Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model
WG Singleton,1,2 AM Collins,3 AS Bienemann,1 CL Killick-Cole,1 HR Haynes,4 DJ Asby,1 CP Butts,5 MJ Wyatt,1 NU Barua,1,2 SS Gill1,2 1Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol, 2Department of Neurosurgery, North Bristol NHS Trust, 3Bristol Centre for Fu...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2017-02-01
|
| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/convection-enhanced-delivery-of-panobinostat-lbh589-loaded-pluronic-na-peer-reviewed-article-IJN |
| _version_ | 1818684625341382656 |
|---|---|
| author | Singleton WG Collins AM Bienemann AS Killick-Cole CL Haynes HR Asby DJ Butts CP Wyatt MJ Barua NU Gill SS |
| author_facet | Singleton WG Collins AM Bienemann AS Killick-Cole CL Haynes HR Asby DJ Butts CP Wyatt MJ Barua NU Gill SS |
| author_sort | Singleton WG |
| collection | DOAJ |
| description | WG Singleton,1,2 AM Collins,3 AS Bienemann,1 CL Killick-Cole,1 HR Haynes,4 DJ Asby,1 CP Butts,5 MJ Wyatt,1 NU Barua,1,2 SS Gill1,2 1Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol, 2Department of Neurosurgery, North Bristol NHS Trust, 3Bristol Centre for Functional Nanomaterials, School of Physics, HH Wills Physics Laboratory, 4Brain Tumour Research Group, School of Clinical Sciences, 5School of Chemistry, University of Bristol, Bristol, UKBackground: 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.Keywords: glioma, micelle, convection enhanced delivery, panobinostat, HDAC inhibitor |
| first_indexed | 2024-12-17T10:53:36Z |
| format | Article |
| id | doaj.art-aab501023622452a81f2d895f5be6579 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-17T10:53:36Z |
| publishDate | 2017-02-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-aab501023622452a81f2d895f5be65792022-12-21T21:51:54ZengDove Medical PressInternational Journal of Nanomedicine1178-20132017-02-01Volume 121385139931453Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma modelSingleton WGCollins AMBienemann ASKillick-Cole CLHaynes HRAsby DJButts CPWyatt MJBarua NUGill SSWG Singleton,1,2 AM Collins,3 AS Bienemann,1 CL Killick-Cole,1 HR Haynes,4 DJ Asby,1 CP Butts,5 MJ Wyatt,1 NU Barua,1,2 SS Gill1,2 1Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol, 2Department of Neurosurgery, North Bristol NHS Trust, 3Bristol Centre for Functional Nanomaterials, School of Physics, HH Wills Physics Laboratory, 4Brain Tumour Research Group, School of Clinical Sciences, 5School of Chemistry, University of Bristol, Bristol, UKBackground: 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.Keywords: glioma, micelle, convection enhanced delivery, panobinostat, HDAC inhibitorhttps://www.dovepress.com/convection-enhanced-delivery-of-panobinostat-lbh589-loaded-pluronic-na-peer-reviewed-article-IJNNano-micelleshigh grade gliomaconvection enhanced deliverypanobinostatHDACi |
| spellingShingle | Singleton WG Collins AM Bienemann AS Killick-Cole CL Haynes HR Asby DJ Butts CP Wyatt MJ Barua NU Gill SS Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model International Journal of Nanomedicine Nano-micelles high grade glioma convection enhanced delivery panobinostat HDACi |
| title | Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model |
| title_full | Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model |
| title_fullStr | Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model |
| title_full_unstemmed | Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model |
| title_short | Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model |
| title_sort | convection enhanced delivery of panobinostat lbh589 loaded pluronic nano micelles prolongs survival in the f98 rat glioma model |
| topic | Nano-micelles high grade glioma convection enhanced delivery panobinostat HDACi |
| url | https://www.dovepress.com/convection-enhanced-delivery-of-panobinostat-lbh589-loaded-pluronic-na-peer-reviewed-article-IJN |
| work_keys_str_mv | AT singletonwg convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT collinsam convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT bienemannas convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT killickcolecl convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT hayneshr convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT asbydj convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT buttscp convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT wyattmj convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT baruanu convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel AT gillss convectionenhanceddeliveryofpanobinostatlbh589loadedpluronicnanomicellesprolongssurvivalinthef98ratgliomamodel |