Preparation Of Hydroxyethyl Starch-Based Docetaxel And Study Of Release Behaviors

Docetaxel is an important cancer therapy agent with a broad spectrum of antitumor activity. Due to water insolubility, it is currently formulated with Tween-80, which causes hypersensitivity reactions and takes more pain for the patient. To solve this problem, several drug delivery systems (DDS) have been developed based on polymer-drug conjugate, liposome, polymeric nanoparticles (including polymeric micelles and polymersomes) and nanoemulsion etc. The hydrophobic drugs can be loaded covalently and noncovalently in DDS to improve solubility and stability of anticancer drugs.Polysaccharides have been developed to be a drug delivery system due to their known biocompatibility and biogradability, especially the nano drug delivery system for hydrophobic drugs based on modified polysaccharides. Some polysaccharides are poor soluble, for example, chitosan should dissolve in weak acidic condition and cellulose can’t dissolve in water. Shieding on the surface with PEG can improve solubility, reduce interaction of opsonins to minimizing clearance in the RES and prolong the in vivo circulation time. However, the PEG coat reduces the cellular interaction and uptake, what is known as the "PEG-dilemma". It’s worth nothing that PEG itself is unable to be degraded and shows toxicity at high parenteral dose and in long-term use. For example, PEG is unable to cross the lysosomal membrane leading to accumulation there and interference with the lysosomal enzymes.Hydroxyethyl starch (HES) is a modified natural polysaccharide of highly branched amylopectin which is available through acid hydrolysis and hydroxyethylation. Through hydroxyethylation, the water solubility of starch is significantly improved, and its half-life in vivo is also increased. Currently HES is used as plasma substitutes, and also as a medicine for the therapy of hypovolemic shock. Therefore, hydrophilic HES carriers are rather safe that no toxic reaction could be observed at maximal approved daily dose1.2g/kg. There are few research about drug delivery system based on HES, and the strategy for encapsulation of hydrophobic drug based on HES even have not been reported.Herein, we have constructed two DDS loading docetaxel covalently and noncovalently based on hydroxyethyl starch. We open up a new field of application about HES, and provide a non-PEGylation approach for hydrophilic modification. This dissertation can be further categorized into four main parts as described below:(1) In the presence of EDC/DPTS, docetaxel was conjugated with HES between ester linkage. To investigate the structure, HES-DTX conjugate were characterized by NMR, FT-IR. The drug delivery in vitro indicated that HES-DTX conjugate provided a sustained drug release, and with enzyme controlled drug release properties.(2) in vivo pharmacokinetic behavior of HES-DTX conjugate was evaluated to demonstrate the potential for drug delivery. Compared with free DTX, AUC (0→∞) value of HES-DTX conjugate was4.0times higher and t1/2β was4.1times longer, indicating that HES-DTX conjugate could achieve long circulation effect. Anti-tumor efficacy studies of HES-DTX conjugate were investigated in the murine mammary carcinoma EMT-6subcutaneous Balb/c mice. The result implied that HES-DTX conjugate administration group displayed a more obvious tumor regression and reduced adverse reaction, compared with free DTX.(3) Amphiphilic copolymers, namely HES grafted polylactides (HES-g-PLAs) with different chain lengths of PLA through ring-open of d,l-lactide initiated by hydroxyl groups of HES. The structure, size and morphology were characterized by NMR, FT-IR, DLS and TEM. HES-g-PLAs self-assembled into monodispersed nanomicelles in aqueous solution with size between in65-130nm. The CMC of HES-g-PLAs micelles was found to be very low, indicating that remarkably stable in water. The size and CMC decrease with the increase of chain lengths of PLA.(4) Docetaxel was selected as a model anti-cancer drug encapsulated in HES-g-PLAs, and in vitro release behavior was investigated. The release behavior meets the first-order kinetics, and the mechanism of release involves both diffusion and polymer relaxation. A further significant result showed that HES-g-PLAs provided a sustained drug release and the release behavior of drugs can be modulated by changing the chain length of the PLA segment.