ABSTRACT
A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.
Subject(s)
Paclitaxel/administration & dosage , Prodrugs/administration & dosage , Animals , Cell Line, Tumor , Drug Stability , Humans , Hydrophobic and Hydrophilic Interactions , Lipids/chemistry , Mice , Mice, Nude , Micelles , Nanoparticles , Neoplasm Transplantation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Polyethylene Glycols , Polystyrenes , Prodrugs/chemistry , Prodrugs/pharmacology , Transplantation, HeterologousABSTRACT
Mechanisms related to the neuropathogenesis of enterovirus 71 infection remain unclear. This investigation conducts a comprehensive study of the apoptotic pathways in neural and non-neural cells following enterovirus 71 infection. Infections with enterovirus 71 not only induce classical cytopathic effects in SF268 (human glioblastoma), SK-N-MC (human neuroblastoma), RD, and Vero cells, but also induce classic signs of apoptosis in all cells, including DNA fragmentation and phosphatidylserine translocation. Apoptosis has also been caused by the efflux of cytochrome c from mitochondria, and subsequently by cleavage of caspase 9 in all cells. Activation of caspase 8 followed by cleavage of the proapoptotic protein Bid only occurs in non-neural cells. Results of this study demonstrate that a mitochondrial pathway of apoptosis mediated by activation and cleavage of caspase 9 is a main pathway in enterovirus 71-induced apoptosis, especially for enterovirus 71-infected neural cells.
