Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: Implications for local drug delivery

Saito, Ryuta; Krauze, Michal T.; Noble, Charles O.; Tamas, Matyas; Drummond, Daryl C.; Kirpotin, Dmitri B.; Berger, Mitchel S.; Park, John W.; Bankiewicz, Krystof S.

doi:10.1016/j.jneumeth.2005.12.027

Cited by 87 publications

(75 citation statements)

References 20 publications

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“…The physicochemical characteristics and hydrophobicity of panobinostat make it an unlikely candidate for CED in its unmodified form. 25 Chemical modification of panobinostat to achieve water solubility risks negation of its biochemical efficacy. To overcome these limitations, we investigated the delivery of panobinostat as a payload in nano-micellar form.…”

Section: Introductionmentioning

confidence: 99%

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Singleton¹,

Collins²,

Bienemann³

et al. 2017

IJN

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Background The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood–brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). Materials and methods The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. Results Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P <0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. Conclusion CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

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Section: Introductionmentioning

confidence: 99%

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Singleton¹,

Collins²,

Bienemann³

et al. 2017

IJN

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show abstract

“…In the past decade, a number of drug delivery strategies have been developed to overcome obstacles presented by the BBB. In particular, direct drug administration into the brain parenchyma, such as convection-enhanced delivery (CED) has shown promising results in both animal models and clinical trials (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). However, CED requires the use of potentially risky surgical procedures to position the catheter into the brain parenchyma of the patient (6,7).…”

Section: Introductionmentioning

confidence: 99%

Regression of Glioma in Rat Models by Intranasal Application of Parvovirus H-1

Kiprianova

Thomas

Ayache

et al. 2011

Clinical Cancer Research

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Purpose: In previous studies, we have shown that the apathogenic rat parvovirus H-1 (H-1PV) is capable to induce regression of advanced symptomatic rat and human gliomas in a rat model, when the virus was injected in the tumor (intracranially) or intravenously. Infection with H-1PV did not provoke any pathology in nontumor tissue. This study addresses the question whether also intranasal application of this oncolytic virus is suitable and sufficient for treating gliomas in this animal model.Experimental Design: Rat (RG-2) or human (U87) glioma cells were grafted stereotactically in the brain of rats (Wistar or RNU, respectively), and after development of tumors visible by MRI, H-1PV was instilled intranasally. Tumor regression was monitored by MRI, and survival was analyzed by Kaplan-Meier analysis. Brains from sacrificed animals were analyzed for histologic alterations, presence of viral DNA and proteins and infectious virions. In addition, distribution of virus to other organs was determined.Results: A single intranasal instillation of H-1PV was sufficient to induce efficient regression of rat glioma, leading to significant prolongation of survival without any toxicity for other tissues. It is shown that the virus reaches brain and other tissues, and that the viral replication-associated (and oncolysis-associated) regulatory proteins are exclusively expressed in the tumor tissue. In rats with xenografts of human glioma, oncolytic activity of H-1PV was less pronounced, however, leading to significant prolongation of survival.Conclusion: In view of an ongoing clinical trial on the use of H-1PV for oncolytic virotherapy of glioma, the option of applying the virus intranasally may be a valuable alternative to invasive routes of infection.

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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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Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: Implications for local drug delivery

Cited by 87 publications

References 20 publications

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

Regression of Glioma in Rat Models by Intranasal Application of Parvovirus H-1

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

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