Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme

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 (T-m) 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 T-m 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 T-m showed more efficient distribution and retention in both normal and tumor tissues while only-PEGylated 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 T-m resulted in superior therapeutic effects for glioblastoma treatment compared to other formulations.