Self-Assembled Cytotoxic Maytansinoid Nanoparticles For In Vitro And In Vivo Drug Delivery

Chemotherapy is one of the main therapeutic measures on tumor,but it is difficult for common chemotherapeutic drugs to flock to the cancerous site.Conventional methods of curing tumors make a great side effect.Common cells are damaged while killing cancer cells.Hence it is hopeful to enhance the clinical application value of drugs by reasonable structure reformation.Maytansine(DM1),a powerful tubulin polymerization inhibitor,restrains normal mitosis of cells thus induces apoptosis of tumor cells.Maytansine has efficient antitumor activity among multiple malignant tumors compared with most antitumor drugs(doxorubicin,camptothecin,cabazitaxel,and so forth)in current clinical studies,but side effects are serious.Various types of antibody-maytansinoid conjugates have been designed and fabricated for cancer treatment based on the high antitumor activity.For example,Kadcyla(?)(ado-trastuzumab emtansine)has already been approved for use in the treatment of HER2-positive metastatic breast cancer by FDA.However,there are still some problems in the clinical application,such as low yield,low drug loading,high cost and potential immunogenicity.In this work,maytansine and iRGD peptide are combined together with the help of docosahexaenoic acid(DHA)for tumor targeted therapy.Cyclic or linear RGD(arginine-glycine-aspartate)peptide has high affinity with the αvβ3 integrin which is over expressed on the surface of many tumor cells.It is reported that iRGD(CRGDK/RGPD/EC)can increase drug penetration into tumor tissue compared with conventional RGD.In chapter 1,the present status and progress of research on nanodrugs,and the recent development of active targeting prodrug nanoparticles are reviewed.In chapter 2,the target products of docosahexaenoic acid(DHA)covalently coupled maytansine(DM1)prodrug and DHA covalently coupled iRGD polypeptide are designed and synthesized.DM1,iRGD are covalently coupled to DHA by N-(2-aminoethyl)maleimide,respectively.The drugs can form stable nanoparticles by self-assembly in water after the DHA modification.The size,morphology and stability of fabricated nanoparticles are characterized.In chapter 3,the therapeutic efficacy of the fabricated iRGD/sDHA-DM NPs in HeLa human cervical tumor xenografts is assessed.The prodrug particles coupled with DHA significantly reduce the side effects of DM1 and show superior tumor inhibition effect in vivo after the introduction of iRGD.This prodrugs retains its antitumor activity while improving its tolerability in vivo.We therefore envision that many traditional chemotherapeutics could be adapted into this nanoplatform to reduce side effects and improve their therapeutic outcomes.In chapter 4,a multistage microfluidic chip was designed to synthesize siRNA and Cabazitaxel drug-loaded nanoparticles in one step.This part of work is still in progress,and more attention will be payed to optimized synthesis of drug-loaded particles and evaluation of their in vitro and in vivo properties.