Anticancer Nanodrugs Based On Amphiphilic Drug-drug Conjugates

Currently,cancer has been a leading cause of death worldwide.Among various cancer treatments,chemotherapy remains an indispensable choice for most cancer cases.However,conventional small molecule anticancer drugs usually suffer from several limitations including poor bioavailability,rapid blood/renal clearance,nonspecific selectivity,low accumulation in tumors,severe multidrug resistance(MDR)and adverse side effects for healthy tissues.To address these limitations,many nano-vehicles have been used as drug carriers.With the help of these nanocarriers,the small molecule anticancer drugs can be delivered to focus sites,demonstrating better therapeutic efficacy against tumors and fewer side effects over free drugs.However,almost all carriers have no therapeutic efficacy by themselves.Even worse,a lot of carriers with low drug loading capacity may cause high toxicity and serious inflammation to kidneys and other organs in the course of degradation,metabolism,and excretion.Without the help of nanocarriers a self-delivery drug system integrating both the advantages of free drugs and nanocarriers will have potential application in the clinic.Aiming at this goal,we put forward a new concept of amphiphilic drug-drug conjugate(ADDC)and developed a series of self-delivery systems for cancer therapy in this dissertation.The main contents are described as below:1.Most of small molecule anticancer drugs are difficultly delivered to tumor sites because of various biological barriers in human body,which leads to lower therapeutic efficacy and higher side effects.To overcome these barriers,an effective drug delivery system for cancer therapy is imperative.In this work,we put forward a new concept,amphiphilic drug-drug conjugate(ADDC),and develop a novel carrier-free drug self-delivery system based on ADDC for cancer therapy.A hydrophilic anticancer drug and a hydrophobic one are linked together via a hydrolyzable ester bond.Ascribing to the amphiphilic property,the ADDC self-assembles into nanoparticles,leading to a longer blood circulation time than the free drugs,which facilitates the accumulation of anticancer drugs in tumor tissues via the EPR effect and the subsequent cellular internalization.Benefiting from the nano-characteristics of ADDC nanoparticles,the multidrug resistance(MDR)of tumor cells can be circumvented,resulting in high intracellular drug concentration.After hydrolysis of the ADDC,the two released free anticancer drugs result in an excellent anticancer activity in vitro and in vivo.We believe that this drug self-delivery strategy based on self-assembly of amphiphilic drug-drug conjugate in the present study may open a new way for chemotherapy in cancer therapy and would eventually be applied in clinic for the treatment of varieties of tumors.2.Currently,simple mixing two small molecule anticancer drugs for combination cancer chemotherapy presents some therapeutic effects,but the synergistic efficacy is not satisfied.On the base of ADDC concept,an amphiphilic drug-drug conjugate(irinotecan-bendamustine,Ir-Bd)was synthesized here.The Ir-Bd conjugate can self-assemble into nanoparticles in water because of its amphiphilic nature.Then we compared the therapeutic efficacy of Ir-Bd conjugate nanodrug and Ir/Bd mixture formulations in cancer combination chemotherapy in vitro.The results demonstrated that Ir and Bd presented a high synergistic efficacy of Ir-Bd nanodrug formulation in cancer combination chemotherapy.3.Recently,the cocktail therapy has been proposed as a promising strategy to treat various cancers.On the base of ADDC concept,we reported a facile approach to construct ternary cocktail nanoparticles,which are composed of three different anticancer drugs through the molecular coassembly of two amphiphilic drug-drug conjugates.The component of these nanoparticles can be simply adjusted by changing the feed ratio of two amphiphilic drug-drug conjugates in the coassembly process.Without the help of any drug carriers,they can self-deliver into tumor cells and release three drugs synchronally.The optimal synergistic therapeutic effect can be obtained through simple tuning the ratio of two different amphiphilhc drug-drug conjugates.4.Multidrug resistance(MDR)of cancer cells is one of the major causes of chemotherapy failures in clinic.Therefore,it has been a great challenge how to circumvent the MDR of tumor cells.On the base of ADDC concept,we design and synthesis one amphiphilic drug-drug conjugate,which is responsive to the tumor environment.The amphiphilic drug-drug conjugate was synthesized through using a disulfide bond linking the hydrophilic anticancer irinotecan(Ir)with the hydrophobic P-gp protein inhibitor quinine(Qu).Based on the amphiphilic characteristic,the amphiphilic drug-drug conjugate(Ir-ss-Qu)is able to self-assembly into nanoparticles in water and shows longer blood retention half-life compared with the Ir and Qu,which is helpful for the nanoparticle accumulating at tumor site via EPR effect.After the Ir-ss-Qu nanoparticles entering drug-resistant cells,the linkage of disulfide bond between hydrophilic and hydrophobic parts is cleaved rapidly by the glutathione(GSH),while the anticancer drug and the inhibitor were released synchronally.The released Qu can markedly reduce expression of P-gp and inhibit the pumping out of the anticancer drug Ir,which increased the accumulation of Ir in drug resistant cells and greatly improved therapeutic efficacy.The stimuli-responsive amphiphilic drug-drug conjugate system exhibits very highly the cytotoxicity by increasing the intracellular accumulation of Ir,and showed the most effective inhibitory about the growth of drug-resistant breast cancer compared with individual free therapeutic agents.