Research and Application of Nanomaterials in Overcoming the Defects of Tumor Chemotherapy

Author:Wang Chao

Supervisor:jiang xiu e


Degree Year:2019





Cancer is not only the foremost cause of death for human,but also an important public health issue.Only in 2018,there were 18.1 million new cancer cases and 9.6 million deaths.It means that there were about 50 thousand people with confirmed cancer,and 26 thousand were killed by it every day.Hence it’s very important to crack the nut.Traditional treatment such as widely used chemotherapy can inhibit the tumor in some way.However,some defects such as poor drug targeting,severe side effects and limited efficacy inhibited its applications.Therefore it’s very necessary to overcoming these deficiencies.The appearance of nanotechnology offers new opportunities for this:many of nanomaterials can not only load and delivery the drugs to tumor tissue but also have been researched and applied in new therapy strategies for tumor.In this article,we try to overcome the defects by fabricating several nanomaterials to load different drugs for multi-model therapy for tumor.First,we synthesized MoSe2@PDA-Dox nanocomposites for chemotherapy and photothermal synergistic therapy for tumor,this way improved the curative effect and reduced side effects comparing with drug chemotherapy;after that,we constructed MOFs-MB-DHA@PLA@PEG nanocomposites for chemotherapy and photodynamic synergistic therapy for cancer,which further enhanced the effect and achieved specific treatment for tumor;at last,we fabricated Cu-TCPP nanosheets for tumor treatment,which not only showed high specificity and low side effects,but also simplified the synthetic routes.The details are as follows:1.We developed a new photothermal nanocarrier based on polydopamine coated selenide molybdenum(MoSe2@PDA)for loading anti cancer drug doxorubicin(MoSe2@PDA-Dox).Conjugation of PDA onto the surface of MoSe2 nanosheets can not only provide anchor points for loading Dox but also enhance the photothermal effect of MoSe2nanosheets and decrease the cytotoxicity.The resulting MoSe2@PDA nanocomposites exhibit good biocompatibility,well stability,and high photothermal conversion efficiency.The subsequent loading of Dox created poor side effects and specific therapy through double-responsive drug release of low pH and heat.In vivo experiments showed strong damage to tumor tissues,and the tumor cells were almost killed thoroughly.In summary,the MoSe2@PDA-Dox nanocomposites play a key role in synergetic therapy for cancer,and have better curative efficiency and lower side effects comparing with drug chemotherapy.2.In the last work,we achieved effective therapy for tumor by constructing drug loaded photothermal nanocarrier.However,the total curative effect and specific treatment for tumor can be further improved.In this work,a kind of small-sized metal organic frameworks(MOFs),the MIL-101(Fe),as an intelligent delivery system was fabricated to load chemotherapy drug dihydroartemisinin(DHA)and photosensitizer methylene blue(MB).In addition,the released Fe ions from MOFs in acidic tumor microenvironment not only enhanced the curative effect of DHA but also catalyzed H2O2 in tumor tissues to produce O2,which further improved photodynamic therapeutic effect of the nanocomposites.The polylactic acid(PLA)and polyethylene glycol(PEG)were consecutively modified on the surface of MOFs-MB-DHA to acquire good biocompatibility to decrease the side effects for normal cells and achieve controllable protease K responsive release of drugs.In total,the nanoplatform not only realized double responsive release of DHA by protease K and low pH,but also enhanced the efficiency by released iron ions through acid stimulation.In vitro and in vivo experiments showed remarkably therapeutic efficiency by synergistic chemo-photodynamic therapy of MOFs-MB-DHA@PLA@PEG,which destroyed the tumor effectively with poor side effects.The nanocomposites can also serve as a T2 magnetic resonance imaging contrast agent at the same time.Thus,a smart multifunctional nanoplatform for diagnosis and therapy was constructed for not only real-time imaging but also synergetic therapy to kill the tumor selectively.3.In the previous works,we overcame some defects of chemotherpapy by constructing nanostructure based therapeutic system,and destroyed the tumor effectively.However,relatively complex synthesis routes and treatments may restricted their applications.In order to simplifying synthesis and achieve specific treatment for tumor,we compounded an ultrathin two-dimensional metal-organic frameworks of Cu-TCPP nanosheets(TCPP=tetrakis(4-carboxyphenyl)porphyrin)by simple solvothermal method,which can selectively generate 1O2 in acidic tumor microenvironment,based on the peroxidation of TCPP ligand by acidic H2O2 followed by reducing to peroxyl radicals under the action of peroxidase-like nanosheets and released Cu2+.At last,two peroxyl radicals spontaneously recombine through the Russell mechanism and generate cytotoxic 1O2 to destroy the tumor cells.In addition,the nanosheets can also deplete GSH in tumor cells through cyclic oxidizing reaction.This process inhibited the elimination of 1O2 by GSH.By these characteristics,the Cu-TCPP nanosheets can specifically destroy tumor with high efficiency,which has higher selectivity and poorer side effects comparing with single drug chemotherapy.