Polyplexes
Inventors
Duvall, Craig • Evans, Brian Connor • Brophy, Colleen • Hocking, Kyle
Assignees
US Department of Veterans Affairs • Vanderbilt University
Publication Number
US-10835549-B2
Publication Date
2020-11-17
Expiration Date
2034-04-11
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Abstract
The present disclosure relates to compounds comprising (i) an active agent, wherein the active agent includes a charge at a predetermined pH, (ii) a polymer, wherein the polymer includes an opposite charge than the active agent at the predetermined pH; and (iii) a polyplex comprising the peptide and the polymer electrostatically bond together at the predetermined pH. In some embodiments, the active agent is a peptide, such as a peptide comprising MAPKAP kinase II inhibitory peptide, and in some embodiments the peptide includes a cell-penetrating peptide. In further embodiments, the disclosure provides methods for treating a disease or condition by administering a composition according to the present disclosure to a subject in need thereof.
Core Innovation
The presently-disclosed subject matter provides compositions comprising polyplexes formed by electrostatically binding an active agent and a polymer, which have opposite charges at a predetermined pH. The active agent can be a peptide, such as a MAPKAP kinase II inhibitory peptide (MK2i), which includes a cell-penetrating peptide portion. The polymer includes an opposite charge to the active agent at the predetermined pH and can be pH-responsive, such as poly(propylacrylic acid) (PPAA), which can undergo charge changes based on the pH environment. These components form polyplexes that disassemble at an activation pH lower than the predetermined pH, enabling release and activation of the active agent within cells.
The problem addressed is the limited efficacy of peptide-based drugs caused by poor cellular uptake and entrapment within endo-lysosomal vesicles, leading to degradation or recycling and thus reduced bioavailability. Specifically, peptides like MK2i have therapeutic potential for vascular conditions such as intimal hyperplasia, but their clinical application is hindered by inefficient intracellular delivery. Existing methods fail to effectively deliver such peptides to cytosolic targets due to endosomal sequestration.
The invention solves this by providing polyplex formulations that enable enhanced cellular internalization, improved endosomal escape, increased intracellular retention time, and consequently enhanced bioactivity of peptide therapeutics. The pH-responsive polymer mediates polyplex dissociation and membrane disruption in endosomal pH ranges, facilitating cytosolic delivery of peptides like MK2i. This approach enhances therapeutic effects such as inhibition of inflammatory signaling and prevention of intimal hyperplasia in vascular grafts, both in vitro and in vivo.
Claims Coverage
The patent includes several independent claims focused on compositions with polyplexes of cationic peptides and anionic pH-responsive polymers, vascular grafts comprising such compositions, and methods for treating vascular conditions using these compositions.
Composition of cationic peptide and anionic pH-responsive polymer polyplex
A composition comprising a cationic peptide electrostatically bound to an anionic pH-responsive polymer comprising a poly((C1-C6)alkyl-acrylic acid) at a pH between about 6.0 and about 8.0, where the polymer and peptide form a polyplex that partially disassembles below the polymer's pKa (between 5.0 and about 7.4). The (C1-C6)alkyl group and carboxylic acid of the polymer are attached to the same carbon. The peptide sequences are selected from SEQ. ID. NOS: 1-4.
Polyplex size range
The polyplex formed by the cationic peptide and anionic pH-responsive polymer has a size between about 50 nm and about 500 nm.
Vascular graft comprising the composition
A vascular graft device comprising the composition of the cationic peptide and anionic pH-responsive polymer polyplex as described.
Method of treating a vascular condition
A method for treating a vascular condition comprising administering an effective amount of the composition containing the cationic peptide and anionic pH-responsive polymer polyplex to a subject in need thereof.
Treatment of intimal hyperplasia
The method of treating a vascular condition wherein the vascular condition treated is intimal hyperplasia.
Administration via vascular graft implantation
The method of treating a vascular condition wherein administering the composition involves implanting a vascular graft that includes the cationic peptide and anionic pH-responsive polymer polyplex composition.
The claims focus on compositions of cationic peptides and anionic pH-responsive polymers forming polyplexes with pH-dependent disassembly, incorporating these compositions into vascular grafts, and methods of treatment for vascular conditions, particularly intimal hyperplasia, by administering these compositions.
Stated Advantages
Enhancement of peptide uptake into cells, overcoming poor cell penetration of peptides alone.
Improved endosomal escape of peptides, allowing cytosolic delivery and reducing degradation via lysosomes or recycling.
Extended intracellular retention time of peptides, improving their bioactivity duration.
Increased bioactivity of therapeutic peptides, including inhibition of inflammatory signaling and prevention of intimal hyperplasia at lower doses compared to free peptides.
Facilitation of single intraoperative treatment during vascular grafting with prolonged therapeutic effects, reducing off-target systemic exposure.
Documented Applications
Treatment of vascular conditions, including intimal hyperplasia related to vein graft failure.
Use in vascular graft devices, such as saphenous vein grafts, to deliver therapeutic peptides locally at implantation sites.
Intracellular delivery of peptide therapeutics for diseases or conditions involving intracellular targets.
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