Integrated Multifunctional Micelles Based On Polypeptide-Ferulic Acid/Lipoic Acid Conjugates For Efficient Doxorubicin Delivery

Cancer has become a global public health problem,which is threatening human life.Thus,it's urgent to seek an efficient treatment for cancer.Nanomedicines can largely improve the solubility,bioavailability,and tumor accumulation of hydrophobic anticancer drugs,thus have received great interests for targeted cancer therapy.However,the clinical results show that nanomedicines currently used are still tortured by low drug loading capacity,poor in vivo stability,insufficient cellular uptake,and slow or incomplete intracellular release.To overcome these challenges,we designed and fabricated integrated multifunctional micelles from polypeptide-ferulic acid/lipoic acid conjugates for efficient and bioresponsive delivery of chemotherapeutics including doxorubicin(DOX)in this thesis.In the first chapter,we briefly introduced the unique characteristics,current situations and challenges of nanomedicines,and outlined various strategies on the development of functional nanocarriers to overcome these challenges.In the second chapter,integrated multifunctional micelles(c RGD-XIMM)were developed by co-self-assembly of poly(ethylene glycol)-b-poly(L-lysine)derivatives with natural ferulic acid(FA)or lipoic acid(LA)for efficient and bioresponsive DOX delivery.FA confers c RGD-XIMM with intrinsic antitumor activity,improved loading of DOX via ?-? stacking,and reduced DOX cariotoxicity.LA provides c RGD-XIMM with reversible crosslinking property which leads to a high colloidal stability with inhibited leakage and triggered intracellular DOX release.Notably,our results showed that c RGD-XIMM had a small size(~56 nm)and superior loading of DOX(27.1 wt.%).DOX-loaded c RGD-XIMM(c RGD-XIMM-DOX)showed high colloidal stablility under physiological conditions,in which lower than 25% of drug was released in 72 hours.On the contrary,over 93% of drug was released in the presence of 10 m M glutathione(GSH)under otherwise the same conditions,signifying their reduction-sensitivity.Thus,these integrated multifunctional micelles with easy accessibility,high drug loading capacity,excellent stability under physiological conditions,and reduction-sensitivity have great potential as safe and efficient nanoplatforms for efficient and triggered delivery of chemotherapeutics.In the third chapter,we further investigated the biocompatibility and in vitro antitumor activity of the integrated multifunctional micelles(c RGD-XIMM)and their DOX formulations.Cell cytotoxicity and apoptosis assays revealed that blank c RGD-XIMM though non-toxic to normal cells like L929 exhibited obvious antiproliferative activity against cancer cells including B16F10 and HCT-116 tumor cells at 150 ?g FA equiv./m L.DOX-loaded c RGD-XIMM displayed enhanced growth inhibition of ?v?3-positive B16F10 and HCT-116 tumor cells with IC50 of 6.1 and 7.9 ?g/m L,respectively.Flow cytometry(FACS)and confocal laser scan microscopy(CLSM)results revealed that c RGD-XIMMDOX could internalize into tumor cells via ?v?3 integrin-mediated endocytosis mechanism,and achieve fast drug release under intracellularly reductive environments.In vivo pharmacokinetics studies displayed that c RGD-XIMM-DOX had a long elimination phase half-life of 3.85 h and relatively high tumor accumulation,which was about 3.0-fold higher than that for clinically used lipsomal DOX formulation(LP-DOX).Interestingly,c RGDXIMM-DOX displayed a high maximum-tolerated dose of over 100 mg DOX equiv./kg.Histological analysis revealed that DOX-loaded c RGD-XIMM at 100 mg DOX equiv./kg caused negligible cardiotoxicity,which is a major issue for clinical use of DOX.These integrated multifunctional micelles with excellent safety and accessibiity have emerged as a promising nanoplatform for targeted cancer chemotherapy.In the last chapter,the results of the whole thesis were briefly summarized and the future perspective was presented.