title: Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.
abstract: OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.
authors.affiliation: Departments of 1 Pediatric Oncology.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: A Charlotte P
authors.initials: ACP
authors.lastname: Sewing
authors.affiliation: Neurosurgery, and.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.affiliation: Departments of 1 Pediatric Oncology.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: Dannis G
authors.initials: DG
authors.lastname: van Vuurden
authors.affiliation: Departments of 1 Pediatric Oncology.|Neurosurgery, and.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: Michaël H
authors.initials: MH
authors.lastname: Meel
authors.affiliation: Departments of 1 Pediatric Oncology.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: Susanna J E
authors.initials: SJE
authors.lastname: Veringa
authors.affiliation: Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de Déu Barcelona, Spain.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
authors.affiliation: 2-BBB Medicines, Leiden.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Gaillard
authors.affiliation: Neurosurgery, and.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: W
authors.initials: W
authors.lastname: Peter Vandertop
authors.affiliation: Pathology.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.|2-BBB Medicines, Leiden.|Department of Pathology, RadboudUMC, Nijmegen.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Neurosurgery, and.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: David
authors.initials: D
authors.lastname: Noske
authors.affiliation: Neuro-Oncology Research Group.|Academy of Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands ; and.
authors.forename: Gertjan J L
authors.initials: GJL
authors.lastname: Kaspers
authors.affiliation: Departments of 1 Pediatric Oncology.|Neuro-Oncology Research Group.|Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam.
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D018481:Convection; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000633:toxicity; D011149:Pons / Q000187:drug effects / Q000473:pathology; D013788:Thalamus / Q000187:drug effects / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: BBB = blood-brain barrier; BLI = bioluminescent imaging; CED; CED = convection-enhanced delivery; DIPG; DIPG = diffuse intrinsic pontine glioma; GBM = glioblastoma multiforme; IC50 = half maximal inhibitory concentration; LG-BSG = low-grade brainstem glioma; MTD = maximum tolerated dose; PBS = phosphate-buffered saline; PLD = pegylated liposomal doxorubicin; TOPIIA = topoisomerase Type IIA; VUMC = VU University Medical Center; anthracyclines; convection-enhanced delivery; diffuse intrinsic pontine glioma; doxorubicin; oncology; pHGG; pHGG = pediatric high-grade glioma; pediatric high-grade glioma; thalamus