Construction And Application Of Functionally Polymeric Therapeutic Systems

Cancer is one of the major diseases which threaten human life.To date,the primary therapeutic methods for malignant tumor in clinic embracing chemotherapy,surgery and radiation therapy,the other therapeutic methods,for instance,immunotherapy,gene therapy,photothermotherapy?PTT?and photodynamic therapy?PDT?,which are still in the research stage.These therapeutic methods have some disadvantages including embracing poor pharmacokinetics,off targeting ability,non-specific distribution and the other shortcomings.Low water solubility and hydrophobicity of anticancer drug molecules are regarded to be the dominating obstacles to the treatment of cancer.Therefore,there is an urgent need to overcome these drawbacks to improve the efficiency of tumor treatment.As the progress of nanotechnology,nanomaterials have been widely used for drug delivery,biosensing,and the like.Nanocarriers mainly embrace liposomes,micelles,vesicles and so on.They can effectively modulate pharmacodynamic and pharmacokinetic properties,and further improve treatment efficiencies.Among these nanocarriers,polymer micelles are considered to be one of the most effective carriers,some of which have been used in various stageof clinical trials.The particular core-shell structure of the polymeric micelles is its most prominent advantage,which can specifically deliver drugs or fluorescent molecules to the focal area.The paper proposes a method for preparing functional polymer nanoparticles.The organic dye molecules or drug molecules are modified onto the polymer by chemical bonding,the resulting micelles can be used for the diagnosis or treatment of cancer.The study content of this dissertat is principally divided into the thereinafter three parts:1.Many nano-agents for fluorescencent imaging have been reported.Here,we design and construct a series of fluorescent single-molecule micelles?FUMs?.The prepared FUMs can effectively improve the poor water solubility,significant toxicity and side effects of the traditional fluorescent compounds.Good water solubility,ultrasmall size,excellent biocompatibility and the other merits let the FUMs can be used as fluorescent nano-agents to label organelles.2.Here,we prepared an acid-stimulated sensitive doxorubicin polymer prodrug?OM@DOX?.This amphiphilic polymer prodrug has a unique chemical structure with a high drug loading efficiency?up to 61.5%?,pH-induced drug release,specific recognition ability of cancer cells and the other outstanding advantages.The particle size of the smart polymer prodrug is about 40 nm.The good micellar stability of the prepared prodrug is beneficial for blood circulation and effective extravasation from tumor blood vessels.In addition,the prodrug micelles are more cytotoxic to tumor cells?HeLa cells?than normal cells?L929 cells?,and the prodrugs are presumed to have tumor-specific targeting capabilities.In order to make the prodrug micelles have targeting properity,the folic acid?FA?molecule was further modified on the prodrug OM@DOX,and the resulting prodrug denotes as FA-OM@DOX,which shows high cytotoxicity to KB tumor cells?FA-receptor positive?and relatively low toxicity to FA-receptor-negative A549 tumor cells.Considered to the above characteristics and efficient cell phagocytosis,we believe that this work designed prodrug has the prospect of nanomedicine applications.3.The tumor microenvironment can alter the physicochemical properties of the drug delivery system such that the drug carriers can deliver the drug molecule precisely to the site of the lesion,however,the therapeutic efficiency is limited by the biological barrier.Here,we designed a hierarchically responsive nanosystem?HRNS?to improve tumor permeability and chemotherapy efficiency.Specifically,HRNS is prepared by attaching a hydrophilic copolymer to the positive charged and camptothecin?CPT?linked star-polymer prodrug(?-CD-P?CPT-co-NH₂??denoted as CD-CPT?,taking advantage of the interaction of positive charge and the negative charge on cell membrane to achieve drug-specific delivery,the disulfide bond of the CPT precursor can be reduced by the high concentrations of glutathione in the tumor microenvironment,and further release CPT drug molecules rapidly.The trial results in vitro and in vivo show that our constructed HRNS system has the following advantages:higher drug loading capacity,controlled drug release,excellent cellular uptake efficiency and significant anti-tumor ability.It provides a clever strategy for the design of intelligent drug delivery systems in chemotherapy.