Principles of controlled drug delivery systems with relevance to tissue engineering implants

POLY 2

Allan S. Hoffman, hoffman@u.washington.edu, Department of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195
The biotechnology field has identified many new biomolecular drugs that act at intracellular sites such as the nucleus or the ribosomes, or interact with mRNA in the cytosol, or are processed via the MHC-1 pathway. Such drugs could be used to stimulate the cells within tissue-engineered scaffolds to differentiate into a desired phenotype and/or to proliferate. Passive or receptor-mediated endocytosis of drug formulations results in localization within the endosome, where the predominant trafficking fate is fusion with lysosomes and subsequent enzymatic degradation of the biomolecular drug. A variety of viruses and toxins have evolved pH-dependent fusogenic proteins to overcome this barrier by enhancing endosomal escape to the cytoplasm at the acidic pH of the endosome. Inspired by the principle behind this biological strategy, we have designed a family of new, pH-responsive polymeric carriers that enhance delivery of fragile drugs to the cytosol from the endosomes. Our results suggest that these novel polymers can enhance intracellular delivery of a variety of biomolecules or drugs where cytoplasmic localization is a critical step.