ABSTRACT
We synthesized two types of triblock copolymers containing PEG and PLA as controlled release carriers of hydrophobic drugs: these are the ABA type (PLA-PEG-PLA) and the BAB type (PEG-PLA-PEG). These polymers are amphiphilic and can form nanomicelles (40-200nm) in aqueous medium. On the surface of PLA-PEG-PLA (ABA) type nanomicelles, the PEG content was enhanced somewhat over the bulk amount; whereas in the PEG-PLA-PEG (BAB type), surface segregation was much higher. The copolymers tested can entrap 35% of paclitaxel by weight on the average. In general, the diffusion-controlled release of paclitaxel is slower for the BAB polymers; furthermore, the actual release rates are influenced by the PLLA lengths in the BAB copolymers. Surface PEG contents influence the "stealth" characteristics of the nanomicelles. Compared with PLA particles, all nanomicellar particles tested, of both BAB and ABA types, showed a four-fold reduction in monocyte cell uptake, with the BAB type copolymer exhibiting a lesser uptake.
Subject(s)
Drug Carriers , Paclitaxel/chemistry , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polymers/chemical synthesis , Delayed-Action Preparations , Drug Delivery Systems , Drug Stability , Micelles , Monocytes/immunology , Monocytes/metabolism , Nanoparticles/chemistry , Paclitaxel/administration & dosage , Particle Size , Polyesters/chemical synthesis , Polyethylene Glycols/chemical synthesis , Polymers/chemistry , Spectrometry, X-Ray Emission , Surface PropertiesABSTRACT
The complete array of those hydrotris(pyrazolyl/thioimidazolyl)borate ligands that were developed and used in the author's laboratories, with N3, N2S, NS2, and S3 donor sets, was scanned for their ability to form Zn-OH2 and Zn-OH complexes. The coordination motifs found were Zn-OH2, Zn-OH, Zn-OH-Zn, and Zn-O2H3-Zn. Of these, the well-established Zn-OH motif was complemented with novel species bearing N3, NS2, and S3 tripods. The Zn-OH2 motif was observed only with pyrazolylborate ligands and only in unusual situations with coordination numbers higher than 4 for zinc. The new Zn-OH-Zn motif was realized for three different pyrazolylborates, for one NS2 tripod, and for two S3 tripods. Finally, it was verified that the Zn-O2H3-Zn motif again occurs only with pyrazolylborate ligands. The new complexes were identified by a total of 11 structure determinations.
Subject(s)
Borates/chemistry , Hydroxides/chemistry , Imidazoles/chemistry , Organometallic Compounds/chemistry , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistry , Zinc Compounds/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
The biologically relevant alkylations of the thiolate ligands in tripod zinc thiolates by methyl iodide were studied kinetically. Five tripod ligands of the pyrazolyl/thioimidazolyl borate type were employed, offering N3, N2S, NS2, and S3 donor sets. For each of them, the ethyl-, benzyl-, phenyl-, and p-nitrophenylthiolate zinc complexes were investigated, yielding a total of 20 second-order rate constants. The comparison of these rate constants shows three effects: (1) the electronic effect among the thiolates, i.e., the ethanethiolates react about 3 orders of magnitude faster than the p-nitrophenylthiolates; (2) the steric effect among the pyrazolylborates, i.e., the phenyl-substituted ones react about 2 orders of magnitude faster than the tert-butyl-substituted ones; and (3) the strong acceleration by the sulfur donors in the tripods, reaching 4 orders of magnitude between the reaction times of the (N3)Zn-SR and (S3)Zn-SR complexes.
