BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 16: Intracellular drug delivery Last time nano- and micro-particle drug carriers Delivery to tissues from systemic circulation Today. Intracellular drug delivery Reading A.S. Hoffman et aL., Design of "smart polymers that can direct intracellular drug delivery, Polym. Adv. Technol. 13, 992-999(2002) Ph gradients and drug delivery: cancer res. 56, 1194(1996): adv drug deliv rev 25, 3 (1997); see asokan minireview J Pharm. sci 2002 Intracellular delivery of molecules Pathways of import into the cell Uptake of extracellular material by cells Size limitations -500 nm or less Occurs in clathrin-coated pits Can be triggered by receptor binding Environment within endocytic vesicle PH lowered in pathw Extracellular fluid DNAses, proteases, peptidases Endosomes 5.5-6.5 Proteases lysosomes 3.0-5 Proteases(e. g cathepsins) cialized scavengers(macrophages, neutrophilsand antigen presenting cells limitations: up to the size of the cell Lecture 16-intracellular delivery 1 of 8BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 16: Intracellular drug delivery Last time: nano- and micro-particle drug carriers Delivery to tissues from systemic circulation Today: Intracellular drug delivery Reading: A.S. Hoffman et al., ‘Design of “smart” polymers that can direct intracellular drug delivery,’ Polym. Adv. Technol. 13, 992-999 (2002) Ph gradients and drug delivery: cancer res. 56, 1194 (1996); adv drug deliv rev 25, 3(1997); see asokan minireview J. Pharm. Sci 2002 Intracellular delivery of molecules Pathways of import into the cell ƒ Uptake of extracellular material by cells o Endocytosis ƒ Size limitations: ~500 nm or less ƒ Occurs in clathrin-coated pits ƒ Can be triggered by receptor binding ƒ Environment within endocytic vesicles: x PH lowered in pathway Compartment Approximate pH Contents relevant for therapeutic delivery Extracellular fluid 7.4 DNAses, proteases, peptidases Endosomes ~5.5-6.5 Proteases lysosomes ~3.0-5.5 Proteases (e.g. cathepsins) cytosol o macropinocytosis, phagocytosis ƒ Specialized scavengers (macrophages, neutrophils) and antigen presenting cells ƒ Size limitations: up to the size of the cell Lecture 16 – intracellular delivery 1 of 8