Chelating complex micelles drug carrier
Inventors
Wang, Chau-Hui • Chen, Chia-Hung • Lin, Johnson • Chen, Jing-Yi • Liao, Wei-Chuan
Assignees
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Publication Number
US-9226967-B2
Publication Date
2016-01-05
Expiration Date
Abstract
This invention provides Chelating Complex Micelles as a drug carrier. The Chelating Complex Micelles can load drugs without changing their structure, and therefore extend the half-life of drugs in the human body. The chelating complex micelles contain a metal ion core, at least one polymer, and at least one drug molecule. The metal ion is considered as a Lewis acid while polymer chain and drug molecules are referred to as Lewis bases. The drug molecule is linked to the polymer via forming coordinate bonds with metal ion, and then self-assembled to form chelating complex micelles as a drug carrier.
Core Innovation
The chelating complex micelle includes a ligand free metal ion core and a ligand that bind to each other by coordinate bonds, where the ligand free metal ion core is a Lewis acid. In this structure, the ligand free metal ion core links a drug, and the ligand is poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA). The coordinate bonds between the ligand free metal ion core and the ligand provide the chelating complex micelle architecture for carrying the drug.
The ligand free metal ion core functions as a Lewis acid and forms coordinate bonds with Lewis base components so that the polymer and the drug act as Lewis bases. The chelating complex micelles self-assemble into micelles without changing the drug structure. This chelation-based association is described as a mechanism to extend drug half-life by reducing drug release behavior.
The disclosure further specifies that the ligand free metal ion core can be formed from a broad allowable set of metal ions, and the ligand/drug can be selected from stated functional-group classes compatible with Lewis base coordination. A cytoprotective embodiment is described using Fe2+ or Gd3+ as the ligand free metal ion core with amifostine or WR-1065 and PEG-b-PGA, and it reports reduced in vitro drug release with higher FeCl2 amount and longer reaction time. Imaging and monitoring uses of metal ions are also mentioned, including MRI with Gd(III), SPECT with Tc-99m, and PET/CT with Ga-68, as well as other radioisotopes.
Claims Coverage
The independent claim defines a chelating complex micelle using a ligand-free Lewis-acid metal ion core coordinated to a ligand, where the ligand is PEG-b-PGA and links a drug; this independent claim includes three core inventive features. Dependent claims further specify allowable metal ion cores, allowable ligand functional-group classes, and that the drug is a Lewis base drug, including both functional-group constraints and enumerated drug candidates.
Lewis-acid, ligand-free metal ion core with coordinate bonding ligand
A chelating complex micelle comprising a ligand free metal ion core, wherein said ligand free metal ion core is a Lewis acid; and a ligand, wherein said ligand and said ligand free metal ion core bind to each other by coordinate bonds.
PEG-b-PGA ligand linking the drug via the metal core
Wherein said ligand free metal ion core links a drug wherein the ligand is poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA).
Allowable metal ion core selection for the Lewis acid
The chelating complex micelle wherein said ligand free metal ion core comprises one or any combination of Fe, Cu, Ni, In, Ca, Co, Cr, Gd, Al, Sn, Zn, W, Sc, Ti, Mn, V, Mg, Be, La, Au, Ag, Cd, Hg, Pd, Re, Tc, Cs, Ra, Ir, and Ga.
Ligand functional-group classes for coordinating ligand selection
The chelating complex micelle wherein said ligand comprises one or more of carboxylic acids, alcohols, ketones, furans, amines, anilines, pyrroles, thiols, esters, amides, imines, pyridines, pyrimidines, imidazoles, pyrazols, sulfonamides, and phosphonic acids.
Lewis base drug in the chelating complex micelle
The chelating complex micelle of claim 1 wherein said drug is a Lewis base drug.
Lewis base drug functional-group constraints
The chelating complex micelle of claim 4 wherein said Lewis base drug comprises one or more functional groups selected from carboxylic acids, alcohols, ketones, furans, amines, anilines, pyrroles, thiols, esters, amides, imines, pyridines, pyrimidines, imidazoles, pyrazols, sulfonamides, phosphonic acids, and any combination thereof.
Enumerated Lewis base drug candidates
The chelating complex micelle of claim 4 wherein said Lewis base drug is selected from amifostine, WR-1065, doxorubicin, pemetrexed, gemcitabine, methotrexate, docetaxel, vinblastine, epirubicin, topotecan, irinotecan, ifosfamide, gefitinib, erlotinib, penicillin class, cloxacillin, dicloxacillin, gentamicin, vancomycin, amphotericin, quinolones, piperazine, fluoroquinolone, nalidixic acid, ciprofloxacin, levofloxacin, trovafloxacin, oseltamivir, metformin, trastuzumab, imatinib, rituximab, bevacizumab, celecoxib, etodolac, ibuprofen, cyclosporine, morphine, erythropoietin, granulocyte colony-stimulating factor, curcumin, glutathione, Vitamin C, acetylcysteine, carnitine, galantamine, insulin, imipenem, cilastatin, ertapenem, meropenem, entecavir, telbivudine, lamivudine, melatonin, tocopherols, tocotrienol (Vitamin E), L-carnitine, carotenes, ubiquinol, lipoic acid, polyphenols, catecholamine, resveratrol, piceid, tempo, asarone, aminoguanidine, tocopherol monoglucoside, glycyrrhizic acid, epicatechin, flavonoid, orientin, vicenin, MPG (2-mercaptopropionyl glycine), Mesna (2-mercaptoethanesulfonic acid), and any combination thereof.
Overall claim coverage is centered on a chelating complex micelle in which a ligand-free Lewis-acid metal ion core binds a ligand by coordinate bonds, with PEG-b-PGA as the ligand that links a drug. Dependent claims narrow the invention by defining the allowable metal ion cores, selecting ligand functional-group classes, requiring that the drug is a Lewis base drug, constraining its functional groups to specified classes, and providing an enumerated list of named Lewis base drug candidates.
Stated Advantages
Extend drug half-life.
Reduced drug release behavior in vitro, with higher FeCl2 amount and longer reaction time associated with reduced drug release.
Provides imaging/monitoring potential using metal ions such as Gd(III) for MRI and Tc-99m for SPECT, including PET/CT imaging with Ga-68.
Documented Applications
Cytoprotective embodiment using Fe2+ or Gd3+ as the ligand free metal ion core with amifostine or WR-1065 and PEG-b-PGA.
Imaging/monitoring uses including MRI with Gd(III), SPECT with Tc-99m, PET/CT with Ga-68, and mentions other radioisotopes including In-111 and Re-188.
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