Advanced Magnetics, Inc.

Baxter Travenol Laboratories, Inc.

Amag Pharmaceuticals, Inc.

Biophysics Assay Laboratory, Inc.

Ernest V Groman

Lee Josephson

Jerome M Lewis

Edward T Menz

Kenneth G Paul

Howard Bengele

Timothy B Frigo

Mark S Chagnon

Roy A Whitehead

Chu W Jung

Michael D Cabelli

Philip M Enriquez

Francis E Kenny

Jeffrey M Rothenberg

George H Parsons, Jr

Stephen Palmacci

Marian E Sacco

Christopher P Reinhardt

Yong-Qian Wu

Iron oxide complexes, pharmacological compositions and unit dosage thereof, and methods for their administration, of the type employing an iron oxide complex with a polyol, are disclosed. The pharmacological compositions employ a polysaccharide iron oxide complex, wherein the polysaccharide is a modified polyol such as a carboxyalkylated reduced dextran. The complex is stable to terminal sterilization by autoclaving. The compositions are suitable for parenteral administration to a subject for the treatment of iron deficiencies or as MRI contrast agent. The complex is substantially immunosilent, provide minimal anaphylaxis and undergo minimal dissolution in vivo. The pharmacological compositions of the complex contain minimal free iron which can be quantified by a variety of methods.

Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents

Pharmacological compositions, and methods for administration, of the type employing an iron oxide complex with a polyol or polyether. The methods of administration may comprise parenteral administration of an effective dose of the complex formulated in a biocompatible liquid delivered at a rate of from about 1 mL/sec to less than 1 mL/min and wherein upon administration the complex provides minimal detectable free iron in a subject, and minimal incidence of anaphylaxis. The pharmacological compositions are of the type employing a polyol or polyether iron oxide complex, which, upon parenteral administration to a subject, are substantially immunosilent, provide minimal anaphylaxis and minimal free iron, and undergo minimal dissolution in vivo.

Compositions, methods of making the compositions, and methods of using the compositions are provided for an enhanced magnetic resonance imaging agent and a hematinic agent, the agents comprising carboxyalkylated reduced polysaccharides coated ultrasmall superparamagnetic iron oxides. Methods of use of the carboxymethyl reduced dextran as a plasma extender are provided.

Heat stable colloidal iron oxides coated with reduced carbohydrates and uses thereof

Stable isotope labeling and neutron activation to measure biological functions are provided, as are the use and method of adding a chemical monitor to correct for neutron flux to sample vials prior to the addition of sample is presented, and the use of stable isotopes as a chemical bar code for vials and other items. Methods are provided also for measuring glomerular filtration rate and glomerular sieving function in a subject, and for measuring other physiological functions.

Synthesis, compositions and methods for the measurement of the concentration of stable-isotope labeled compounds in life forms and life form excretory products

Heat stable colloidal iron oxides coated with reduced carbohydrates and carbohdrate derivatives

Novel compositions of nucleotide analog prodrugs for the treatment of viral infections and cancer are herein disclosed. The prodrugs have a biocompatible polymeric carrier conjugated to the nucleotide analog via an amino-phosphate linkage. The amino group is provided by the carrier, which either inherently possesses a primary amine, or is modified with reactive groups that incorporate the primary amine onto the carrier. The carrier can be a polyamino acid, a polyvinylic polymer, a polysaccharide or combinations thereof, such as polylysine, HPMA, dextran, hydroxyethyl starch, or polyethylene glycol; the nucleotide analog can be ribavirin araA, AZT, acyclovir, 5-FUDR, araC or ddI. Methods of treating a viral infection of cancer using these prodrugs are also disclosed. The prodrugs endow the nucleotide analogs with substantially enhanced therapeutic efficacy and reduces toxicity in comparison to the nucleotide analog alone.

Polymeric carriers linked to nucleotide analogues via a phosphoramide

This invention relates to a method of directing a therapeutic agent to selected cells, wherein a complex is formed between a polysaccharide capable of interacting with a cell receptor and a therapeutic agent. The resulting complex is administered to a subject, and permitted to be internalized into the selected cells through a process known as receptor mediated endocytosis (RME). The polysaccharide may be, for example, arabinogalactan, gum arabic, mannan or hydrolysis products thereof; the therapeutic agent may be, for example, an antiviral agent, a nucleic acid, hormone, steroid, antibody, chemoprotective or radioprotective agent. The cell receptor may be for example, the asialoglycoprotein receptor or the mannose receptor.

Delivery of therapeutic agents to receptors using polysaccharides

Chemoactive radioprotectants are coupled to carrier molecules capable of binding cell receptors to form complexes that can be directed to specific non-target cells in a mixture of cells prior to radiation of the mixture so that target cells are selectively destroyed while the non-target cells are protected from radiation. Radioprotection of non-target cells is provided by using chemoactive radioprotectant complexes.

Directed delivery of radioprotectants using a receptor specific carrier

A new class of magnetic resonance (MR) contrast agents are described whose in vivo biodistribution is based upon the ability of certain cells to recognize and internalize macromolecules, including the MR contrast agents of the present invention, via a process which substantially involves receptor mediated endocytosis. The RME-type MR contrast agents described herein comprised of biodegradable superparamagnetic metal oxides associated with a variety macromolecular species, including but not limited to, serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates these molecules with other polymeric substances such as a poly(organosilane) and dextran. One of the advantages or these MR contrast agents is that they may be selectively directed to those cells which bear receptors for a particular macromolecule or ligand and are capable of undergoing receptor mediated endocytosis. An MR contrast agent prepared from biodegradable superparamagnetic iron oxide and asialofetuin, or more preferably arabinogalactan, for example, is selectively localized in the hepatocytes the liver with no significant accumulation in the spleen. An MR experiment which can be carried out shortly after administration to the subject of the contrast agents of the invention can thus provide a method for obtaining an enhanced MR image, as well as valuable information regarding the functional or metabolic state of the organ or tissue under examination. Preparative methods, biodistribution data, and time function MR images are further provided.

Hepatocyte specific composition and their use as diagnostic imaging

The invention relates to a method for the targeting of a therapeutic agent to a specific population of cells, wherein a complex is formed between the therapeutic agent and a polysaccharide capable of interacting with a cell receptor, and wherein the resulting complex is internalized into the cell by receptor mediated endocytosis (RME). In one embodiment of the invention, a complex of a therapeutic agent containing iron and the polysaccharide arabinogalactan may be formed and used to deliver iron specifically to hepatocytes by RME.

Targeting of therapeutic agents using polysaccharides

The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.

Vascular magnetic resonance imaging agent comprising nanoparticles

A new class of magnetic resonance (MR) contrast agents are described whose in vivo biodistribution is based upon the ability of certain cells to recognize and internalize macromolecules, including the MR contrast agents of the present invention, via a process which substantially involves receptor mediated endocytosis. The RME-type MR contrast agents described herein comprised of biodegradable superparamagnetic metal oxides associated with a variety of macromolecular species, including but not limited to, serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates of these molecules with other polymeric substances such as a poly(organosilane) and dextran. One of the advantages of these MR contrast agents is that they may be selectively directed to those cells which bear receptors for a particular macromolecule or ligand and are capable of undergoing receptor mediated endocytosis. An MR contrast agent prepared from biodegradable superparamagnetic iron oxide and asialofetuin, or more preferably arabinogalactan, for example, is selectively localized in the hepatocytes of the liver with no significant accumulation in the spleen. An MR experiment which can be carried out shortly after administration to the subject of the contrast agents of the invention can thus provide a method for obtaining an enhanced MR image, as well as valuable information regarding the functional or metabolic state of the organ or tissue under examination. Preparative methods, biodistribution data, and time function MR images are further provided.

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Brookline, MA, United States of America

Ernest V Groman