Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system

Chen, Mike Y.; Hoffer, Alan; Morrison, Paul F.; Hamilton, J. F.; Hughes, Jeffrey A.; Schlageter, Kurt S.; Lee, Jeongwu; Kelly, Brandon R.; Oldfield, Edward H.

doi:10.3171/jns.2005.103.2.0311

Cited by 106 publications

(79 citation statements)

References 30 publications

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“…Chen et al 46 and MacKay et al 47 demonstrated that polystyrene nanoparticles and liposomes with a diameter of 200 nm only penetrated short distances into the striatum of rats. Interestingly, however, Chen et al demonstrated that coating the nanoparticles with albumin to shield the hydrophobic particle surface significantly improved their distribution.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, however, Chen et al demonstrated that coating the nanoparticles with albumin to shield the hydrophobic particle surface significantly improved their distribution. 46 Furthermore, Neeves et al 48 demonstrated that preinfusing the striatum with isotonic saline significantly improved the distribution of 53 nm diameter polystyrene nanoparticles in the striatum of rats. This effect was greater than was observed with preinfusion of hyaluronidase to degrade the brain extracellular matrix or with hyperosmotic mannitol to osmotically expand the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 ml min À1 ) and high infusion rates (2.5 ml min À1 ) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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“…This study used MRI to follow the distribution of the MR contrast agent, Gd-DTPA. The range of tracers used in CED studies is wide, including small-molecular-weight compounds such as Gd-DTPA, 18,19,32 dendrimers, 21 iron oxides, 20,36 nanoparticles, 33 and viruses 5,32,33 with attached Gd moieties. The Gd-DTPA tracer is a small-molecularweight contrast agent with the widest FDA approval for use in CNS, body, and head and neck applications in both adults and children.…”

Section: Discussionmentioning

confidence: 99%

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Fan

Nelson

Ai³

et al. 2015

JNS

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OBJECT Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. METHODS The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. RESULTS All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. CONCLUSIONS These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

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“…Therefore, alternative strategies have been developed for delivering nanoparticles to affected brain tissue. Intracranial infusion, or convection-enhanced delivery (CED), has been used to deliver low molecular weight molecules [2,25,1], proteins [24,23,26], and several kinds of particles, including liposomes [28,42,43,19,44,36] and polymeric nanoparticles [6]. Although small molecules and some proteins can be distributed throughout the brain with CED, it has proven difficult to distribute nanoparticles over comparable distances.…”

Section: Introductionmentioning

confidence: 99%

Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles

et al. 2007

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This study investigates methods of manipulating the brain extracellular matrix (ECM) to enhance the penetration of nanoparticle drug carriers in convection-enhanced delivery (CED). A probe was fabricated with two independent microfluidic channels to infuse, either simultaneously or sequentially, nanoparticles and ECM-modifying agents. Infusions were performed in the striatum of the normal rat brain. Monodisperse polystyrene particles with a diameter of 54 nm were used as a model nanoparticle system. Because the size of these particles is comparable to the effective pore size of the ECM, their transport may be significantly hindered compared with the transport of low molecular weight molecules. To enhance the transport of the infused nanoparticles, we attempted to increase the effective pore size of the ECM by two methods: dilating the extracellular space and degrading selected constituents of the ECM. Two methods of dilating the extracellular space were investigated: co-infusion of nanoparticles and a hyperosmolar solution of mannitol, and pre-infusion of an isotonic buffer solution followed by infusion of nanoparticles. These treatments resulted in an increase in the nanoparticle distribution volume of 50% and 123%, respectively. To degrade hyaluronan, a primary structural component of the brain ECM, a pre-infusion of hyaluronidase (20,000 U/mL) was followed after 30 min by infusion of nanoparticles. This treatment resulted in an increase in the nanoparticle distribution of 64%. Our results suggest that both dilation and enzymatic digestion can be incorporated into CED protocols to enhance nanoparticle penetration.

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Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system

Abstract: These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS.

Cited by 106 publications

References 30 publications

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles

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