ABSTRACT
Drug delivery vehicles that combine ultrasonic and molecular targeting are shown to locally concentrate a drug in a region-of-interest. The drug delivery vehicles, referred to as acoustically active lipospheres (AALs), are microbubbles surrounded by a shell of oil and lipid. In a region limited to the focal area of ultrasound application, circulating AALs are deflected by radiation force to a vessel wall and can subsequently be fragmented. Ligands targeting the alphavbeta3 integrin are conjugated to the AAL shell and increase in vitro binding by 26.5-fold over nontargeted agents. Toxicity assays demonstrate that paclitaxel-containing AALs exert a greater antiproliferative effect after insonation than free paclitaxel at an equivalent concentration. Lastly, ultrasound and molecular targeting are combined to deliver a model drug to the endothelium and interstitium of chorioallantoic membrane vasculature in vivo.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Drug Delivery Systems , Paclitaxel/administration & dosage , Sonication , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Cell Death/drug effects , Chick Embryo , Chorioallantoic Membrane/metabolism , Contrast Media , Drug Carriers , Humans , Integrin alphaVbeta3/metabolism , Ligands , Melanoma/metabolism , Melanoma/pathology , Microbubbles , Neoplasm Proteins/metabolism , Paclitaxel/pharmacokinetics , Tumor Cells, CulturedABSTRACT
Lipid-coated microbubbles represent a new class of agents with both diagnostic and therapeutic applications. Microbubbles have low density. Stabilization of microbubbles by lipid coatings creates low-density particles with unusual properties for diagnostic imaging and drug delivery. Perfluorocarbon (PFC) gases entrapped within lipid coatings make microbubbles that are sufficiently stable for circulation in the vasculature as blood pool agents. Microbubbles can be cavitated with ultrasound energy for site-specific local delivery of bioactive materials and for treatment of vascular thrombosis. The blood-brain barrier (BBB) can be reversibly opened without damaging the neurons using ultrasound applied across the intact skull to cavitate microbubbles within the cerebral microvasculature for delivery of both low and high molecular weight therapeutic compounds to the brain. The first lipid-coated PFC microbubble product is currently marketed for diagnostic ultrasound imaging. Clinical trials are currently in process for treatment of vascular thrombosis with ultrasound and lipid-coated PFC microbubbles (SonoLysis Therapy). Targeted microbubbles and acoustically active PFC nanoemulsions with specific ligands can be developed for detecting disease at the molecular level and targeted drug and gene delivery. Bioactive compounds can be incorporated into these carriers for site-specific delivery. Our aim is to cover the therapeutic applications of lipid-coated microbubbles and PFC emulsions in this review.
Subject(s)
Drug Carriers , Drug Delivery Systems , Lipids , Microspheres , Blood-Brain Barrier , Chemistry, Pharmaceutical , Drug Stability , Emulsions , Fluorocarbons , Gene Transfer Techniques , Humans , Oxygen/administration & dosage , Thrombolytic Therapy/methods , Ultrasonics , Ultrasonography/methodsABSTRACT
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
As part of a research effort to design and prepare high affinity ligands for the galactosyl ceramide (GalCer) binding site on the HIV cell surface glycoprotein, gp120, several GalCer analogues have been prepared and characterized. The molecular design of analogues permits independent variations of the carbohydrate, the length of a hydrophilic spacer between the ligand and the lipid, and the composition of the hydrophobic lipid chains. Five different galactosyl analogues were synthesized having hydrophilic spacers of tri-, tetra-, and penta-ethylene glycol separating the carbohydrate from the lipid region which has either oleoyl or stearoyl lipid chains. The synthetic design allows for a convergent synthesis of the three components of the glycolipid conjugate. The structural characterization includes the proton and carbon chemical shifts, which were assigned after analysis of 1D and 2D NMR spectra.
Subject(s)
Glycolipids/chemical synthesis , Glycolipids/pharmacology , HIV Envelope Protein gp120/drug effects , Galactose/chemistry , Galactosylceramides/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
No Abstract
ABSTRACT
A critical spacer arm length necessary to promote efficient binding of the HIV-1 surface glycoprotein rgp120 to several synthetic galactosyl-conjugated lipids, reconstituted into planar lipid bilayers, was identified. This should aid the design of anti-HIV-1 agents based on membrane-tethered, carbohydrate-based receptors for gp120.
