TARGETING OF PHARMACEUTICAL AGENTS TO PATHOLOGIC AREAS USING BIFUNCTIONAL FUSION POLYMERS

• US 20160106858A1
• Filed: 09/29/2015
• Published: 04/21/2016
• Est. Priority Date: 09/29/2014
• Status: Active Grant

• Current Assignee: Counterpoint Biomedica LLC
• Original Assignee: Counterpoint Biomedica LLC
• Inventors: Hall, Frederick L., Gordon, Erlinda M.
• Granted Patent: US 10,420,820 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/1754 Insulin-like growth factor binding proteins
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1833 Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/2053 IL-8
• CPC Class Codes: A61K 38/385 Serum albumin
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Provided herein are new compositions and methods to target pharmaceutical agents to pathological areas by utilizing bifunctional fusion polymers or nanoparticles. These fusion polymers and nanoparticles contain two or more domains: (i) sequences that bind to exposed collagenous (XC-) proteins present in pathological areas, including cancerous lesions and (ii) domains that bind to pharmaceutical agents. The drug-binding functionality of these fusion polymers and nanoparticles is based on high-affinity, non-covalent interactions.

Claims

1. A fusion polymer comprising (i) a tumor targeting aptamer sequence that binds to exposed collagenous (XC) proteins, and (ii) a drug binding domain that binds to a drug or biologic agent.

4. The fusion polymer of claim 1, wherein the drug binding domain is an RNA, growth factor, immunoglobulin, chemotherapeutic agent or human serum albumin binding domain, and the drug is an RNA, a growth factor, an immunoglobulin, a chemotherapeutic agent or human serum albumin, respectively.

103. A method of treating a tumor in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the fusion polymer of claim 1 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

107. A method of treating cancer in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the fusion polymer of claim 1 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

2-3. -3. (canceled)

5-21. -21. (canceled)

22. A fusion polymer comprising (i) a tumor targeting aptamer sequence that binds to exposed collagenous (XC) proteins, and (ii) a di-block copolymer comprising a hydrophilic block and a hydrophobic block.

91. A method of making the fusion polymer of claim 22, comprising:

(a) providing the tumor-targeting domain that binds to exposed collagenous proteins and a first linker bound to the N-terminus of the tumor-targeting domain, and wherein a cysteine residue is bound to the N-terminus of the first linker;

(b) providing the di-block copolymer comprising the hydrophilic block and the hydrophobic block, wherein a second linker is bound to the terminus of the hydrophilic block and wherein a maleimide-group is bound to the second linker terminus that is unbound to the hydrophilic block; and

(c) combining (a) and (b) under conditions such that the maleimide-group of (b) reacts with the thiol group of the cysteine residue of (a) to form a covalent bond between (a) and (b), thereby creating the fusion polymer.

93. A method of making a micelle, comprising:

(a) providing the fusion polymer of claim 22 and a plurality of di-block copolymers, each comprising a hydrophobic block and a hydrophilic block;

(b) mixing the fusion polymer with the plurality of di-block copolymers to thereby form a micelle.

98. A micelle comprising a hydrophobic interior and a hydrophilic surface and at least one fusion polymer according to claim 22, wherein the tumor targeting domain of the at least one fusion polymer extends outwardly from the hydrophilic surface of the micelle, such that the tumor targeting domain can bind to XC proteins while associated with the micelle.

99. A drug-delivery nanoparticle comprising (i) the micelle of claim 98;

and (ii) a drug sequestered in the hydrophobic interior of the micelle.

104. A method of treating a tumor in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the drug-delivery nanoparticle of claim 99 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

108. A method of treating cancer in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the drug-delivery nanoparticle of claim 99 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

23-32. -32. (canceled)

33. A fusion polymer comprising (i) a tumor targeting aptamer sequence that binds to exposed collagenous (XC) proteins, and (ii) a multi-block polymer comprising sequentially a first hydrophilic block, a first hydrophobic block, a second hydrophobic block, and a second hydrophilic block.

96. A method of making a liposome, comprising:

(a) providing the fusion polymer of claim 33 and a plurality of multi-block polymers, each comprising sequentially a first hydrophilic block, a first hydrophobic block, a second hydrophobic block, and a second hydrophilic block;

(b) mixing the fusion polymer with the plurality of multi-block polymers to thereby form a liposome.

100. A liposome comprising a lipid bilayer having a hydrophilic exterior surface and an aqueous interior and comprising at least one fusion polymer according to claim 33, wherein the tumor targeting domain of the at least one fusion polymer extends outwardly from the hydrophilic exterior surface of the liposome, such that the tumor targeting domain can bind to XC proteins while associated with the liposome.

101. A drug-delivery nanoparticle comprising (i) the liposome of claim 100 and (ii) a drug sequestered inside the aqueous interior of the liposome.

102. A drug-delivery nanoparticle comprising (i) the liposome of claim 100 and (ii) a drug sequestered inside the lipid bilayer of the liposome.

105. A method of treating a tumor in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the drug-delivery nanoparticle of claim 101 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

106. A method of treating a tumor in a subject, the method comprising:

administering to a subject in need of such treatment a pharmaceutical composition comprising the drug-delivery nanoparticle of claim 102 and a pharmaceutically acceptable carrier in an amount sufficient to treat the tumor.

34-90. -90. (canceled)

92. A method of making a micelle, comprising:

(a) providing a first and a second plurality of di-block copolymers, each comprising a hydrophobic block and a hydrophilic block, wherein the di-block copolymers of the second plurality each comprise a linker bound to the terminus of the hydrophilic block, and wherein a maleimide group is bound to the linker terminus that is unbound to the hydrophilic block;

(b) mixing the first and second plurality of di-block copolymers to thereby form a micelle;

(c) providing a tumor-targeting domain that binds to exposed collagenous proteins and that comprises a cysteine residue on a terminus of the domain; and

(d) combining the micelle of (b) with the tumor-targeting domain of (c) under conditions such that a maleimide of the di-block copolymers of the second plurality in the micelle reacts with the cysteine residue of the tumor-targeting domain, thereby connecting the tumor-targeting domain and the micelle.

94. (canceled)

95. A method of making a liposome, comprising:

(a) providing a first and a second plurality of multi-block polymers, each comprising sequentially a first hydrophilic block, a first hydrophobic block, a second hydrophobic block, and a second hydrophilic block, wherein the multi-block polymers of the second plurality each comprise a linker bound to the terminus of the first hydrophilic block, and wherein a maleimide group is bound to the linker terminus that is unbound to the hydrophilic block;

(b) mixing the first and second plurality of multi-block polymers to thereby form a liposome;

(c) providing a tumor-targeting domain that binds to exposed collagenous proteins and that comprises a cysteine residue on a terminus of the domain; and

(d) combining the liposome of (b) with the tumor-targeting domain of (c) under conditions such that a maleimide of the multi-block polymers of the second plurality in the liposome reacts with the cysteine residue of the tumor-targeting domain, thereby connecting the tumor-targeting domain and the liposome.

97. (canceled)