Synthesis And Characterization Of Water-soluble PCL-paclitaxel Prodrugs

Many opportunities exist for the application of synthetic biodegradable polymers in the biomedical area particularly in the fields of controlled drug delivery. In the field of controlled drug delivery, biodegradable polymers offer tremendous potential either as a drug delivery system alone or in conjunction to functioning as a medical device. Polymer-drug conjugates have been employed as carriers to deliver various anticancer drugs, which can maximize the bioavailability of the drugs by improving solubility and increasing circulation time. In order to solve the problem of low water solubility, reduce or modulate their toxicity and enhance the therapeutic efficacy of anticancer drugs, this work presents a novel approach to aliphatic polyester PCLs with functional pendant carboxylic groups that might be applied as a novel material for drug delivery. General aspects in this study were described as below:In recent years, the attachment of covalent bond between water-soluble polymer-drug conjugates and drugs to prepare prodrug has aroused great concern throughout the world. By the form of prodrug, the water-solubility, pharmacokinetics and pharmacodynamics of drugs can be improved. In this paper, we prepared water-soluble PCLs through introducing functional groups based on good biocompatibility and biodegradability of aliphatic polyester PCLs. The side chain of polymers containing a lot of pendant carboxyl groups, which can be used to react with drugs that have hydroxyl groups through ester linkages and then do as drug delivery carriers, which could be of great potential application.In this paper, cyclohexanone and 1,4-cyclohexanediol was respectively used as materials to synthesize two new caprolactone based monomers containingα- orγ-functional groups which was characterized by means of FTIR and NMR. The PCL homopolymers containing functional pendant bromine groups were synthesized by ring opening polymerization ofα- orγ-functional monomers catalyzed by stannous octoate, methanol as initator. Through the thio-bromo "Click" of mercaptosuccinic acid and mercaptopropionic acid, polymers with functional pendant carboxylic groups were obtained and characterized by means of FTIR,1H NMR and GPC. And water-soluble contrast study was then carried out, which was showed as the results that the conjugation of mercaptosuccinic acid has better water-solub, while the conjugation of mercaptopropionic acid has poor water-solubility. We have synthesized a series of mercaptosuccinic acid conjugated polymers with different molecular weights to study the molecular effect on water-solubility. The results show that within the scope of the molecular weight in this paper, the changing of molecular weight would not lead to an obvious change on the water-solubility.Paclitaxel prodrugs were then prepared by conjugation of paclitaxel to water-soluble PCLs through the Steglich esterification reaction. They were characterized by means of FTIR,1H NMR, GPC and UV-Vis spectra. The drug loading of paclitaxel prodrug and water solubility of the prodrugs with different drug loading were determined by UV-Vis spectra. Results turned out that the content of paclitaxel prodrug was about 10 to 40 percent which reached 75 to 85 percent of the theoretical drug loading. And water-solubility study was then carried out by dissolving the product into water. All results proved that paclitaxel prodrugs by the conjugation of paclitaxel to water-soluble PCLs have high drug loading rate and good water-solubility.