Study And Construction Of Nanodrug Deliveries Based On β-Cyclodextrin

Chemotherapy is one of the primary modes for cancer treatment.However,the further application of conventional chemotherapy in clinic is severely limited by some drawbacks such as short half-life,lack of selectivity and multidrug resistance effect.Therefore,how to improve the therapeutic efficacy and reduce the side effects of chemotherapeutic agents is a serious problem to be solved in the research of chemotherapy.With the rapid development of nanotechnology and biomedical technology,functional nanomaterials with small size,easy surface modification and unique physical and chemical properties have been widely used in drug delivery and cancer treatments.Nanomaterials can be designed as multi-functional targeted drug delivery systems for effectively loading chemotherapy drugs,specificity toward to tumor sites and accurate release in the tumor cells.In addition,the combination of chemotherapeutic agents with other treatments（eg.photothermal therapy,chemodynamic therapy and starvation）is an especially encouraging approach to optimize cancer therapy.Therefore,the development of new multi-functional targeted nanodrug delivery is of great significance in clinic.In the work,three multifunctional targeted drug deliveries were constructed based onβ-cyclodextrin derivatives,polypyrrole and polydopamine,then used for the delivery of anticancer drugs doxorubicin and camptothecin,and multimodal combination therapy.The main research contents are as follows:Chapter 1:The cancer treatments are introduced in brief.The research progress of nanodrug deliveries and especially nanodrug deliveries based on cyclodextrin derivatives are reviewed,respectively.Chapter 2:β-cyclodextrin derivatives are easily synthesized and have good biocompatibility.They can be used to increase the solubility and stability of hydrophobic drugs by forming host-guest complexes.A multi-functional targeted drug delivery was constructed based onβ-cyclodextrin derivatives,Fe₃O₄nanoparticles,polypyrrole and active targeted molecule（hyaluronic acid）.The nanodrug delivery with a high equilibrium adsorption capacity（447 mg/g）for anti-cancer drug doxorubicin（DOX）and good biocompatibility.Furthermore,DOX can be released from the nanodrug delivery in response to both p H and near-infrared stimulation.Chapter 3:Photothermal therapy,as an emerging strategy,has gained increased attentions for cancer therapy.Photothermal agents are used with light irradiation to induce hyperthermia damage in cancer cells.More importantly,hyperthermia effect has been demonstrated to augment the cytotoxicity of some chemotherapeutic agents by promoting the cellular uptake of drug carrier and accelerating the release of drugs from the drug carrier.Herein,we synthesized polypyrrole nanoparticles doped with the temperature sensitive dye-rhodamine B,then modified its surface with a thin layer of polydopamine to covalently bond lactobionic acid-modifiedβ-cyclodextrin derivatives.DOX can be loaded into cyclodextrin cavities through host-guest interaction,or adsorbed on the surface of polydopamine throughπ-πstacking,with a loading capacity of 326.6 mg/g.The nanodrug delivery can be used for real-time temperature detection during photothermal therapy,with a high photothermal conversion efficiency（ηis 31.7%）and thermal sensitivity(S_R is 1.44%°C^-1).MTT assay showed that the drug delivery had low toxicity and good biocompatibility.After loading of DOX,the drug delivery could be applied to kill SMMC-7721 cells with highly effective chemo-photothermal synergistic therapy.Under near-infrared light irradiation,the temperature in tumor cells increased,which led to the fluorescence quenching of Rh B.This experimental phenomenon could be observed by laser confocal imaging.This nanodurg delivery has some certain reference meanings for the synthesis of multifunctional nanodrug carrier for chemo-photothermal synergistic therapy.Chapter 4:Chemodynamic therapy（CDT）is a rising tumor therapy strategy triggered by endogenous chemical energy.Tannic acid（TA）,as a natural compound,has the similar adhesion properties with polydopamine.And TA can be easily complexed with Fe³⁺to form a metal-polyphenol network for chemodynamic therapy.Herein,we present a facile method to construct a multifunctional nanodrug delivery for chemotherapeutic/photothermal/chemodynamic synergistic therapy.At first,we modified the surface of polypyrrole nanoparticles with TA-Fe³⁺network（denoted as PTF）.Thenβ-cyclodextrin derivative loaded with hydrophobic anti-cancer drug camptothecin（CPT）and folic acid modified bovine serum protein loaded with glucose oxidase were layer-by-layer assembled on the surface of PTF（denoted as PTF-CD-BSA-FA/CPT/GOD）.The glucose oxidase in the nanodrug delivery can catalyze the oxidation of glucose to produce abundant H₂O₂ in tumor cells.Then,the H₂O₂was catalyzed by Fe²⁺,which is produced from Fe³⁺by the reduction of TA,to generate highly toxic hydroxyl radical.With the help of laser confocal microscope,the hydroxyl radical was captured with active oxygen probe DCFH-DA,which can be oxidized to produce the green fluorescence.The nanodrug carrier not only serves as a cascaded nanocatalytic drug,but also be used as drug carrier to load CPT with a loading capacity of 151 mg/g,and photothermal agents with a high thermal conversion efficiency（ηis 38.02%）.In vitro cytotoxicity assay showed that the multifunctional nanodrug delivery can effectively kill A549cells by chemo-photothermal/chemodynamic synergistic therapy.It has a great potential in the clinical application of tumor therapy.Chapter 5:Summary and outlook.All the works in this dissertation are summarized.According to the research status and the development trend of multi-functional nanodrug delivery systems,the directions of the future research in this area are introduced.