Direct convective delivery of macromolecules to the spinal cord

Rr, Lonser; Gogate, Nitin; Pf, Morrison; Jd, Wood; Eh, Oldfield

doi:10.3171/jns.1998.89.4.0616

Cited by 99 publications

(88 citation statements)

References 11 publications

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“…Although delivery of the gene for Bcl-2 or Bcl-XL is not now clinically practical, methods of delivering protein to the central nervous system via direct infusion into the brain, cerebrospinal fluid, spinal cord, or peripheral nerves have been established in animals (63,64) and man (65,66). Thus, delivery of proteins that prevent apoptosis may inhibit certain neurodegenerative conditions.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Liu¹,

Collier²,

Youle³

2001

Journal of Biological Chemistry

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Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegenerative disease, and trauma. To test a new anti-apoptosis strategy for neuroprotection, we engineered nontoxic components of anthrax toxin into a Bcl-XL delivery system. Delivery of Bcl-XL by this system prevented apoptosis of cultured rat cerebellar granule cells and macrophages, and the prevention depended on both the Bcl-XL and the anthrax toxin receptor binding/translocation moieties. Furthermore, neuronal death in vivo in a retinal ganglion cell model of axotomy-induced apoptosis was inhibited by administration of this fusion protein. Thus, Bcl-XL protein can be delivered into cells from the medium or interstitial space, offering a new way to block apoptosis upstream of many caspases and the mitochondria dysfunction phase of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Liu¹,

Collier²,

Youle³

2001

Journal of Biological Chemistry

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“…These characteristics make CED a valuable tool to investigate the therapeutic potential of various compounds for the treatment of injury and spinal cord diseases [39].Regional convective delivery provides reproducible, safe, region-specific, and homogeneous distribution of macromolecules over large longitudinal segments of the spinal cord. This delivery method overcomes the various obstacles associated with current delivery techniques, as suggested by the increase in the mean Vd/Vi ratio in corresponding studies of macromolecule administration via CED [39,40,41]. These findings call for further research done in order to investigate new treatments of various conditions of the spinal cord.…”

Section: Modeling Ced In the Spinal Cordmentioning

confidence: 99%

“…Could the injured spinal cord also have limited diffusion via CED similar to nerves, needs to confirm. Small silica cannula inserted in peripheral nerve; (10,20,30,40, and 80 ml) of 14C-labeled or gadolinium-labeled albumin were infused unilaterally or bilaterally into the tibial nerves of primates @ 0.5ml/min; and one primate infused bilaterally with gadoliniumbound albumin (40 ml/nerve) underwent MR imaging 16 weeks after infusion.…”

Section: Modeling Ced In the Spinal Cordmentioning

confidence: 99%

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

2017

ARC Journal of Neuroscience

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“…Because convective distribution of an infusate occurs in the interstitial space, the distribution volume achieved by CED of a given infusate volume is inversely proportional to the size of the extracellular space available in the target tis- 22,54,58,63 Perfusion into the tightly compacted white matter fibers of the brainstem is associated with larger distribution volume to infusion volume ratios, generally in the range of 6:1 to 10:1. 60,72,99 This property of CED allows large, clinically relevant volumes of CNS tissue to be perfused relatively rapidly.…”

Section: Reproducible Distributionmentioning

confidence: 99%

“…Autoradiographic analysis of infusate distribution in a large-animal brain, brainstem, spinal cord, and peripheral nerve demonstrates the homogeneity of convective delivery. 7,58,63,72 Analysis of the distribution of radiolabeled compounds in animals euthanized immediately after completing a brief infusion via CED demonstrates a homogeneous "squareshaped" distribution pattern in gray and white matter consistent with a uniform high concentration of infusate over a perfused CNS region. Thus, biological and pharmacological effects that depend on the concentration of a molecule of interest exceeding a certain threshold can be precisely targeted.…”

Section: Homogeneous Distributionmentioning

confidence: 99%

Convection-enhanced delivery to the central nervous system

Lonser

Sarntinoranont

Morrison

et al. 2015

JNS

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187

148

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Based on the rapid progression in understanding the precise pathobiology underlying various neurological diseases, a number of promising new putative therapeutics have been developed for specific disorders that have been ineffectually treated or are not currently treatable. While these agents have been successful in reversing disease-related pathology in vitro and/or in animal models, they have not been successfully translated into clinically effective therapies. One of the largest obstacles to the successful conversion of putative therapeutics into effective treatments is the inability to deliver these agents past the CNS blood-brain barrier (BBB) in a reliable, targeted, and homogeneous way using currently available approaches for drug delivery, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation. 6,15,47,67,80 To surmount the limitations of available CNS drug delivery techniques, targeted direct perfusion of regions of the nervous system using the convection-enhanced delivery (CED) of infusate is increasingly used in research models of neurological disease and in clinical trials to treat neurological disorders. Because infusate is driven by a hydrostatic pressure differential (bulk flow), 7,67 CED can be used to bypass the BBB and distribute putative therapeutics to targeted regions. Further, convective bulk flow properties allow for homogeneous and reproducible perfusion of variably sized regions of the nervous system using compounds with a wide range of molecular weights. The development of co-infused surrogate imaging tracers now permits noninvasive real-time monitoring of convective delivery. We review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS. Biophysical Principles of Convective FlowWithin the extracellular space of the CNS, fluids and agents move either by diffusion or by bulk flow. Diffusive flux (J) depends on the concentration gradient (∇C, where ∇ is the gradient operator), as stated by Fick's law, J = -D∇C, where tissue diffusivity (D) is highly dependent on the molecular weight of the molecule. Unfortunately, effective diffusion times are long for macromolecular therapeutic agents, and transport depends on large concentration gradients, often requiring unacceptably high Convection-enhanced delivery (CED) is a bulk flow-driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review t...

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Direct convective delivery of macromolecules to the spinal cord

Cited by 99 publications

References 11 publications

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

Convection-enhanced delivery to the central nervous system

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