Engineering of liposomal drugs for the treatment of glioblastoma via convection-enhanced delivery

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor having low median survival time with conventional therapy. The presence of blood-brain barrier (BBB) impedes the delivery of therapeutic agents in bloodstream into brain parenchyma. Local delivery methods can circumvent BBB, but distribution of drugs is restricted due to the absence of driving force. A convention-enhanced delivery (CED) is the local injection method driven by pressure gradient via injection pump, resulting in the enhanced penetration of drugs. However, unprotected free drugs can be readily degraded by enzymes or cleared by drainage system. In this study, we have engineered the optimal formulation of liposome that shows enhanced penetration, cellular uptake and retention in brain tissue after CED. Liposomes with various size, surface chemistry and fluidity were synthesized and their capability of cellular uptake to tumor cell was assessed. Liposome with strong positive charge, no PEGylation and low fluidity enters well into tumor cells via endo-lysosomal pathway. CED of liposomes with low fluidity to healthy mouse brain revealed that PEGylation increased the distribution while the quantity was very low. Positive charge liposome aggregated near the injection site. Liposome that has both PEG and positive charge showed the best capability of distribution and accumulation. This formulation also indicated great retention after 48 hours. Biodistribution of liposomes in organs further demonstrated that PEGylated liposome cleared from brain and accumulated in the liver, spleen and cervical lymph nodes. This trend was repeated in tumor condition, with even faster clearance of PEGylated formulation. Finally, we examined the therapeutic efficacy of everolimus (Eve)-embedded liposomes. Both in vitro and in vivo, liposome with both PEG and positive charge demonstrated better effects than only-PEGylated liposome. This optimized liposomal formulation with enhanced penetration, cellular uptake and retention can further improve the therapeutic outcomes for GBM treatment.