Advanced Magnetics, Inc.

The General Hospital Corporation

Massachusetts Institute of Technology

Baxter Travenol Laboratories, Inc.

Visen Medical, Inc.

Lee Josephson

Ernest V Groman

Jerome M Lewis

Edward T Menz

Ralph Weissleder

Mark S Chagnon

Roy A Whitehead

Chu W Jung

Stephen Palmacci

Alexei A Bogdanov

Umar Mahmood

Ching-Hsuan Tung

J Manuel Perez

Philip M Enriquez

Elisabeth Garanger

Francis E Kenny

Jeffrey M Rothenberg

Michael John Cima

Yi Sun

Jason Philip Holland

Rui Hong

Yong-Qian Wu

David Sosnovik

Howard Chen

Debra A Gaw

Alexei Bogdanov

The present disclosure provides nucleic acid binding nanoprobes having one or more fluorochromes and a polymer, where each of the fluorochromes is connected to the polymer, and methods of using the same.

Theranostic nucleic acid binding fluorescent nanoprobes and uses thereof

A method of synthesizing a radiolabeled nanoparticle. The method includes heating a solution including an iron oxide nanoparticle and at least one radioactive metal ion to bind the iron oxide nanoparticle and the at least one radioactive metal ion, thereby forming the radiolabeled nanoparticle. The method further includes adding a quenching agent to the solution to complex with non-bound radioactive metal ions remaining in the solution. The method further includes separating the complexed quenching agent from the radiolabeled nanoparticle.

Heat-induced radiochemical labeling of an iron oxide nanoparticle

Multifunctional probes include a substrate (e.g., a nanoparticle, polymer, antibody, protein, low molecular weight compound, drug) and a multifunctional single-attachment-point (MSAP) reagent. The MSAP reagents can include three components: (i) a peptide scaffold, (ii) a single chemically reactive group on the peptide scaffold for reaction of the MSAP with a substrate having a complementary reactive group, and (iii) multiple functional groups on the peptide scaffold. The peptide scaffold can include any number of residues; however, for ease of synthesis and reproducibility in clinical trials, it is preferred to limit the residues in the peptide to 20 or less.

Methods and reagents for preparing multifunctional probes

This invention relates generally to magnetic resonance (MR)-based methods and kits for measuring the viscosity of liquid samples.

Magnetic resonance-based viscometers and methods

The present invention provides novel compositions of binding moiety-nanoparticle conjugates, aggregates of these conjugates, and novel methods of using these conjugates, and aggregates. The nanoparticles in these conjugates can be magnetic metal oxides, either monodisperse or polydisperse. Binding moieties can be, e.g., oligonucleotides, polypeptides, or polysaccharides. Oligonucleotide sequences are linked to either non-polymer surface functionalized metal oxides or with functionalized polymers associated with the metal oxides. The novel compositions can be used in assays for detecting target molecules, such as nucleic acids and proteins, in vitro or as magnetic resonance (MR) contrast agents to detect target molecules in living organisms.

Magnetic-nanoparticle conjugates and methods of use

Multifunctional probes are synthesized in a single step using peptide scaffold-based multifunctional single-attachment-point reagents. To obtain multifunctional probes using the methods of the invention, a substrate (e.g., a nanoparticle, polymer, antibody, protein, low molecular weight compound, drug, etc.) is reacted with a multifunctional single-attachment-point (MSAP) reagent. The MSAP reagents can include three components: (i) a peptide scaffold, (ii) a single chemically reactive group on the peptide scaffold for reaction of the MSAP with a substrate having a complementary reactive group, and (iii) multiple functional groups on the peptide scaffold. The peptide scaffold can include any number of residues; however, for ease of synthesis and reproducibility in clinical trials, it is preferred to limit the residues in the peptide to 20 or less. The reagent can be prepared to yield a predetermined stoichiometric ratio of the functional groups on the scaffold such that the probe has a fixed stoichiometric ratio of the functional groups.

This invention relates to magnetic resonance-based sensors and related methods.

Water relaxation-based sensors

An intramolecularly-quenched, near infrared fluorescence probe that emits substantial fluorescence only after interaction with a target tissue (i.e., activation) is disclosed. The probe includes a polymeric backbone and a plurality of near infrared fluorochromes covalently linked to the backbone at fluorescence-quenching interaction-permissive positions separable by enzymatic cleavage at fluorescence activation sites. The probe optionally includes protective chains or fluorochrome spacers, or both. Also disclosed are methods of using the intramolecularly-quenched, near infrared fluorescence probes for in vivo optical imaging.

Intramolecularly-quenched near infrared fluorescent probes

Amine functionalized magnetic nanoparticle compositions and processes for synthesizing the same are described. The process consists of obtaining a carboxylated polymer in substantially pure form, which is used to prepare a substantially size homogeneous, polymer coated carboxyl, functionalized magnetic nanoparticle. The carboxyl groups are converted to reactive primary amino groups by the use of a water-soluble carbodiimide followed by reaction of a large excess of a diamine. The amine-terminated nanoparticles are then reacted with bifunctional crosslinking agents and with various biomolecules to make nanoparticles for in vitro assays, cell sorting applications and target specific MR contrast agents.

Amine functionalized superparamagnetic nanoparticles for the synthesis of bioconjugates and uses therefor

Intramolecularly-quenched near infrared flourescent probes

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

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 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 receptor-mediated endocytosis-type compositions

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.

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Arlington, MA, United States of America

Lee Josephson