Subject(s)
DNA/administration & dosage , Gene Transfer Techniques , Genetic Therapy , Plasmids/genetics , Ultrasonics , Animals , Chloramphenicol O-Acetyltransferase/metabolism , Enzyme-Linked Immunosorbent Assay , HeLa Cells , Humans , Liposomes/administration & dosage , Mice , NIH 3T3 Cells , Plasmids/chemistry , TransfectionSubject(s)
Colonic Neoplasms/therapy , DNA/administration & dosage , Gene Transfer Techniques , Genetic Therapy , Plasmids/genetics , Ultrasonics , Adenocarcinoma/therapy , Animals , Carcinoma, Squamous Cell/therapy , Cations , Chloramphenicol O-Acetyltransferase/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Interleukin-12/administration & dosage , Liposomes/administration & dosage , Mice , Muscles/metabolism , Plasmids/chemistry , Transfection , Tumor Cells, CulturedABSTRACT
Camptothecin-based drugs, because of their poor solubility and labile lactone ring, pose challenges for drug delivery. The purpose of this research was to develop a nanoparticle delivery system for camptotheca alkaloids. After initial investigations SN-38 was selected as the candidate camptotheca alkaloid for further development. Nanoparticles comprising SN-38, phospholipids and polyethylene glycol were developed and studied in vitro and in vivo. The SN-38 formulations were stable in human serum albumin and high lactone concentrations were observed even after 3 h. In vivo studies in nude mice showed prolonged half-life of the active (lactone form) drug in whole blood and increased efficacy compared to Camptosar in a mouse xenograft tumor model.
Subject(s)
Camptothecin/analogs & derivatives , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Topoisomerase Inhibitors , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/blood , Antineoplastic Agents, Phytogenic/pharmacokinetics , Body Weight/drug effects , Body Weight/physiology , Camptothecin/administration & dosage , Camptothecin/blood , Camptothecin/pharmacokinetics , Drug Delivery Systems , Enzyme Inhibitors/blood , HT29 Cells , Half-Life , Humans , Injections, Intravenous , Irinotecan , Lactones/chemistry , Light , Mice , Mice, Nude , Microspheres , Neoplasm Transplantation , Particle Size , Scattering, Radiation , Serum Albumin/chemistryABSTRACT
RATIONALE AND OBJECTIVES: New targeted microbubbles directed to the GPIIb IIIa receptor have been developed. The objective was to determine whether targeting microbubbles to clots would enhance ultrasound imaging. Systematic studies were designed to determine whether in vitro methodology is an acceptable predictor of in vivo efficacy. MATERIALS AND METHODS: Bioconjugate ligands were inserted into lipid-coated membranes of perfluorocarbon gas microbubbles and binding studies performed on activated platelets immobilized on cell culture plates. Targeted microbubble binding to clots in a flow through chamber was also assessed. Finally, microbubble binding studies on arteriolar and venular clots in a mouse cremasteric muscle model were conducted. RESULTS: Binding studies on platelet-immobilized plates demonstrated an affinity for targeted microbubbles versus untargeted microbubbles. Semiquantitative light obscuration techniques helped to measure extent of targeted microbubble binding. Targeted microbubbles similarly bound to platelet clots in the flow model. Finally, studies in the mouse model confirmed binding of targeted microbubbles in both venules and arterioles. CONCLUSION: The use of receptor selective targeted microbubbles improved binding to vascular thrombi in both in vitro and in vivo settings.
Subject(s)
Contrast Media/chemical synthesis , Contrast Media/pharmacokinetics , Platelet Aggregation/drug effects , Thrombosis/diagnostic imaging , Ultrasonography/methods , Animals , Fluorocarbons , Ligands , Male , Mice , Mice, Inbred C57BL , Microspheres , Photomicrography , Platelet Glycoprotein GPIIb-IIIa Complex/metabolismABSTRACT
Microbubbles, currently used as contrast agents have potential therapeutic applications. Microbubbles, upon insonation of sufficiently intense ultrasound will cavitate. Cavitation with microbubbles can be used to dissolve blood clots or deliver drugs. Targeting ligands and drugs can be incorporated into microbubbles to make highly specific diagnostic and therapeutic agents for activation with ultrasound. In this paper I will review some of these potential applications and experimental results using such agents for thrombolysis, drug and gene delivery.
