ABSTRACT
The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.
Subject(s)
Drug Carriers/pharmacokinetics , Nanoparticles/chemistry , Polymers/pharmacokinetics , Animals , Blood Circulation Time , Drug Carriers/administration & dosage , Drug Carriers/adverse effects , Enzyme-Linked Immunosorbent Assay , Hydrophobic and Hydrophilic Interactions , Immunoglobulin M/blood , Injections, Intravenous , Male , Metabolic Clearance Rate , Nanoparticles/administration & dosage , Nanoparticles/adverse effects , Polymers/administration & dosage , Polymers/adverse effects , Polyvinyls/administration & dosage , Polyvinyls/adverse effects , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Pyrrolidines/blood , Rats , Rats, WistarABSTRACT
PURPOSE: We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. METHODS: The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. RESULTS: Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. CONCLUSIONS: This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).
Subject(s)
Nanoparticles/administration & dosage , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Animals , Blood Circulation Time/drug effects , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Particle Size , Rats , Rats, Wistar , Time FactorsABSTRACT
PURPOSE: Prostaglandin E(1) (PGE(1)) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE(1) in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. METHODS: In order to encapsulate PGE(1) in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE(1) phosphate derivatives and tested their efficacy. RESULTS: Among them, PGE(1) 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE(1) in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE(1). In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE(1) phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of L-PLA instead of D,L-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles. CONCLUSIONS: We consider that C2-encapsulated nanoparticles prepared with L-PLA and PEG-D,L-PLA have good sustained-release profile of PGE(1), which is useful clinically.
Subject(s)
Alprostadil/administration & dosage , Alprostadil/chemical synthesis , Drug Carriers/chemistry , Nanoparticles/chemistry , Phosphates/chemistry , Alprostadil/metabolism , Alprostadil/pharmacology , Animals , Humans , Hydrolysis , Lactic Acid/chemistry , Particle Size , Phosphates/chemical synthesis , Platelet Aggregation/drug effects , Polyesters , Polyethylene Glycols/chemistry , Polymers/chemistry , Prodrugs/metabolism , Rats , Rats, Wistar , Regional Blood Flow/drug effects , Serum/metabolism , Skin/blood supply , Zinc/chemistryABSTRACT
Two compounds were synthesized which have a structural component other than those of our new series histone deacetylase (HDAC) inhibitors to determine the structure-activity relationship. It was also examined whether the inhibitory effects on cancer cell proliferation by HDAC inhibitors involve p21/WAF1 induction and G(1) or G(2)/M arrest in p53-mutated MG63 human osteosarcoma cells as do other HDAC inhibitors. It was demonstrated that inhibitors with the 2-naphthylcarbonyl group and hydroxamic acid at both termimal sides as well as the phenylene component at the center of molecule markedly induce the p21/WAF1 protein by stimulating p21/WAF1 gene promoter activity. Furthermore, cell cycle analysis revealed that these compounds arrest MG63 cells in the G(2)/M phase.
Subject(s)
Cell Division/drug effects , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , G2 Phase/drug effects , Histone Deacetylase Inhibitors , Cell Division/physiology , Cell Line, Tumor , G2 Phase/physiology , Histone Deacetylases/metabolism , HumansABSTRACT
The screening tests of N-hydroxybenzamides for their HDAC-inhibitory activities led to the discovery of the promising compounds with a 2-naphthylcarbonyl group and with a 1,4-biphenylcarbonyl group. These compounds were further modified to optimize their physico-chemical profile. As a result, the inhibitor with a 6-amino-2-naphthylcarbonyl was obtained, which showed not only promising growth inhibitions against a panel of tumor cells, but also an improved water solubility. It exhibited the maximal 185% of survival rate (%T/C) in a in vivo experiment with P388 cell-inoculated mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Histone Deacetylase Inhibitors , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Mice , Xenograft Model Antitumor AssaysABSTRACT
Utilizing tranexamic acid as a starting material, a series of N-hydroxycarboxamides were synthesized in order to seek new histone deacetylase (HDAC) inhibitors. Further structure optimization involving the replacement of the 1,4-cyclohexylene group with the 1,4-phenylene group yielded the promising HDAC inhibitors which possess a terminal bicyclic aryl amide.
