Protein transduction domain-mediated delivery of anticancer proteins

Abstract

Advances in molecular and cellular biological techniques and genomic information obtained through the human genome project have been accelerating the elucidation of the molecular mechanisms underlying cancer. Both genetic mutations and epigenetic alterations have been associated with cancer [1]. The former include deletions, point mutations, or amplification of genes, chromosomal translocations, and gain or loss of entire chromosomes. The latter are modifications of genomic DNA, such as methylation and acetylation. All of these alterations lead to a gain of function of oncogenes or loss of function of tumor suppressor genes and have been recognized as effective targets for cancer therapy. Not only small chemicals but also various high-molecular weight biomacromolecules, such as oligonucleotides, antisense nucleotides, antisense peptide nucleic acids, small interference RNA, DNA (cDNA), peptides, proteins, and antibodies, have proven useful for regulating the function of these target genes. However, the plasma membrane of the cell surface forms an effective barrier and limits the internalization of such macromolecules into cells; therefore, the application of these information-rich macromolecules to cancer therapy has long been restricted. Although various methods to internalize macromolecules into living cells in vivo have been proposed, most of them resulted in inefficient delivery. Additionally, other problems such as complex manipulation, toxicity, and immunogenicity have prevented the routine therapeutic use of macromolecules. © 2009 Springer-Verlag New York.