Optimizing Design of Nanomedicines to Improve Antitumor Effects

Author:Zhao Yang Yang

Supervisor:wang yu cai


Degree Year:2019





Nanomedicines can load traditional drugs in a variety of ways,increase their stability in vivo,extend the half-life of drugs in the blood and improve their bioavailability.Nanomedicines can efficiently accumulate in the tumor site through EPR effect,which increases the concentration of the drug in the tumor site,and reduces the drug concentration in the normal site,thereby improving the therapeutic effect of the tumor and reducing the side effects.These advantages endow nanomedicines with great potential in the field of anti-tumor therapy.At present,some nanomedicines have been in clinical trials or approved for clinical tumor treatment.However,only a relatively small percentage of nanomedicines could be clinically approved because of the unsatisfying results of most clinical trials,which is also the reason why nanomedicines have not been widely used in anti-tumor therapy.Therefore,how to improve the therapeutic effect of anti-tumor nanomedicines is still the key scientific problem to be solved.A series of characteristics of nanomedicines(such as size,charge,hydrophilicity,surface chemistry,etc.)significantly affect their interactions with organisms and their fate in vivo.Therefore,the study of the correlation between the characteristics and the biological behaviors of nanomedicines will be great importance in establishing guidelines for the design of nanomedicines and improving their therapeutic index.On the other hand,radiotherapy is one of the common tumor therapies.Clinically,over half of cancer patients receive radiation therapy.However,it is still limited by a number of factors.Therefore,combinating nanomedicines with radiotherapy may provide new opportunities for developing enhanced tumor therapies.In this dissertation,we developed two strategies to improve the anti-tumor therapeutic effect of nanomedicines.Firstly,to systematically study the effect of the surface property of hydrophilicity on the fate of nanomedicines,and then the anti-tumor effect of nanomedicine could be optimized by precisely regulating surface hydrophilicity.Secondly,to combine nanomedicines with radiotherapy for a synergistic effect,thereby enhancing the therapeutic effect The main content of this dissertation is divided into two parts as below:1.We constructed micellular nanoparticles with polyphosphate(PPE)as hydrophilic shell and polycaprolactone(PCL)as hydrophobic core.By changing the chemical structure of the PPE,we controlled the surface hydrophilicity of the nanoparticles.The size,surface potential and morphology were controlled,and a series of nanoparticles with single surface hydrophilicity changes were obtained.We systematically studied the effects of surface hydrophobicity on stability,protein absorption,in vitro and in vivo cellular uptake,blood circulation,tumor accumulation and final anti-tumor effect.It was found that nanoparticles with higher surface hydrophilicity could inhibit the proteins adsorption and are therefore rarely recognized and eliminated by MPS,resulting in longer blood circulation and higher tumor accumulation.However,nanoparticles with higher surface hydrophilicity also inhibited the uptake by tumor cells.Finally,due to the balance between tumor accumulation and cellular uptake,NPPMOEEP@DTXL and NPPMEP@DTXL showed similar therapeutic effects on both breast tumor and metastatic melanoma models.In addition,both NPPMOEEP@DTXL and NPPMEP@DTXL showed high anti-tumor effects,indicating that optimizing the surface hydrophilicity of nanomedicine is feasible and necessary to improve the anti-tumor efficacy of nanoparticles.2,Radiotherapy produces oxygen free radical by consuming oxygen.We speculated that radiotherapy could enhance the hypoxia of tumors,which could be used in combination with hypoxia-activated chemotherapy.We constructed DOCPe@(Vor+AQ4N),a reversed liposome with ultra-long blood circulation,to simultaneously deliver vorinostat and AQ4N.The DOCPe@(Vor+AQ4N)was expected to enhance tumor therapy by synergistic effect of radiotherapy and chemotherapy.Because of the heterogeneity of tumors,single radiotherapy or chemotherapy is difficult to effectively kill all tumor cells.In the system we constructed,vorinostat could enhance the effect of radiotherapy by inhibiting DNA damage repair.Radiation could enhance the hypoxia of the tumor while killing the normoxic cells,and further activate the AQ4N to kill the residual hypoxic cells.We confirmed the radiosensitization of vorinostat by immunofluorescence staining ofγ-H2AX.The hypoxia staining and MTT experiment results also proved that radiotherapy aggravated tumor hypoxia both in vitro and in vivo,thereby activated AQ4N to kill remaining hypoxic tumor.The results of 4T1 tumor inhibition experiment also confirmed the synergistic effect of nanomedicines and radiotherapy.