Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>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 &amp; 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.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>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.</jats:p></jats:sec>

Localized delivery of therapeutic doxorubicin dose across the canine blood–brain barrier with hyperthermia and temperature sensitive liposomes

“…We employed TSL similar to the formulation initially proposed by Needham et al. ( 2000 ), and loaded with the chemotherapy doxorubicin as this drug is effective against glioma in vitro (Stan et al., 1999 ; Veringa et al., 2013 ; Sewing et al., 2017 ), but cannot cross the BBB. To elicit localized brain hyperthermia, we employed an interstitial needle probe based on radiofrequency heating, inserted through skull burr holes.…”

“…Doxorubicin is currently not used in the treatment of brain tumors because it cannot cross the BBB, but is effective against high-grade gliomas in culture (Stan et al., 1999 ; Veringa et al., 2013 ; Sewing et al., 2017 ) and in vivo (Gong et al., 2011 ; Sewing et al., 2017 ), and also patient benefit has been demonstrated when administered in liposomal form (Fabel et al., 2001 ). Thus, proof of doxorubicin delivery across the BBB has potential therapeutic value, but would also demonstrate viability of the proposed approach in delivering drugs across the BBB that otherwise could not cross (Sewing et al., 2017 ). In addition, we wanted to examine long-term survival in large animals to evaluate the neurotoxicity of doxorubicin delivered to focal areas of the brain in the setting of transient hyperthermia, which has not been evaluated in prior studies.…”

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

“…To our knowledge, intratumoral delivery of TMZ has not been clinically tested yet but promising results have been presented in experimental brain tumor models and clinical trials also with other TMZ formulations or cytostatic drugs [31][32][33][34][35]. Other mechanisms of local drug administration have also been used.…”

The intersect of neurosurgery with diffuse intrinsic pontine glioma

“…In 2002, our group demonstrated the feasibility and safety of CED within the brainstem in a rodent model. 59 The safety and toxicity of potential therapeutic agents as well as the distribution pattern of the infusate have subsequently been studied in further animal studies 41,62,63,65,69,70,76,77 that have confirmed that CED does not cause relevant injury to the brainstem.…”