Effective treatment of brain
neurological disorders such as
Alzheimer's disease,
multiple sclerosis, or
tumors should be possible with
drug delivery through blood-brain barrier (BBB) or blood-
brain tumor barrier (BTB) and targeting specific types of brain cells with drug release into the cell cytoplasm. A polymeric nanobioconjugate
drug based on biodegradable, nontoxic, and nonimmunogenic
polymalic acid as a universal delivery nanoplatform was used for design and synthesis of nanomedicine
drug for i.v. treatment of
brain tumors. The polymeric
drug passes through the BTB and
tumor cell membrane using tandem
monoclonal antibodies targeting the BTB and
tumor cells. The next step for polymeric
drug action was inhibition of
tumor angiogenesis by specifically blocking the synthesis of a
tumor neovascular trimer
protein, laminin-411, by attached
antisense oligonucleotides (AONs). The AONs were released into the target cell cytoplasm via pH-activated
trileucine, an endosomal escape moiety.
Drug delivery to the
brain tumor and the release mechanism were both studied for this nanobiopolymer. Introduction of a
trileucine endosome escape unit resulted in significantly increased AON delivery to
tumor cells, inhibition of laminin-411 synthesis in vitro and in vivo, specific accumulation in
brain tumors, and suppression of intracranial
glioma growth compared with pH-independent
leucine ester. The availability of a systemically active polymeric drug delivery system that passes through the BTB, targets
tumor cells, and inhibits
glioma growth gives hope for a successful strategy of
glioma treatment. This delivery system with drug release into the brain-specific cell type could be useful for treatment of various brain pathologies.