Studies on Smart Bio-macromolecular Drug Carriers and Its Biomedical Applications

Author:Xia Dong Lin

Supervisor:hu yong


Degree Year:2019





Targeted drug delivery,is a promising method of delivering medication to a patient in such a targeted sequence that increases the absorption of delivered medicines in targeted body part,as it with nowly pharmacokinetics,effect,toxicity,and immunogenicity.This means of delivery is largely founded on nanomedicine,which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery.Therefore,along with the deepened study gradually,there are some importance problems demanded discussing and resolving,such as low targeting effect,non-specific releasing behavior,uncontrolled release rate.While this nanoparticle-mediated drug delivery is widely researched in targeted release system,many of the most vexing diseases,such as insulin therapy,cancer treatment,are heterogeneous in their expression,necessitating more individualized and tailored methods of treatment.Targeted medicines delivery,which responds to external stimuli such as pH,temperature,pressure,that active targeting can be accomplished.The bio-macromolecular drug carriers have been widely used in disease prevention,treatment or diagnosis,as it can simulate normal physiological activity when stimulated.The aim of the study was to investigate bio-macromolecular drug carriers with smart response to the blood glucose level or the tumor microenvironment.We hope it could provide proper amounts of insulin in response to blood glucose concentration in diabetes treatment or improve efficacy of treatment by reducing side effects of medicines administration in tumor treatments.Details were provided as following:(1)Insulin(INS)delivery system that can mimic normal insulin secretion to maintain the blood glucose level in the normal range is an ideal treatment of diabetes.However,most of existed close-loop INS delivery systems respond slowly to the changes of blood glucose level(BGL),resulting in a time lag between the abnormal BGL and the release of INS,which is not suitable for the practical application.Herein,glucose oxidase(GOx)modified erythrocytes are used as INS carriers(GOx-INS-ER)which can self-regulate the release of INS upon the changes of BGL rapidly.In this system,glucose can be decomposed to gluconic acid and hydrogen peroxide by GOx-INS-ER,and the latter will rapture the erythrocyte membrane to release INS within minutes.A pulsatile release of INS can be achieved upon the changes of the glucose concentration.This GOx-INS-ER enables diabetic rats to overcome hyperglycemia,and a single injection of this GOx-INS-ER into the STZ-induced diabetic rats can maintain the BGL in the normal range up to 9 days.(2)Hypoxia,as characterized by the low local oxygen,renders cancer cells resistant to oxygen-consuming photodynamic therapy(PDT).The limited success of re-oxygenation-based strategies in alleviating hypoxia drives us to revisit the design of therapeutic approach.Herein,we have demonstrated a multi-stage delivery system can conquer the PDT-resistance of cancer.Unlike previous methods that only elevate the availability of oxygen in a temporal fashion,our strategy is proposed to inhibit the intrinsic oxygen consumption,as mediated by atovaquone(Ato)that potently suppresses the activity of oxidative phosphorylation.Specifically,these therapeutics were encapsulated into a gelatin-based vehicle,whose size could shrink subtly responding to matrix metallopeptidase 2,an enzyme overexpressed in the tumor microenvironment.Such a feature allows the deep hypoxia region being affected by the therapeutics.The anti-hypoxic performance of our platform was verified by using flow-cytometry,immune-staining as well as micro-PET imaging.Furthermore,the antitumoral effect and consequent survival benefits offered by these multistage nanoparticle have been confirmed,which was not accompanied by any apparent long-term cytotoxicity.We hope such a strategy could shed light on the development of alternative hypoxia-relieving treatments in existent clinical trials.(3)Radiotherapy(RT)is one of the main components in the treatment of cancer.Several preclinical studies support the use of RT in combination with immunotherapy obtaining better local and systemic tumor control.Herein,atovaquone(Ato)and nano-Au were loaded in natural platelets for treatment of ovarian cancer.Unlike previous methods that only improving radiotherapy dose in a temporal fashion,our strategy is proposed to increase the sensitivity of tumor cells to radiotherapy by Ato and nano-Au.Results showed that Ato-Au@Pt facilitated intracellular drug accumulation through "tumor cell-induced platelet aggregation" and released Ato and nano-Au into the medium in a pH-controlled manner.This phenomenon reduced the adverse effects and enhanced the therapeutic efficacy.Atovaquone rapidly decreases the OCR by more than 80%in a wide range of cancer cell lines at pharmacological concentrations.That is to say,mitochondria treated by Ato could not provide sufficient energy to cancer cells as a result of easy to be killed in low dose of X-ray irradiation.In mouse models of HeLa cancer,intravenous injected PBS treated with low doses of X-ray irradiation led to the eradication of local tumours and,when loaded with Ato-Au@Pt,the irradiated Ato-Au@Pt led to consistent abscopal responses that rejected distal tumors.By combining the advantages of local radiotherapy and systemic tumor rejection via synergistic X-ray-induced in situ vaccination and Ato inhibited the intrinsic oxygen consumption to improve sensitivity to radiotherapy;Ato-Au@Pt may overcome some of the limitations of heigh dose X-ray irradiation in cancer treatment.