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

Abstract

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.

The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery

“…One method to overcome this limitation is to package the drug in a water-soluble nanoparticle or micelle. 26 The translation of this nanoparticle formulation of panobinostat to the clinic is challenging, as the breakdown and metabolism of the encapsulating nanoparticle within the brain is unknown, as is its potential for long-term accumulation or toxicity. An alternative method of producing a water-soluble formulation of panobinostat designed for CED may allow a quicker path to the clinic.…”

Gliomas in Children

“…Panobinostat, among other drugs, is being currently considered for early stage clinical trials facilitating drug delivery by convection-enhanced delivery-a catheterbased method in which the study agent is directly infused into the target tissue. 74,75 Another HDAC inhibitor that has been studied in the context of HGGs is vorinostat (SAHA); early studies in children with HGGs demonstrated good tolerability and have now moved to phase II studies in combination with radiation and TMZ 76 (ClinicalTrials.gov NCT01189266). A combination of vorinostat and the mTor inhibitor temsirolimus (NCT02420613) is also currently ongoing.…”

Nanomaterials for convection-enhanced delivery of agents to treat brain tumors

“…CED of nanodiamonds complexed with doxorubicin enhanced tissue retention, localized its toxicity and provided prolonged survival in rats with intracranial tumors [27]. Nano-micelles loaded with panobinostat, a strongly hydrophobic drug that is unstable when delivered in its unmodified form, prolonged survival of tumor-bearing rats [28]. Lipidoid nanoparticles encapsulating truncated diphtheria toxin were delivered by CED and inhibited brain tumor growth [29].…”

“…These include EGFR inhibitors (cetuximab, erlotinib, gefitinib), PI3K/mTOR inhibitors (everolimus, tacrolimus, sirolimus), pan-histone deacetylase inhibitor (panobinostat), and monoclonal antibodies such as those against VEGF (bevacizumab) [82]. Panobinostat, a strongly hydrophobic drug with poor BBB permeability, has been shown to be much more effective when loaded into nano-micelles [28]. Nanoencapsulation and local delivery of these agents could dramatically improve their activity against GBM tumors.…”