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WIREs Nanomed Nanobiotechnol
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Crossing the barrier: treatment of brain tumors using nanochain particles

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Despite advancements in surgery and radiotherapy, the aggressive forms of brain tumors, such as gliomas, are still uniformly lethal with current therapies offering only palliation complicated by significant toxicities. Gliomas are characteristically diffuse with infiltrating edges, resistant to drugs and nearly inaccessible to systemic therapies due to the brain‐tumor barrier. Currently, aggressive efforts are underway to further understand brain‐tumor's microenvironment and identify brain tumor cell‐specific regulators amenable to pharmacologic interventions. While new potent agents are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. To tackle the drug delivery issues, a multicomponent chain‐like nanoparticle has been developed. These nanochains are comprised of iron oxide nanospheres and a drug‐loaded liposome chemically linked into a 100‐nm linear, chain‐like assembly with high precision. The nanochain possesses a unique ability to scavenge the tumor endothelium. By utilizing effective vascular targeting, the nanochains achieve rapid deposition on the vascular bed of glioma sites establishing well‐distributed drug reservoirs on the endothelium of brain tumors. After reaching the target sites, an on‐command, external low‐power radiofrequency field can remotely trigger rapid drug release, due to mechanical disruption of the liposome, facilitating widespread and effective drug delivery into regions harboring brain tumor cells. Integration of the nanochain delivery system with the appropriate combination of complementary drugs has the potential to unfold the field and allow significant expansion of therapies for the disease where success is currently very limited. WIREs Nanomed Nanobiotechnol 2016, 8:678–695. doi: 10.1002/wnan.1387 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
(a) Schematic of a linear nanochain particle composed of three IO nanosphere and one drug‐loaded liposome. (b) TEM image of nanochain particles (Reprinted with permission from Ref . Copyright 2014 Elsevier B.V.). (c) Reaction scheme of the controlled assembly of nanochains using solid‐phase chemistry. In the first step, chemical bifunctionality on the surface of parent IO nanospheres is topologically controlled resulting in nanospheres with two faces, one displaying only amines and the other only thiols. (d) In the second step, the two unique faces on the parent nanosphere serve as fittings to chemically assemble them into nanochains. (e) Size distribution of nanochain particles and their parent nanospheres obtained by DLS (data presented as mean ± SD). (f) Comparison of in vitro blood plasma stability of nanochains to 30‐nm and 100‐nm liposomal DOX. In a typical leakage procedure, 1 mL of formulation was placed in dialysis tubing with 100 k MWCO and dialyzed against blood plasma at 37°C. (Reprinted with permission from Ref . Copyright 2015 American Association for Cancer Research)
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Histologic evaluation of the nanochain treatment. (a) Histological evaluation of the anticancer effect of nanochains was performed in the orthotopic CNS‐1 model in mice [magnification, ×5; green, CNS‐1 glioma cells (GFP); blue, nuclear stain (DAPI); violet, doxorubicin]. Fluorescence imaging of an entire histologic section of the brain shows the primary tumor and its invasive sites (left). Fluorescence imaging of the same histologic section shows the widespread distribution of doxorubicin molecules after a 60‐min application of RF (right). (b) higher magnification imaging (×20) of an invasive site shows the location of nanochains (blue) with respect to the location of endothelial cells (green, CD 31) and brain tumor cells (left), and the RF‐triggered release of doxorubicin (right) in the same histologic section. Nanochains were visualized by staining iron with Prussian blue. The distribution of doxorubicin molecules is shown with (c) or without (d) RF with respect to the location of cancer cells. DOX, doxorubicin. (Reprinted with permission from Ref . Copyright 2015 American Association for Cancer Research)
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Evaluation of the ability of nanochains to target invasive brain tumors in mice. At 8 days after orthotopic inoculation of CNS‐1 cells in mice, the animals were injected with various formulations of doxorubicin (DOX) at a dose 0.5 mg/kg DOX. At 24 h after injection, animals were euthanized, brain tumors were excised and DOX content was measured. (Reprinted with permission from Ref . Copyright 2015 American Association for Cancer Research)
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Illustration of the nanochain therapeutic concept to successful deliver drugs to invasive brain tumors via vascular targeting and RF‐triggered drug release.
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