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Real-Time Imaging of Perivascular Transport of Nanoparticles During Convection-Enhanced Delivery in the Rat Cortex

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Abstract

Convection-enhanced delivery (CED) is a promising technique for administering large therapeutics that do not readily cross the blood brain barrier to neural tissue. It is of vital importance to understand how large drug constructs move through neural tissue during CED to optimize construct and delivery parameters so that drugs are concentrated in the targeted tissue, with minimal leakage outside the targeted zone. Experiments have shown that liposomes, viral vectors, high molecular weight tracers, and nanoparticles infused into neural tissue localize in the perivascular spaces of blood vessels within the brain parenchyma. In this work, we used two-photon excited fluorescence microscopy to monitor the real-time distribution of nanoparticles infused in the cortex of live, anesthetized rats via CED. Fluorescent nanoparticles of 24 and 100 nm nominal diameters were infused into rat cortex through microfluidic probes. We found that perivascular spaces provide a high permeability path for rapid convective transport of large nanoparticles through tissue, and that the effects of perivascular spaces on transport are more significant for larger particles that undergo hindered transport through the extracellular matrix. This suggests that the vascular topology of the target tissue volume must be considered when delivering large therapeutic constructs via CED.

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Acknowledgments

This work was supported by the National Institutes of Health (Grant NS-045236 to WLO), the Ellison Medical Foundation (Grant AG-NS-0330-06 to CBS), and the American Heart Association (Grant 0735644T to CBS). This work was performed in part at the Cornell NanoScale Facility, a member of the National Nanotechnology Infrastructure Network, which is supported by the National Science Foundation (Grant ECS-0335765). Also, this work made use of STC shared experimental facilities supported by the National Science Foundation under Agreement No. ECS-9876771.

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Authors and Affiliations

  1. School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, 14853, USA

    Conor P. Foley & William L. Olbricht

  2. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA

    Nozomi Nishimura, Chris B. Schaffer & William L. Olbricht

  3. Chemical Engineering Department, Colorado School of Mines, Golden, CO, 80401, USA

    Keith B. Neeves

  4. Citigroup Biomedical Imaging Center, Radiology Department, Weill Cornell Medical College, 516 E 72nd Street, New York, NY, 10021, USA

    Conor P. Foley

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  1. Conor P. Foley
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Correspondence to Conor P. Foley.

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Associate Editor Daniel Elson oversaw the review of this article.

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10439_2011_440_MOESM1_ESM.mov

Movie of real-time images corresponding to the time-course in Fig. 2. Images were captured at a static plane 243 μm above the outlet of the microfluidic device. Movie shows perivascular transport of 24 nm nanoparticles (red) with gradual filling of the ECS (Supplementary material 1 MOV 47128 kb)

10439_2011_440_MOESM2_ESM.mov

Movie of real-time images corresponding to the time-course in Fig. 4. Movie shows perivascular transport of 24 nm nanoparticles (red) in the perivascular space of a vessel lying in the image plane 360 μm above the microfluidic probe outlet (Supplementary material 2 MOV 8619 kb)

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Foley, C.P., Nishimura, N., Neeves, K.B. et al. Real-Time Imaging of Perivascular Transport of Nanoparticles During Convection-Enhanced Delivery in the Rat Cortex. Ann Biomed Eng 40, 292–303 (2012). https://doi.org/10.1007/s10439-011-0440-0

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  • DOI: https://doi.org/10.1007/s10439-011-0440-0

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