BEH. 462/3.962J Molecular Principles of Biomaterials Spring 2003 Issues in Drug Targeting ‘ collateral damage o how unique is target? Is it expressed in normal tissues often ratio of drug delivery tumor normal tissue is not high enough In certain cases, elimination of healthy cells is acceptable E.g. hematopoietic system(T cells, B cells)can be replenished by bone marrow transplant Many times the normal tissue from which tumors are derived cannot be safely destroyed Tumor and viral escape o Loss of target antigen expression due to rapid mutations(antigen-loss variants) Immunological response to targeting agent o Early studies used mouse antibodies for targeting Low efficacy due to very short half-life and development of anti-sera Integrating targeting, activation, and intracellular delivery Example of targeted delivery to cytosol by functionalized pH-sensitive liposomal carriers o Shi et al. 2002 Objective: intracellular delivery of a cellular toxin to tumors o Target receptor also triggers receptor-mediated endocytosis (-) 680 incubation (min) (Shi et aL. 2002) Charge neutralization at low pH drives irreversible aggregation of particles at low pH(membrane fusion on particle aggregation) Rapid aggregation at 37C Lecture 17-Drug targeting 6 of 7BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 17 – Drug targeting 6 of 7 Issues in Drug Targeting ƒ ‘collateral damage’ o how unique is target? Is it expressed in normal tissues ƒ often ratio of drug delivery tumor:normal tissue is not high enough ƒ In certain cases, elimination of healthy cells is acceptable • E.g. hematopoietic system (T cells, B cells) can be replenished by bone marrow transplant ƒ Many times the normal tissue from which tumors are derived cannot be safely destroyed ƒ Tumor and viral escape o Loss of target antigen expression due to rapid mutations (antigen-loss variants) ƒ Immunological response to targeting agent o Early studies used mouse antibodies for targeting ƒ Low efficacy due to very short half-life and development of anti-sera Integrating targeting, activation, and intracellular delivery ƒ Example of targeted delivery to cytosol by functionalized pH-sensitive liposomal carriers o Shi et al. 20025 ƒ Objective: intracellular delivery of a cellular toxin to tumors o Target receptor also triggers receptor-mediated endocytosis (Shi et al. 2002) (+) (-) QuickTime™ and a Graphics decompressor are needed to see this picture. QuickTime™ and a Graphics decompressor are needed to see this picture. ƒ Charge neutralization at low pH drives irreversible aggregation of particles at low pH (membrane fusion on particle aggregation) • Rapid aggregation at 37°C