Construction And Applications Of Drug Self-Framed Delivery Systems Based On Polyphosphazenes Nanoparticles

Compared with small-molecule anticancer drugs,the traditional drug delivery systems(DDSs)have controllable drug-loaded rate and good blood circulation stability.With the help of DDSs,the drug could accumulate in the tumor site via the EPR effect and be released in a controllable way,resulting the reduced side effects on the body.Therefore,the traditional DDSs have been widely studied and achieved great development.However,the further development of DDSs was hindered by such disadvantage as low drug-loaded capacity,carrier-induced toxicity and immunogenicity,and complex synthetic operations.Drug self-delivery systems(DSDSs),in which active drugs exhibit nanoscale characteristic to realize intracellular delivery by themselves without the help of nanocarriers,have been rapidly developed to address these issues.However,there are still many unavoidable potential issues,such as short circulation time,low selectivity,insufficient stability and easy drug burst release.There is no doubt that the DSDSs need further development as the next generation of anticancer drugs-delivery system.In view of the above problem,a series of drug self-framed delivery systems(DSFDSs)based on polyphosphazenes nanoparticles were constructed in this thesis.Different types of DSFDSs are obtained through meticulous design of DSFDSs structure.The DSFDSs accumulate in the tumor site via the EPR effect,and control drug release by the tumor micro-environmental stimulation.The in vitro and in vivo antitumor activities of DSFDSs were evaluated and demonstrated that the multi-drug resistance(MDR)tumors were inhibited obviously.This series of work proves that the DSFDSs based on polyphosphazene nanoparticles provide a new idea for the construction of new DSDSs.(1)A novel pH-responsive DSFDSs(DOX-CPPZ NPs)based on polyphosphazene nanoparticles,which has a high drug-loading efficiency(90 wt %),long blood circulation time and better antitumor efficacy.DSFDSs reduced the toxicity of DOX to normal cells,increased its blood circulation time and increased its drug concentration in tumor tissues via EPR effect.Compared with free DOX,it has better tumor inhibition effect.Fluorescence images showed that nanoparticles enter into lysosomes after endocytosis.DOX were released from the DSFDS via hydrolysis in subacid lysosomal environment and then were delivered into the cell nucleus by diffusion.Compared with free DOX,DSFDSs had good inhibitory effect on tumor tissues and low toxicity to major organs in animal experiments and histopathological sections.Overall,the pH-responsive DSFDSs approach opens a new door for the design of DDSs for cancer chemotherapy.(2)A novel DSFDSs(DOX-CysM-CPPZ NPs)with dual GSH and pH response was synthesized by simple polycondensation for efficient anticancer drug delivery.The dual-stimuli-responsive DSFDSs showed a high drug-loading efficiency of over78 wt%,high stability during blood circulation,good sensitivity to tumor micromilieu and high tumor accumulation mass by EPR effect.These characteristics endowed the DSFDSs with low side-effects and high killing efficiency on tumors.Due to the high drug-loaded capacity of the DSFDSs,it may even be possible to use the strategy to deliver a multitude of therapeutic agents into tumors for combination therapy.(3)DSFDSs were developed as a novel and universal platform for the combination chemotherapy against MDR cancer.The DSFDSs have an extremely high drug-loaded capacity and can be prepared by simple ultrasound-assisted precipitation polymerization.After intracellular hydrolysis of the DSFDSs composed of DOX-RES-CysM-CPPZ NPs,the two released antitumor agents could kill tumor cells synergistically,block over-expression of P-gp and increase the effect of chemotherapy.Therefore,the DSFDSs exhibited higher apoptotic ratio and antitumor activity of He La cells than the single antitumor agent.The in vitro and in vivo anticancer experiments indicated that co-delivery of the DOX/RES via DSFDSs exhibited a synergistic therapeutic effect and superior antitumor efficacy,achieving complete inhibition of tumor growth.The co-delivery ofanticancer drugs via DSFDSs may provide a new method for combination chemotherapy against MDR cancer.(4)Through a simple and effective ultrasound-assisted precipitation polymerization,a novel DSFDS was developed for the combination of photothermal therapy and chemotherapy(CT-PTT)against tumor.The drug self-frame-carrying polymer(DOX-CysM-CPPZ NPs)coated Au NRs(Au Nanorods)formed a nanocomposite carrier(Au NRs@DOX-CysM-CPPZ NPs)for the co-deliverying both anticancer chemotherapy drugs and photothermal nanoparticles simultaneously.In vitro experiment proved that the combination therapies of Au NRs@DOX-CysM-CPPZ NPs have synergistic therapeutic effect on tumor cells,and their combination apoptosis rate and anticancer activity are higher than those of the single therapy.Au NRs@DSFDS NPs,which is a single composite nanoparticle with high drug loading properties for the combination therapy of cancer treatment,may open up a new way for combination anticancer therapy with multiple anticancer strategies.