BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Multi-function molecular backbone("masked") UNmasked" backbone carriers disrupts endosomal Acid-dogradable acetal Enkerg R n endosome Peptide DRUG Free DRUG delivered PEG grafts mask" backbone丰 ODN DRUG Released in high ionic strength of cytosol murthy et al., 2003) endosomes 3 functionalities of polymer carrier 1. targeting ligand for receptor-mediated endocytosis 2. pH-responsive element for endosomal membrane disruption, exposed only when endosomes are reached 3. therapeutic drug attached, released in endosomes pH-responsive element: acetal linkages o degradation rate of acetal linkages sensitive to identity of para group on attached benzene ring N->o tu drops by 60-fold(JACS 77, 5590(1955)) o t1/2=15 min at pH 5. 4 for the given structure hydrolysis rate 100X at pH 5.4 compared to pH 7.4 Lecture 16-intracellular delivery 6 of 8BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Multi-function molecular carriers: Reduced to -SH in cytosol Released in high ionic strength of cytosol (Murthy et al., 2003) (1) (2) (3) (4) endosomes Receptor targeting ƒ 3 functionalities of polymer carrier: 1. targeting ligand for receptor-mediated endocytosis 2. pH-responsive element for endosomal membrane disruption, exposed only when endosomes are reached 3. therapeutic drug attached, released in endosomes ƒ pH-responsive element: acetal linkages o degradation rate of acetal linkages sensitive to identity of para group on attached benzene ring ƒ N -> O t1/2 drops by 60-fold (JACS 77, 5590 (1955)) o t1/2 = 15 min at pH 5.4 for the given structure ƒ hydrolysis rate 100X at pH 5.4 compared to pH 7.4 o Lecture 16 – intracellular delivery 6 of 8