Preperation Of Polymeric Micelles And Their Applications On The Treatment And Diagnosis To Tumors

Malignant tumors have become one of the most important diseases that threaten human health in recent years.The treatment and diagnosis of tumors are two important directions for cancer research.Conventional treatments include chemotherapy,gene therapy and so on,but these treatments generally have a variety of deficiencies.For example,the drugs used in chemotherapy have the disadvantages of poor efficacy and large side effects,and the gene drugs used in gene therapy also have the defects of low gene transfection efficiency and easy degradation in the body,which seriously affect the effect of clinical tumor treatment.With the continuous advancement of medical technology,various tumor diagnosis techniques have also been developed,such as magnetic resonance imaging and computed tomography.Contrast agents are an indispensable part of tumor imaging technology,which can improve the resolution of tumor tissue imaging.How to achieve the enrichment of contrast agents in tumor tissues has also attracted the attention of more and more researchers.Polymeric micelles as nano-carriers are developed in recent years.They can be used to load chemotherapeutic drugs,gene drugs and contrast agents to improve their enrichment levels in tumor tissues,thereby improving the therapeutic effect and imaging accuracy of tumors,and reducing side effects.By designing the structure of the micelles,it is also possible to impart them the ability to intelligently control-release drugs.In this paper,based on the basic points of the treatment and diagnosis of tumors,we design and synthesis several polymeric micelles for the delivery of chemotherapy drugs,gene drugs and magnetic resonance contrast agents,and the intelligent controlled release of drugs.The main research contents and results are as follows:(1)Preparation of cationic polymeric micelles and their study on delivery of chemotherapeutic drugs for cancer therapyA novel cationic triblock copolymer of polyethylene glycol-polyaspartic acid benzyl ester-branched polyethyleneimine was synthesized and assembled to a novel polymeric micelle drug delivery system.The outermost layer of the micelle consists of hydrophilic PEG and hyPEI.PEG provides a good"stealth"effect for micelles and hyPEI positively charges the surface of the micelles to promote the entry of micelles into the tumor cells.PBLAsp acts as a hydrophobic core to efficiently support DOX and impart good biocompatibility to micelles.The drug release test indicates themicelles have the ability to slowly release drugs.The cell experiment indicates that the DOX-loaded micelles can enter cancer cells easily,and have a strong killing effect on tumor cells,while the blank micelles do not have cytotoxicity.Therefore,the novel polymer micelles are a promising carrier for delivery of anticancer drugs to enhance cancer treatment.(2)Multifunctional polymeric micelles for co-delivery of siRNA and contrast agents to achieve the integration of diagnosis and treatment of cancersiRNA is a gene drug commonly used in gene therapy,which can inhibit tumor growth by down-regulating certain genes in tumors.SPIO is a commonly used contrast agent in magnetic resonance imaging,which can improve the contrast between tissues such as tumors and normal tissues.In this part,we make polymeric micelles simultaneously loaded with siRNA and SPIO to construct a theranostic nano-probe,which could achieve MRI-Visible siRNA therapy.In vitro studies showe that SPIO and siRNA-loaded micelles can enter cancer cells easily and they have no cytotoxicity.And in vivo studies indicate that polymeric micelle can deliver SPIO and siRNA into tumors efficiently.Our results strongly demonstrate that the novel polymeric micelle is a promising carrier for delivery of siRNA and SPIO to enable noninvasive imaging-assisted therapy in vivo.(3)Preparation of hypoxia sensitive polymeric micelles and their study on the control release of chemotherapeutic drugs to enhance cancer treatmentIn this part,a novel diblock hypoxia-sensitive polymer consisting of polyethylene glycol and poly(glutamic acid(3-(2-nitro-imidazolyl)-propyl))is synthesized for the control-release of chemotherapy drugs.Under normoxic conditions the copolymer may self-assemble into a micelle with DOX loaded in the hypoxia-sensitive core.The hydrophobic nitroimidazole core can turn to the hydrophilic aminoimidazole under hypoxic conditions,which could make the micelle disintegrated.Drug release test proves that polymer micelles have good hypoxia sensitive drug release properties.The cytotoxicity and apoptosis tests also demonstrate that DOX-loaded micelles have a stronger killing capacity on tumor cells under hypoxic conditions,while the blank micelles do not have cytotoxicity.Our experiments prove that the novel polymer micelles are a promising carrier for the control-release of anticancer drugs to enhance cancer treatment.