BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 spleen s tagged by different opsonins removed by cells in different organs e.g.liver vs Complement proteins, particularly C3 and C5 Immunoglobulins Other proteins known to facilitate particle uptake o Fibronectin o C-reactive protein Tuftsin Protein adsorption to particles is key Hydrophobic particles quickly removed from circulation in vivo(Int/ J. Pharm. 29, 53 Penetration through capillary walls into tissues o Passive delivery due to leakiness of vessels at sites of inflammation or tumor vasulature abnormalities Avoid induction of antibodies against molecules/particles O FUTURE OBJECTIVE o Pre-targeting drugs that trigger permeability of vasculature at desired sites to allow tissue access-a needed advance to make tissue-specific targeting truly work Stealth particles"," How to avoid uptake by scavenger cells? o Van Oss showed in 1978(Ann. Rev. Microbiol. 32, 19(1978)that many bacteria have a highly hydrophilic hydrated surface layer of protein, polysaccharide, and glycoprotein that reduces interactions with blood components and inhibits phagocytosis o Davis at about the same time (J Biol Chem. 252, 3578(1977) showed that PEGylated proteins are non- immunogenic and have greatly increased half-lives in vivo Concept 5 Similar to design of protein adsorption-resistant surfaces, provide entropic barrier o Eliminate protein binding to particle/molecule o Enhanced solubility(proteins)stability(particles)in water Functionalization of particles with PEG increases in vivo circulation time o Reduced protein adsorption to particle/molecule surface ptors of macrophages unable to bind particle/molec Same polymers employed as in the design of protein-resistant surfaces o Most studied: poly(ethylene glycol) o Others: dextran PEGylation applied to all forms of molecular, nano, and micro-particulate carriers Lecture15-‘ stealth’ particles 2 of 8BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 15 – ‘stealth’ particles 2 of 8 • Particles tagged by different opsonins removed by cells in different organs e.g. liver vs. spleen ƒ Components: • Complement proteins, particularly C3 and C5 • Immunoglobulins • Other proteins known to facilitate particle uptake: o Fibronectin o C-reactive protein o Tuftsin ƒ Protein adsorption to particles is key • Hydrophobic particles quickly removed from circulation in vivo (Intl. J. Pharm. 29, 53 (1986)) ƒ Penetration through capillary walls into tissues o Passive delivery due to ‘leakiness’ of vessels at sites of inflammation or tumor vasulature abnormalities1 ƒ Avoid induction of antibodies against molecules/particles o FUTURE OBJECTIVE: o Pre-targeting drugs that trigger permeability of vasculature at desired sites to allow tissue access – a needed advance to make tissue-specific targeting truly work1 Stealth particles2,3 ƒ How to avoid uptake by scavenger cells? o Van Oss showed in 1978 (Ann. Rev. Microbiol. 32, 19 (1978)) that many bacteria have a highly hydrophilic hydrated surface layer of protein, polysaccharide, and glycoprotein that reduces interactions with blood components and inhibits phagocytosis o Davis at about the same time (J. Biol. Chem. 252, 3578 (1977)) showed that PEGylated proteins are non￾immunogenic and have greatly increased half-lives in vivo Concept4,5 ƒ Similar to design of protein adsorption-resistant surfaces, provide entropic barrier o Eliminate protein binding to particle/molecule o Enhanced solubility (proteins)/stability (particles) in water ƒ Functionalization of particles with PEG increases in vivo circulation time o Reduced protein adsorption to particle/molecule surface o Receptors of macrophages unable to bind particle/molecule ƒ Same polymers employed as in the design of protein-resistant surfaces o Most studied: poly(ethylene glycol) o Others: dextran ƒ PEGylation applied to all forms of molecular, nano-, and micro-particulate carriers