The Children's Hospital of Philadelphia

Drexel University

University System of Maryland

Michael Chorny

Ivan Alferiev

Robert J Levy

Ilia Fishbein

Darryl Williams

Garrett M Brodeur

Benjamin B Yellen

Boris Polyak

Gennady Friedman

Vladimir R Muzykantov

Elizabeth Hood

Masahiro Iwamoto

Zachary G Forbes

Kenneth A Barbee

Ilia Fischbein

Provided are macromolecular prodrugs in which camptothecin analogs are covalently bonded to polymers via ester bonds that are labile under physiological conditions. Also provided are methods of treating cancer, especially neuroblastoma with the macromolecular prodrugs.

Polymer-based macromolecular prodrugs

The invention relates to compositions and methods as part of a pharmacotherapeutic strategy that targets the endochondral ossification process in a pharmacologically selective and site-specific manner. A variety of orthopedic pathologies are caused by or associated with generalized or local dysregulation of endochondral ossification, for example trauma to the bone growth plate or diaphysis can cause a serious imbalance in bone growth, leading to progressive deformity that today can only be treated surgically. Dysregulated endochondral ossification is also behind heterotopic ossification, which arises in soft tissues and causes pain, decrease in mobility and other clinical problems. The invention therefore provides RARy agonist and antagonist nanoparticle compositions for treating abnormal endochondral ossification and bone growth that can deliver robust local therapeutic control over a particular long bone's growth with a long-lasting effect.

Selective RAR&#x3b3; ligand-loaded nanoparticles for manipulation of targeted bone growth

A co-drug according to Formula (I) or Formula (II) is provided,R&#x2014;X&#x2014;NH&#x2014;CO&#x2014;CO&#x2014;OR&#x2003;&#x2003;(I)R&#x2014;X&#x2014;CO&#x2014;O&#x2014;CH&#x2014;CO&#x2014;OR&#x2003;&#x2003;(II)wherein R is a tocol moiety, a tocol analog moiety, or a capsaicinoid moiety; X is a direct bond or a linking group; and ORis the residue of an anticancer or antirestenotic agent bearing at least one hydroxyl group by which the CO&#x2014;ORester linkage is formed. Nanoparticles that include the abovementioned co-drug are also provided, as well as a method of treating a cancer patient that includes administering an effective amount of the co-drug or nanoparticles.

Cleavable esters for nanocarrier-based cancer therapy

A water-soluble photo-activatable polymer including: a photo-activatable group adapted to be activated by an irradiation source and to form a covalent bond between the water-soluble photo-activatable polymer and a matrix having at least one carbon; a reactive group adapted to covalently react with a biomaterial for subsequent delivery of the biomaterial to a cell; a hydrophilic group; and a polymer precursor. A composition including a monomolecular layer of the water-soluble photo-activatable polymer and a matrix having at least one carbon, wherein the monomolecular layer is covalently attached to the matrix by a covalent bond between the photo-activatable group and the at least one carbon. The composition further includes a biomaterial having a plurality of active groups, wherein the biomaterial is covalently attached to the monomolecular layer by covalent bonding between the active groups and reactive groups. Also provided is a method for delivery of a biomaterial to a cell.

Photochemical activation of surfaces for attaching biomaterial

A therapeutic particle comprises a particle comprising one or more therapeutic agents and one or more fibrin-avid peptide variants attached to the surface of the particle. A method for magnetically targeting a therapeutic agent toward a device in a subject, such as a temporarily introduced magnetizable catheter or an implanted stent, comprises administering the therapeutic particles to the subject and generating a magnetic field, which targets the magnetic particles toward the device. The affinity peptide-modified therapeutic particles may comprise an effective amount of an anti-proliferative agent, such as paclitaxel, to inhibit or prevent in-stent restenosis.

Affinity peptide-modified particles and targeted drug delivery methods

A prodrug according to formula (I) wherein Ris a residue of a drug, said drug having a hydroxyl group by which the COORgroup is formed; Z is O or NH; m is 0 or 1; and Ris an organic moiety comprising a lipophilic group or a residue of a polymer, provided that Z is 0 if the polymer is carboxymethyl dextran. A system includes a plurality of magnetic nanoparticles including a prodrug as described above, a stent and a source of uniform magnetic field capable of producing temporary magnetization of the stent and/or the magnetic nanoparticles. A method of treating a medical condition with a drug includes administering to a patient in need of the drug a prodrug as described above, the prodrug being capable of releasing the drug in the patient after the administration step.

Hydrolytically releasable prodrugs for sustained release nanoparticle formulations

Systems and methods for magnetic targeting of therapeutic particles are provided. Therapeutic particles comprise one or more magnetic or magnetizable materials and at least one therapeutic agent. Therapeutic particles are specifically targeted using uniform magnetic fields capable of magnetizing magnetizable materials, and can be targeted to particular locations in the body, or can be targeted for capture, containment, and removal. Also provided are bioresorbable nanoparticles prepared without the use of organic solvents, and methods for therapeutically using such bioresorbable nanoparticles.

Uniform field magnetization and targeting of therapeutic formulations

A treatment system includes a magnetic targeting catheter and a plurality of MNP. The MNP may include one or more magnetic field-responsive agents and one or more therapeutic agents. The catheter may include an inner shaft having at least one lumen and a fluid delivery balloon adapted to administer a fluid from the inner shaft into a space surrounding the catheter. An expandable mesh formed of a magnetizable material may surround the fluid delivery balloon. The catheter may further include one or more occlusion balloons for controlling blood flow through a vessel in which the catheter is placed. A method of treating a medical condition may include advancing a magnetic targeting catheter to a site, deploying an expandable mesh connected to the catheter, applying a magnetic field to the mesh and depositing a plurality of MNP or cells loaded with MNP near the mesh.

Magnetic targeting device, system and method

Systems and methods for magnetic targeting of therapeutic particles are provided. Therapeutic particles comprise one or more magnetic or magnetizable materials and at least one therapeutic agent. Therapeutic particles are specifically targeted using uniform magnetic fields capable of magnetizing magnetizable materials, and can be targeted to particular locations in the body, or can be targeted for capture, containment, and removal. Therapeutic particles can comprise antioxidant enzymes, and can be targeted to cells to protect the cells from oxidative damage.

A particle including a matrix-forming agent and a polyelectrolyte-amphiphilic agent adduct wherein the polyelectrolyte-amphiphilic agent adduct is in physical communication with the matrix-forming agent. The particle further includes a coated magnetic field-responsive agent and a biomaterial. Methods of making the particle are provided. Also provided are methods of delivery of the biomaterial to a target cell or a target tissue including administering the particle having the matrix-forming agent, polyelectrolyte-amphiphilic agent adduct, the coated magnetic field-responsive agent and the biomaterial; providing a magnetic device associated with the target cell or the target tissue; applying a magnetic force to the particle; and guiding the particle toward the magnetic device by the magnetic force.

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Philadelphia, PA, United States of America

Michael Chorny