Delivery of Biologics Across the Blood-Brain Barrier Through Nanoencapsulation

Abstract

Drug delivery through nanoencapsulation is a promising approach that offers systemic protection of the pharmaceutical and targeted delivery to the diseased tissue. Especially cancer therapeutic and gene-based medicine may benefit from the advantages offered by encapsulation in nanocarriers, since the off-target effect of anti-cancer drug often is severe and gene-based medicine have low systemic stability on its own. This thesis presents four different nanocarrier system with specific focus on delivery of small interfering RNA (siRNA) and cancer therapeutics. The first nanocarrier presented is a polymeric micelle made from an anionic triblock copolymer and was intended for delivery of drugs to the central nervous system (CNS), which is protected by the largely impermeable blood-brain barrier (BBB). In order to target the nanocarrier to the brain endothelial cells and obtain receptor-mediated trancytosis across the BBB, it was functionalized with the ligand angiopep. The functionalized micelles demonstrated high uptake in vitro but had no preference for the BBB when systemic administrated to mice. The middle block of the polymer was in the next study changed into two polycations of different charge density, which allowed for complexation of siRNA. These polyplexes were analysed for their ability to facilitate down-regulation of specific proteins in the targeted cells and the study showed that the more dens structure had better condensation of siRNA and mediated a more efficient inhibition of the reporter protein. One of the great challenges for drug delivery by nanocarriers is the dilemma of designing a particle that is highly stable whit no cellular interaction while in the blood stream but has a high uptake and efficient drug release in the diseased cells. As a solution to this dilemma, a liposomal nanocarrier containing an enzymatic cleavable lipopeptide was designed. The lipopeptide linked the protective poly(ethylene glycol) (PEG) to the liposome and when enzymatic cleaved it activated the liposome by removing the repulsive PEG coating. The dePEGylated liposome had increased cellular uptake and endosomal escape, which was utilized for highly effective delivery of siRNA to tumour cells. The enzyme sensitive liposomes were also applied for targeted delivery of chemotherapeutic agent. By a combination of targeting ligands and the cleavable lipopeptide the liposome was able to facilitate high delivery of the compound and efficient intracellular release and consequently killing the cancer cells.