Lanthanide nanoparticle conjugates and uses thereof
Inventors
Boyes, Stephen G. • Rowe, Misty D. • Thamm, Douglas H. • Kraft, Susan L.
Assignees
Colorado School of Mines • Colorado State University Research Foundation
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Publication Number
US-8916135-B2
Publication Date
2014-12-23
Expiration Date
Abstract
The present disclosure is directed generally to lanthanide nanoparticle conjugates, such as gadolinium nanoparticle conjugates, nanoparticle conjugates including polymers, conjugation to targeting agents and therapeutic agents, and their use in targeting, treating, and/or imaging disease states in a patient.
Core Innovation
The invention relates to gadolinium nanoparticle conjugates that include Gd(1,4-benzenedicarboxylate)1.5(H2O)2 directly grafted onto a polymer, polymer precursor, or initiator by a covalent bond or non-covalent bond. The gadolinium nanoparticle conjugate has structural formula I, in which n is an integer and R2, R3, and R4 are each independently selected from a defined group of chemical substituent types.
The invention further encompasses structural formula I systems in which additional functional group(s) are provided beyond the directly grafted Gd(1,4-benzenedicarboxylate)1.5(H2O)2 unit. The polymer-associated functional groups can include functional-group selections defined as a long enumerated list, supporting attachment through covalent association between the polymer and an added functional group.
In addition, the invention includes methods of making the gadolinium nanoparticle conjugates by sequentially contacting Formula (III) or Formula (II) compounds, or salts, with Formula (V) compounds, or salts, to form an intermediate, followed by contacting the intermediate with Gd(1,4-benzenedicarboxylate)1.5(H2O)2 to form a gadolinium nanoparticle conjugate having structural formula I. The invention also allows for a reducing-agent contacting step prior to contacting Gd(1,4-benzenedicarboxylate)1.5(H2O)2 in a refined method.
Claims Coverage
The partial content includes three independent claims. Across these claims, the coverage centers on a structurally defined gadolinium-carboxylate nanoparticle conjugate grafted onto a polymer system via covalent or non-covalent bonding with defined substituent selections, and on sequential contacting steps using Formula-defined intermediates to produce the conjugate, with a refinement that includes a reducing-agent contacting step.
Gadolinium nanoparticle conjugate with covalent or non-covalent grafting onto polymer system
A gadolinium nanoparticle conjugate comprising Gd(1,4-benzenedicarboxylate)1.5(H2O)2 directly grafted onto a polymer, polymer precursor, or initiator by a covalent bond or non-covalent bond, the gadolinium nanoparticle conjugate having structural formula I where n is an integer and R2, R3, and R4 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy.
Sequential contacting to form conjugate via Formula-defined intermediate (III/V→VI then Gd carboxylate)
A method of making a gadolinium nanoparticle conjugate comprising contacting a compound of Formula (III) or salt thereof with a compound of Formula (V) or a salt thereof to form the compound of Formula (VI), contacting the compound of Formula (VI) with Gd(1,4-benzenedicarboxylate)1.5(H2O)2 to form a gadolinium nanoparticle conjugate having structural formula I wherein n is an integer and R2, R3, R4, R7, and R8 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy.
Sequential contacting to form conjugate via Formula-defined intermediate (II/V→VII then Gd carboxylate)
A method of making a gadolinium nanoparticle conjugate comprising contacting a compound of Formula (II) or salt thereof with a compound of Formula (V) or a salt thereof to form the compound of Formula (VII), contacting the compound of Formula (VII) with Gd(1,4-benzenedicarboxylate)1.5(H2O)2 to form a gadolinium nanoparticle conjugate having structural formula I wherein n is an integer, and R2, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy.
The independent claim set is directed to a structurally defined gadolinium nanoparticle conjugate in which a Gd(1,4-benzenedicarboxylate)1.5(H2O)2 moiety is grafted onto a polymer, polymer precursor, or initiator via covalent or non-covalent bonding, and to methods that generate that conjugate through sequential contacting of Formula-defined compounds with an intermediate followed by contacting with Gd(1,4-benzenedicarboxylate)1.5(H2O)2.
Stated Advantages
Improved biocompatibility.
Retains MRI T1 positive contrast behavior while enabling drug-targeted performance.
Documented Applications
Imaging and in vitro efficacy/testing, including MRI T1 positive contrast behavior.
Conjugates directed to therapeutic agents and targeting agents including folic acid, RGD, paclitaxel, and methotrexate, with in vitro testing described in the partial content.
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