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Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

ABSTRACT: The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery.

SUBMITTER: Zhuang X

PROVIDER: S-EPMC4754550 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

Zhuang Xiaoying X Teng Yun Y Samykutty Abhilash A Mu Jingyao J Deng Zhongbin Z Zhang Lifeng L Cao Pengxiao P Rong Yuan Y Yan Jun J Miller Donald D Zhang Huang-Ge HG

Molecular therapy : the journal of the American Society of Gene Therapy 20151007 1

The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity o ...[more]

PMID: 26444082

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Project description:Abstract Background Tumor Treating Fields (TTFields) is an antimitotic cancer treatment that utilizes low intensity (1–3 V/cm) alternating electric fields in the intermediate frequency (100–300 kHz), approvedfor the treatment of Glioblastoma Multiforme (GBM) located in the supratentorial regions of the brain. A clinical trial testing the efficacy of TTFields for treating brain metastases is currently underway (METIS, NCT02831959). TTFields are delivered via two pairs of transducer arrays placed on the patient’s skin in proximity to the tumor. The standard array layouts used to deliver TTFields involve placement of the arrays on the supratentorial regions of the head. Using these layouts, therapeutic field intensities above 1 V/cm are achieved within the surpatentorial brain. However, field intensities in the infratenorium fall to sub-therapeutic levels. . Brain metastases commonly occur in the infratentorium. In addition, infratentorial tumors are common in the pediatric population. Hence, there is a need to for array layouts that can be used to deliver TTFields effectively to the infratentorial brain. Here we present a new array layout designed to deliver high field intensities to the infratentorial brain. Materials and methods To simulate delivery of TTFields to the brain, realistic computerized head models of an adult human female and an adult human male were used. Virtual transducer arrays were placed on the models, and boundary conditions were set to simulate delivery of TTFields at 200 kHz. Various array layouts were tested, and field distributions resulting from the layouts were evaluated. Results In both models, TTfields was delivered to the infratentorium most effectively with a layout, in which each array of one pair was laterally placed superficially to the lower region of the occipital lobe, and the two arrays of the second pair were placed on the calvarium and the superior aspect of the neck. In both models, the pair of arrays in which one array was placed on the calvarium and one array on the superior aspect of the neck delivered field intensities above 1.1 V/cm to over 95% of the volume of the infratentorial brain, and the pair of arrays placed on the lateral aspects of the occipital lobe delivered field intensities above 1 V/cm to over 95% of the infratentorial brain. Both pairs of arrays delivered field intensities above 1 V/cm to significant portions of the supratentorial brain. Conclusions This work suggests a practical approach for delivering TTFields to the cerebellum, brain-stem and surrounding regions which are located inferior to the tentorium.

Dataset Information

Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

Publications

Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

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