Drug delivery vehicle
Inventors
Lacko, Andras G. • Remaley, Alan T. • Sabnis, Nirupama A.
Assignees
University of North Texas Health Science Center • US Department of Health and Human Services
Publication Number
US-9314532-B2
Publication Date
2016-04-19
Expiration Date
2033-08-07
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Abstract
The present disclosure provides targeted drug delivery vehicle compositions comprising a drug composition and targeted poly-amino-acid subunits, methods of manufacture, and methods of treatment for numerous diseases.
Core Innovation
This invention provides compositions for targeted drug delivery vehicles comprising targeted poly-amino-acid subunits bound to a biocompatible polymer, methods of manufacture, and methods of treatment for numerous diseases. The compositions enable tailored drug delivery of pharmaceutical agents to specific cells, tissues, or organ types by utilizing naturally occurring affinities such as specific amino acid chains with affinity to membrane-bound receptors or other target molecules.
The problem addressed is that many drug candidates fail in development due to harmful side effects associated with passive drug delivery methods, which lack specificity and result in drugs accumulating non-specifically in healthy tissues. This is particularly concerning for cytotoxic drugs like chemotherapy agents that damage both diseased and healthy cells. Current drug delivery vehicles often use large proteins that are expensive to produce and do not sufficiently avoid impacting healthy cells.
The invention solves these challenges by providing a targeted drug delivery vehicle that is specific for diseased cells, minimally immunogenic, biodegradable, and stable in bodily fluids with extended plasma residence time. The vehicle is largely composed of multiple targeted poly amino acid subunits, each comprising a targeting amino acid chain conjugated to a fatty acid such as myristic acid. The targeting amino acid chain typically has affinity to receptors such as scavenger receptor class B1 (SR-B1) and can be amphipathic alpha-helical peptides shorter than 50 amino acids. The vehicle forms a substantially spherical nanoparticle with a hydrophobic core to encapsulate drugs and a hydrophilic exterior for stability.
Claims Coverage
The claims disclose multiple inventive features relating to a targeted drug delivery vehicle composed of specific targeted poly-amino-acid subunits and their properties, drug associations, and methods of manufacture and use.
Targeted drug delivery vehicle composition with fatty acid-conjugated targeting amino acid chains
The vehicle consists essentially of 5-50 targeted poly-amino-acid subunits, each comprising a targeting amino acid chain conjugated to a fatty acid. The targeting amino acid chain has at least 70% identity to specific sequences (SEQ ID NOs: 20, 63, 64, 65, or 66) and affinity to scavenger receptor class B1 or a portion thereof.
Fatty acid nature and linkage
The fatty acid is a saturated fatty acid, preferably between 3 and 15 carbons in length, and specifically can be myristic acid. The targeting amino acid chain is covalently linked to the fatty acid in a 1:1 ratio.
Structural features of targeting amino acid chain
The targeting amino acid chain forms one or more amphipathic alpha-helical domains, with some claims specifying two such domains.
Targeting amino acid chain affinity and specificity
The targeting amino acid chain further comprises sequences that have affinity to transmembrane molecules, receptors including HDL receptors, rapidly dividing cells, and cancer cells. The scavenger receptor class B1 functions as HDL or LDL receptor facilitating uptake of the drug composition into target cells.
Composition lacking certain lipids and proteins
The vehicle is free of unesterified cholesterol, cholesteryl esters, various phospholipids including phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and sphingomyelin, and does not include apolipoprotein A-1 protein.
Size range of drug delivery vehicle
The vehicle has a diameter ranging approximately from 20 nm to 300 nm, with alternative embodiments comprising larger particles from 300 nm to 1000 nm when containing polynucleotide drug compositions and other components.
Drug payload versatility
The vehicle can carry diverse drug types including hydrophobic drugs, cytotoxic agents, antibodies, proteins, peptides, mimetic peptides, nucleic acids, vaccines, albumin, and nonionic surfactants such as polyoxyl castor oil.
Alternative vehicle compositions with polynucleotide, phospholipids, and excipients
An alternative vehicle composition comprises targeted poly-amino-acid subunits each containing a polynucleotide drug, a phospholipid (e.g., phosphatidylcholine), an excipient, and a targeting amino acid chain, neutralized prior to incorporation. These vehicles have sizes from 300 nm to 1000 nm.
Enhanced uptake via scavenger receptor class B1 affinity
The targeting amino acid chain's affinity to scavenger receptor class B1 or its portion promotes uptake of the drug composition into target cells.
Targeting amino acid chain length and identity
The targeting amino acid chain is about 10 to 40 amino acids long and specifically corresponds to SEQ ID NOs: 20, 63, 64, 65, or 66.
The claims collectively cover a targeted drug delivery vehicle composed of poly-amino-acid subunits conjugated to fatty acids, specifically tailored targeting amino acid sequences with affinity for scavenger receptor class B1, free from certain lipids and apolipoproteins, with defined size ranges and ability to carry diverse drug payloads, enabling targeted uptake by specific cells such as cancer cells.
Stated Advantages
Increased stability in biological fluids compared to phospholipid-based vehicles, reducing premature drug leakage.
Improved bioavailability and more accurate drug dosing at the disease site.
Enhanced therapeutic index of drugs by increasing efficacy and reducing toxicity to healthy cells.
Increased plasma residence time and favorable pharmacokinetic profiles such as increased Cmax and AUC and decreased Tmax compared to passive drug delivery.
Suitability for commercial scale manufacture due to readily assembled subunit composition and synthetic components.
Documented Applications
Targeted delivery of chemotherapeutic agents to cancer cells, improving cytotoxicity to malignant cells while sparing non-malignant cells.
Administration of monoclonal antibody therapies for various diseases including cancer and autoimmune disorders.
Delivery of vaccines for infectious diseases such as anthrax, chickenpox, hepatitis, influenza, HPV, meningococcal infections, rabies, rotavirus, shingles, smallpox, tetanus, tuberculosis, typhoid, and yellow fever.
Treatment of hyperproliferative disorders including a wide range of malignant and benign tumors and cancers of various origins.
Delivery of diverse therapeutic agents including antibiotics, antivirals, anti-inflammatory drugs, kinase inhibitors, cytokines, anticoagulants, and more.
Gene therapy delivery including RNA interference (RNAi) agents and antisense therapeutics for silencing disease-causing genes.
Treatment of neurological diseases such as brain tumors, Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, and stroke.
Treatment of diabetes mellitus using insulin, insulin analogs, or other diabetes drugs associated with the vehicle.
Treatment of coronary artery disease using statins, insulin, or combinations thereof delivered by the targeted vehicles.
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