REGULATED UPTAKE OF BIOPOLYMERS Role of cell surface proteoglycans Implications for drug and gene delivery

Abstract: Cells continuously export, import, and recycle molecules over the plasma membrane. Internalization, i.e. cellular import of extracellular material, is a fundamental process, which provides cells with nutrients and enables the immune cells of higher organisms to remove debris, sample their surroundings for antigens and to fight microbes. Moreover, internalization regulates complex cellular signalling events involved in cellular division, motion, and communication with the surrounding extracellular matrix. However, the preserved routes of internalization are exploited by a large number of microbes and pathological factors such as bacterial toxins and viral proteins. The HIV-1 TAT protein was shown to enter cells and to target their nuclei, thus acting as a paracrine transcription factor, a finding that initiated the field of so called cell penetrating peptides (CPPs). Due to their ability to efficiently deliver macromolecular cargo over the plasma membrane, CPPs have proven to be useful tools in basic research. More importantly, the technology has been shown to enhance delivery of a number of macromolecular compounds in vivo, including anticancer drugs. The proteoglycan family of molecules has previously been shown to participate in the interaction with and internalization of a number of ligands, including polyamines, growth factors, morphogens, and microbes. This thesis deals with the role of proteoglycans in cellular internalization of charged biopolymers, i.e. the polyamine family of growth factors, HIV-Tat peptide, antimicrobial peptides, and nucleic acids. The presented findings bring proteoglycans into focus as a general internalization pathway for charged macromolecules, with implications for drug and gene delivery.