Hydroxyethyl Starch-based Nanocarriers For Anticancer Drug Delivery

Nanomedicine is of great value in the diagnosis and treatment of cancers.In recent years,the advances in polymer science have made polymer synthesis more controllable and allowed for synthesis of polymers with multifunctionality and tailored properties,which greatly promotes the development of polymeric nanodrug delivery systems and their clinical translations.At present,a large number of polymers including natural polymers,semi-synthetic polymers and synthetic polymers,have been explored for the construction of multifunctional and smart nanodrug delivery systems to deliver drugs more effectively.Hydroxyethyl starch(HES)is a semi-synthetic polysaccharide,which has been widely used as plasma volume expander in clinical for decades.The good water solubility,biocompatibility,biodegradability,polyfunctionality and tailorability make HES an ideal material for the construction of nanodrug delivery systems.In the present thesis,three kind of HES-based nanodrug delivery systems were developed for tumor-targeted drug delivery.The main contents and results of the present thesis are as follows:1.HES was characterized by 1H-NMR,gel permeation chromatography(GPC),dynamic light scattering(DLS),and atomic force microscope(AFM).The results show that HES are intrinsically near spherical nanoparticles,which is most probably due to the relatively high degree of branching(~6%).The hydrodynamic diameter of HES increases with increasing molecular weight and decreasing colloidal osmotic pressure.2.To alleviate side effects and enhance the antitumor efficacy of doxorubicin(DOX),reduction-responsive hydroxyethyl starch-doxorubicin conjugate(HES-ss-DOX)was developed for passive tumor-targeted drug delivery.HES-ss-DOX can release drug in response to GSH and exhibits enhanced cytotoxicity against tumor cells as compared to non-responsive HES-DOX.HES-ss-DOX exhibits prolonged in vivo half-life time and enhanced tumor accumulation,as well as reduced cardiac and renal toxicity as compared to free DOX.As a result,HES-ss-DOX exhibits the highest antitumor effect over those of HES-DOX and free DOX in in vivo antitumor activity study.3.To further improve the therapeutic effect,galactose-decorated hydroxyethyl starch-polycaprolactone conjugate(Gal-HES-PCL)was designed and synthesized to prepare DOX/ICG-loaded nanoparticles(NPs)for active tumor-targeted imaging-guided photothermal/chemo combination therapy.DOX/ICG@Gal-HES-PCL NPs exhibit enhanced stability and photothermal effect as compared to free ICG.Owing to the distinctive structure,DOX/ICG@Gal-HES-PCL NPs possess selective drug release behaviors,which are beneficial for potent chemotherapy and thermal therapy.Taking the advantage of the active targeting ability,DOX/ICG@Gal-HES-PCL NPs achieve better tumor accumulation and deep tumor penetration as compared to DOX/ICG@HES-PCL NPs and free DOX.DOX/ICG@Gal-HES-PCL NPs also exhibit enhanced in vivo photothermal response as compared to DOX/ICG@HES-PCL NPs and free ICG.As a result,DOX/ICG@Gal-HES-PCL NPs exhibit the highest antitumor effect over those of DOX/ICG@HES-PCL NPs,DOX/ICG mixture,and free DOX in in vivo antitumor activity study,and the antitumor effect of DOX/ICG@Gal-HES-PCL NPs are significantly enhanced combined with laser irradiation.4.To achieve smarter drug delivery,i RGD-decorated reduction-responsive hydrophobically modified hydroxyethyl starch nanoclusters(i RGD-HES-ss-C18 NCs)were developed for active tumor-targeted drug delivery.DOX was loaded into the NCs as a model drug.DOX can be easily loaded into the NCs through hydrophobic interactions between DOX and C18 chains,resulting in high encapsulation efficiency and high drug loading content.The resultant DOX@i RGD-HES-ss-C18 NCs show good stability in PBS buffer,while disintegrate into smaller clusters and release DOX under reduction stimuli.Due to the specific ligand-receptor interactions between i RGD and integrin ?V over-expressed on Hep G-2 and 4T1 cells,DOX@i RGD-HES-ss-C18 NCs exhibit enhanced cellular uptake as compared to DOX@HES-ss-C18 NCs.After internalization,the NCs are transported to lysosomes and release DOX in response to reduction stimuli,which significanly reduces the cellular efflux.As a result,DOX@i RGD-HES-ss-C18 NCs exhibit enhanced cytotoxicity as compared to DOX@HES-ss-C18 NCs and free DOX in in vitro antitumor activity study.