Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme
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ORIGINAL ARTICLE
Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme Yunho Han 1 & Ji-Ho Park 1
# Controlled Release Society 2020
Abstract The blood-brain barrier (BBB) impedes the efficient delivery of systemically administered drugs to brain tumors, thus reducing the therapeutic efficacy. To overcome the limitations of intravascular delivery, convention-enhanced delivery (CED) was introduced to infuse drugs directly into the brain tumor using a catheter with a continuous positive pressure. However, tissue distribution and retention of the infused drugs are significantly hindered by microenvironmental factors of the tumor such as the extracellular matrix and lymphatic drainage system in the brain. Here, we leveraged a liposomal formulation to simultaneously improve tissue distribution and retention of drugs infused in the brain tumor via the CED method. Various liposomal formulations with different surface charge, PEGylation, and transition temperature (Tm) were prepared to test the cellular uptake in vitro, and the tissue distribution and retention in the brain. In in vitro studies, PEGylated liposomal formulations with a positive surface charge and high Tm showed the most efficient cellular uptake among the tested formulations. In in vivo studies, the liposomal formulations were infused directly into the brain via the CED method. PEGylated liposomal formulations with a positive surface charge and high Tm showed more efficient distribution and retention in both normal and tumor tissues while onlyPEGylated formulations displayed rapid clearance from the tissues to cervical lymph nodes. Furthermore, we demonstrated that the CED of liposomal everolimus prepared with the PEGylated formulation with a positive surface charge and high Tm resulted in superior therapeutic effects for glioblastoma treatment compared to other formulations. Keywords Cervical lymph node . Chemotherapy . Convection-enhanced delivery . Glioblastoma . Liposome
Introduction Glioblastoma multiforme (GBM) originates from the astrocyte, which accounts for the majority of cellular composition in the brain. The World Health Organization (WHO) classifies GBM as a grade IV astrocytoma because it is the most aggressive malignant brain tumor. Malignant gliomas account for ~ 40% of primary brain tumors and more than 15,000 new cases are diagnosed in the USA each year [1]. Although the incidence rate of GBM is low, the median survival with standardElectronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-020-00773-w) contains supplementary material, which is available to authorized users. * Ji-Ho Park [email protected] 1
Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
of-care therapy is only 14.6 months and 12.1 months with radiotherapy alone [1, 2]. The standard treatment procedure for GBM is maximal surgical resection, followe
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