Preparation And Properties Of Novel Paclitaxel Drug Delivery Systems

Paclitaxel（PTX）is one of the most effective chemotherapeutic drugs,which is active against a variety of cancers,such as lung cancer,ovarian cancer and breast cancer.However,the clinical application of PTX is limited due to its low water solubility and serious side effects of adjuvant.Recently,nano drug delivery systems with enhanced permeability and retention（EPR）effect for passive tumor targeting become a hotspot in chemotherapy drug strategy.Besides,PTX nano-systems present much improved drug efficacy as well as reduction of side effects.In this thesis,we designed two unique nano drug delivery systems to address the shortcomings of PTX delivery.The detailed content and results are described as follows:First part:Combination of multiple chemotherapeutics is a common strategy for enhanced efficacy in cancer treatment,but the essential antagonistic performance of the combined drugs has limited their utilization.In this part,a novel dual functional liposomal formulation based on dimeric artesunate glycerophosphorylcholine（di-ART-PC）conjugate assembled liposomes was developed for synergistical delivery of the established PTX.The PTX/di-ART-PC liposomes demonstrated high drug loading content（10.52%）,loading efficiency（83.9%）of PTX,reasonable size（174.6nm）and well-defined spherical structure.In vitro release profiles revealed that PTX/di-ART-PC liposomes have controlled release profile of PTX and ART in a weakly acidic environment.Moreover,the nanoscaled characteristics and dual functionality make the resultant 2-in-1 liposomes capably internalized into tumor cells and thereby,synergistically enhanced antitumor response,as confirmed by in vitro experiments.In particular,the liposomes displayed more efficacious antitumor effects compared with free drug cocktail solution,at which the combination index（CI）of PTX/di-ART-PC liposomes for MCF-7,HepG-2 and A549 cells were 0.753,0.724and 0.606,respectively.These results suggested that di-ART-PC liposomes will be a promising candidate for synergistic delivery of chemotherapeutics in 2-in-1 system to improve cancer treatment integrating efficacy.Second part:Crosslinked PTX prodrug micelles were developed through covalently conjugating PTX onto water soluble poly（ethylene glycol）-dihydrolipoic acid(MeO-PEG_2k-DHLA)via a disulfide linkage.The structure of polymer-PTX prodrug(MeO-PEG_2k-SS-PTX)was determined by ¹H NMR.MeO-PEG_2k-SS-PTX could self-assembled to micelles possessing high PTX loading efficiency（26 wt%）after disulfide crosslinking.The MeO-PEG_2k-SS-PTX micelles were spherical morphology with the uniform size of 87.6 nm in phosphate buffer（PBS,pH 7.4）,as confirmed by transmission electron microscopy（TEM）and dynamic light scattering（DLS）.Compared with the uncrosslinked micelles,crosslinked ones showed significantly improved colloidal stability in a normal physiological environment and harsh micelle-breaking conditions.In addition,the in vitro cumulative released amount of PTX from micelles was<15%,which was much less than the uncrosslinked one（up to 40.3%）after 72 h incubation in PBS（pH 7.4）.In contrast,the release was drastically accelerated under the stimulated intracellular reductive envirmonment of 10 mM glutathione（GSH）,highlighting their reduction-sensitive profile.Cytotoxicity assay and apoptosis analysis showed that the crosslinked MeO-PEG_2k-SS-PTX micelles had significantly high antitumor activity against MCF-7,A549 and BEL-7402 cells(half maximal inhibitory concentration,IC₅₀:0.353±0.069μM,0.351±0.072μM and 0.325±0.077μM,respectively),comparing with free PTX.More importantly,such micelles were found to hold a longer circulation time in bloodstream and were able to passively targeting accumulate in tumor sites of4T1-transplanted BALB/c mice model.Taken together,the crosslinked polymer-PTX prodrug micelles with reduction response could be used as a promising tumor-targeted delivery system in clinical applications.In summary,two novel PTX contained nano drug delivery systems were developed,which had good anti-tumor effect,a potential application value,and the significance of in-depth study.