Synthesis Of Dihydroartemisinin-loaded Nanomaterials And Their Application For Enhancing Tumor Therapeutic Effect

Cancer is currently considered to be one of the most dangerous diseases all over the world.So far,the treatment of this serious disease has received great attention.Among the various methods of cancer treatment,chemotherapy has been introduced into the clinic for more than sixty years,and is considered an ideal anti-cancer treatment option because of its high efficacy.As the semi-synthetic derivative and active metabolite of artemisinin,dihydroartemisinin?DHA?shows the advantages of both antimalarial activity and high metabolic rate.In recent years,domestic and foreign researchers have successively discovered that DHA can be used as an emerging tumor therapeutic agent,which can significantly inhibit about 55 kinds of cancer cell lines.DHA contains a peroxide bridge structure in its molecule,which reacts with transition metal ions to generate reactive oxygen radicals to kill cancer cells.Researchers have proposed different anti-cancer mechanisms of DHA,which show that the killing effect of DHA on tumor cells can be derived from the production of reactive metal oxygen?ROS?mediated by transition metal ions,which in turn oxidizes lipids,destroys cell membranes,proteins and DNA,and finally induces tumor cell apoptosis.In order to improve the pharmacological and therapeutic properties of drugs and the efficiency of drug delivery,researchers have designed nanomaterial-based drug delivery systems?DDSs?in the past few years.So far,scientists have successfully synthesized nanocarriers based on polymers,mesoporous silica,carbon nanomaterials,organics or metal compounds,which show excellent dimensional structure,tunable nanometer size,and enhanced penetration and retention effects?EPR?of passive tumor targeting capabilities.Most research results indicate that complex synthetic steps also limit the application of drug delivery systems.Therefore,it is necessary to design and synthesize simple but effective nanocarrier-loaded DHA to treat cancer.In this article,we have wisely designed and synthesized three kind of nanomaterials as drug delivery vehicles loaded with DHA to achieve chemotherapy and synergistic treatment of tumors.First,we synthesized a nano-sized metal-organic framework coordinating with Fe,and further loaded DHA to form a DHA@PCN-224-Fe nanocomposite combined with chemotherapy and sonodynamic therapy to achieve dual-mode synergistic therapy of tumor cells;After that,by constructing Fe-coordinated hollow polydopamine?HPDA?nanospheres and loading DHA in the cavity of HPDA,we prepared a biocompatible DHA@HPDA-Fe nanocomposite to achieve tumor selective chemotherapy;At last,through improvement,after loading DHA in the cavity of HPDA,the outer layer was coated with MnO₂ nano-coating,and DHA@PDA@MnO₂ nanospheres with tumor microenvironment-responsive degradation and drug release were constructed,combined with magnetic resonance imaging and chemotherapy.Integration of diagnosis and treatment,the treatment effect is further improved.This article mainly includes the following parts,Chapter 1.IntroductionIn this chapter,we briefly overview the concepts,characteristics and applications of nanomaterials in biomedical fields.Then,the advantages and disadvantages of various methods about tumor treatment based on nanomaterials are summarized in details,especially chemotherapeutic drugs.Finally,the structural characteristics of dihydroartemisinin and its potential reasons for anticancer chemotherapeutic drugs were reviewed.Chapter 2.Dihydroartemisinin encapsulated metal-organic framework nanoplatform for enhanced chemo and sonodynamic synergy therapy to tumor cellsWe designed and synthesized DHA-loaded metal organic framework?MOF?nanocomposites—DHA@PCN-224-Fe nanoparticles.The nanoparticles release Fe ions in response to tumor microenvironment and permits synergistic chemotherapy?CT?and sonodynamic therapy?SDT?to achieve passive but specific tumor targeting.In addition to the powerful ability of the material to generate singlet oxygen?¹O₂?presumably through ultrasound?US?irradiation of MOF,the reduced ferrous ions from the nanoparticles will also generate reactive oxygen free radicals by reacting with DHA and consume glutathione in tumor cells?GSH?,reducing the antioxidant capacity of tumor cells and enhancing the effect of chemotherapy thereby.Moreover,the Fe ions from the nanoparticles can react with H₂O₂ to produce O₂ to relieve the characteristics of tumor hypoxia.We believe that due to the low pH of the tumor microenvironment,the high concentration of GSH and H₂O₂,and the local US radiation characteristics,side effects shall be largely avoided.Chapter 3.Biodegradable iron-coordinated hollow polydopamine nanospheres for dihydroartemisinin delivery and selectively enhanced therapy in tumor cellsThe synthesis of nano-MOF usually requires higher temperature and complicated synthetic materials and steps.In order to avoid these disadvantages,herein,we develop a facile yet efficient strategy based on facile-prepared iron-coordinated hollow polydopamine?HPDA-Fe?to load DHA?DHA@HPDA-Fe?.The as-prepared nanoagent shows biodegradable and controllable release of DHA and Fe ions in tumor microenvironments,resulting in ferrous ion-enhanced production of cytotoxic reactive oxygen species?ROS?by DHA and thus effectively killing the tumor cells.In vitro and in vivo therapy experiments indicated that the antitumor efficacy of DHA@HPDA-Fe was about 3.05 times greater than free DHA,and the tumor inhabitation ratio was 88.7%compared with the control group,accompanied with negligible side effects,conferring the proposed nanomedicine platform was promising for anti-tumor applications.Chapter 4.Glutathione-depleted prodrug platform of MnO₂-coated hollow polydopamine nanospheres for effective cancer diagnosis and therapyAccording to previous reports,DHA reacts with Mn²⁺to generate more free radicals,causing tumor cell growth inhibition and enhancing apoptosis.Herein,a biocompatible and efficient nanoplatform for tumor treatment was fabricated based on manganese oxides coated hollow polydopamine?HPDA@MnO₂?.Dihydroartemisinin?DHA?,a kind of derivative of Chinese traditional anti-malarial medicine artemisinin,was selected to be loaded into the cavity of HPDA@MnO₂ to form the final nanodrug DHA@HPDA@MnO₂.As a unique nanoplatform,DHA@HPDA@MnO₂ showed biodegradable and controllable releasing of DHA and Mn ions upon reaching to the tumor sites.It was worth mentioning that the reduced Mn²⁺would interact with DHA to generate cytotoxic reactive oxygen species?ROS?which effectively damaged proteins and nucleic acid,then induced the tumor cells death.More importantly,the Mn ion reducing from MnO₂ shows capable of in vivo magnetic resonance imaging selectively in response to tumor microenvironment.In vitro and in vivo therapy experiments showed that the tumor inhibition of DHA@HPDA@MnO₂ was more efficient than free DHA,accompanied by negligible side effects,which conferred the proposed nanomedicine platform promising for applications in tumor chemotherapy.