| 摘要 |
<p>#CMT# #/CMT# A carrier and localization system for active or functional molecules (A) comprising particles of biodegradable polyester (I) having a single or multiple functionalized surface layer of proteins covalently or non-covalently bonded to (I) and/or amphiphilic molecules non-covalently bonded to (I), is new. #CMT#USE : #/CMT# (A) Are specifically: (a) antitumor agents, antibiotics, anticoagulants, germicides, antiarrhythmic agents or drug precursors or derivatives; (b) biologically active peptide or protein therapeutic or diagnostic agents; or (c) non-biological molecules such as pesticides, herbicides or fertilizers (claimed). Pharmaceutical compositions containing the particles are claimed, specifically where the compositions have immunomodulatory, antiinfective and/or antitumor activity. #CMT#POLYMERS : #/CMT# Preferred Composition: The particles have a core of a polyester (I) having similar component units to those polymerized by polyester synthesizing esters to a polyoxoester or polythioester; and are preferably nanoparticles (10-100 nm), submicroparticles (100-900 nm), microparticles (1-3 Microm) or films. The particles are enveloped in phospholipids, ether lipids, proteins, lipopolysaccharides and/or amphiphilic molecules, bonded to the granule surface. Alternatively the particles are enveloped by proteins formed by fusion of enzymes and/or specific binding mediating proteins with polyhydroxyalkanoate (PHA) synthases, PHA depolymerases, phasines, proteins with phasine function and/or PHA regulator proteins; in particular in this case the particles are enveloped with fusion proteins having a (I) surface binding domain and a specific function mediating domain (preferably for mediating enzyme activity, surface stabilization and/or specific molecular interactions). Preferred Production: The particles are formed in vivo in eubacteria or archaebacteria, the composition of (I) being controlled by selection of the culture conditions (precursor substrates, sequential precursor feed). micro-organisms (wild strains, mutants or genetically modified strains) and metabolic flow control (using inhibitors of metabolic flow or metabolic pathways established by genetic modification) and the particle size being controlled by ratio of (I)-synthesizing enzymes to polymerizable substrates and/or the copy number of phasines, the PhaP of Ralstonia eutropha or proteins with PhaP function. Particles with defined size are recovered by gel filtration chromatography, density gradient chromatography and/or ultrafiltration. The particle surfaces are activated with chemical reagents and (A) are bonded via the active sites. Preferably activation is effect using the amino acid residue modifying coupling reagents bis-(2-oxo-3-oxazolidinyl)-phosphonyl chloride, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, dicyclohexyl carbodiimide, disuccinimidyl carbonate, 1-(3-dimethylaminopropyl)-3-ethyl-carbodimide, bis-(2-oxo-3-oxazolidinyl)-phosphine, 2-(1H-benzotrioxazolyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, , p-nitrophenyl chloroformate or O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; the reagents triethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo-(5.4.0)-7-undecene, N,N-dimethylamino-pyridine or N,N-diisopropyl-ethylamine; and the additives hydroxybenzotriazole, pentafluorophenol or N-hydroxy-5-norbornene-2,3-dicarboximide. #CMT#PHARMACEUTICALS : #/CMT# Preferred Active Agents: (A) are: (1) antitumor agents, such as dideoxyinosine, floxuridine, 6-mercaptopurine, doxorubicin, daunorubicin, 1-darubicin, cisplatin, methotrexate or taxol; (2) antibiotics, such as erythromycin, vancomycin, oleandomycin or ampicillin; anticoagulants, such as heparin; (3) germicides, such as ara-A, acrylguanosine, nordeoxyguanosine, azidothymidine, dideoxyadenosine or didesoxythymidine; (4) antiarrhythmic agents; (5) drug precursors or derivatives; (6) biologically active peptide or protein therapeutic or diagnostic agents, especially insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic release factors, prolactin, thyroid stimulating hormone, endorphine, enkephalins, vasopressins, non-naturally occuring opiates, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminase, adenosine deaminase, ribonuclease, trypsin, chymoytrypsin or pepsin; or (7) non-biological molecules such as pesticides, herbicides or fertilizers.</p> |
