microdevice is linear and highly dependent on the number of holes in the cap (c). (Figure 3b and 3c were reprinted with permission from Ref 121. Copyright 2015 Elsevier)
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Mauro Ferrari

Mauro Ferrari

started out in mechanical engineering and became interested in nanotechnology with his studies on nanomechanics and nanofluidics. His research work and involvement with setting up some of the premier nano centers and alliances in the world, bringing together universities, hospitals, and federal agencies, showcases interdisciplinarity at work.

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