“Smart” pH-Responsive Carriers for Intracellular Delivery of Biomolecular Drugs
A large number of therapeutic drugs that utilize biological molecules, i.e., DNA, RNA, and proteins, are under current development in the biotechnology and pharmaceutical industries. Their potential is widely recognized, but bringing them into medical practice remains a major challenge. For proteins such as antibodies that act at the extracellular membrane face, considerable progress has been made in bringing them into medical practice. However, for biomolecules that function at intracellular locations (e.g., immunotoxins, antisense oligonucleotides, siRNA, antigens for vaccines), there is the additional difficult barrier of cytoplasmic entry (Kyriakides et al., 1999, 2001) in addition to the general challenges of drug stability, tissue penetration and transport, and therapeutic targeting. The predominant fates of internalized biomolecules are enzymatic degradation in the lysosome or recycling and extracellular clearance. In this chapter, we review the development of synthetic polymeric carriers that mimic the highly efficient intracellular delivery systems found in pathogenic viruses and organisms. Their most important property ties together the sensing of pH changes to membrane-destabilizing activity. The carriers are applicable to a wide range of biotherapeutics, and might additionally open up new families of protein or nucleic acid candidates that attack intracellular targets.
KeywordsReversible Addition Fragmentation Chain Transfer Polymeric Carrier Intracellular Delivery Proton Sponge Cytosolic Delivery
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