Application Of Drug Delivery Nanosystem And Nanovaccine Based On Polymeric Micelles In Tumor Imaging And Therapy

In recent decades,polymeric micelle systems composed of amphiphilic block copolymers have received extensive attention in the field of nanomedicine research.It is mainly due to the following advantages:first of all,the core-shell structure of polymer micelle system can not only efficiently encapsulate poorly soluble therapeutic drugs into the hydrophobic core to protect the drugs from the external environment and improve their pharmacokinetics,but also avoid accidental drug loss in serum and prevents rapid clearance of drugs from the systemic circulation;secondly,polymeric micelle systems can be endowed with chemical or physical stimuli-responsive properties,which are beneficial for controlling their accumulation or drug release at tumor site;third,thanks to the surface chemistry of polymer micelle system,which is easy to be modified with functionalized molecules,thus realizing various functions such as tumor targeting,delivery of therapeutic genes and antigens,and multi-modal imaging as well.Therefore,the polymer micelle system integrating diagnostic and therapeutic functions can be used as a multifunctional tumor precision therapy nanoplatform.Focusing on the scientific issue of"Application of drug delivery nanosystems and nanovaccines based on polymeric micelles in tumor imaging and therapy",this dissertation explored the magnetic resonance imaging(MRI)-guided combination of chemotherapy and gene therapy for breast cancer and remodeling immunosuppressive tumor microenvironment(TME)via nanovaccines to potentiate the effcacy of cancer immunotherapy.Specifically,we constructed an integrated nanosystem based on hybrid micelle(HM)for cancer diagnosis and treatment.The self-assembly,drug release behavior in vitro,cellular uptake and lysosomal escape ability of the prepared HM were investigated in detail,and in vivo imaging and therapy efficiency were explored in tumor-bearing mice.The details are listed as follows,1.The hybrid micelle(HM)utilizing two amphiphilic diblock copolymers,polyethylenimine-polycaprolactone(PEI-PCL)and diethylenetriaminepentaacetic acid gadolinium(III)-conjugated-polyethyleneglycol-polycaprolactone(Gd-PEG-PCL)to codeliver the poorly soluble chemotherapy drugs doxorubicin(Dox)and therapeutics gene micro RNA-34a(mi R-34a)was fabricated,which was denoted as Gd-HM-Dox/34a.Conjugating Gd-DTPA on the surface of hybrid micelles resulted in a more than 1.4-fold increase in the relaxation rate of Gd-DTPA(13.6 m M^-1 S^-1).Furthermore,when Gd-HM-Dox/34a taken up by tumor cells,the ability of mi R-34a and Dox to escape from lysosomes is promoted due to the proton sponge effect of PEI.In addition,the released mi R-34a subsequently downregulates the expression of Bcl-2,cyclin D1,CDK6,and Bax,and inhibits proliferation and migration of tumor cells.Notably,compared with Gd-HM-Dox and Free Dox,the suitable micelle size enhanced the penetration of Dox into three-dimensional(3D)multicellular spheroids(MCs),generating efficient cell killing in the3D MCs.Furthermore,the Gd-HM-Dox/34a exhibited augmented accumulation in tumor tissues,which improved the MRI contrast in solid tumors and enhanced the combined efficiency of chemotherapeutic drugs Dox and therapeutic gene mi R-34a in inhibiting tumor growth on MDA-MB-231 tumor-bearing mice.Therefore,the Gd-HM-Dox/34a established in this study provides a promising therapeutic approach for inhibiting tumor growth and enhancing MR imaging.2.The clinical outcomes of cancer nanovaccine have been largely impeded by low rates of antigen-specific T cell responses and acquired drug resistance elicited by immunosuppressive tumor microenvironment(TME).Here,a nanovaccine that responds to the tumor acidity is prepared to remodel the immunosuppressive TME and expand the recruitment of tumor infltrating lymphocytes(TILs).Utilizing hybrid micelles(HM),which encapsulated colony stimulating factor 1 receptor(CSF1-R)inhibitor BLZ-945 and indoleamine 2,3-dioxygenase(IDO)inhibitor NLG-919 in its core and displayed a model antigen ovalbumin(OVA)on its surface to constitute the nanovaccine BN@HM-OVA.The nanovaccine is coated with a polyethylene glycol(PEG)shell to prolong its in vivo circulation and the shell can be shed in response to the weakly acidic TME.Remarkably,the nanovaccine dramatically enhance antigen presentation by dendritic cells(DCs)and drugs transportation into M2-like tumor-associated macrophages(TAMs)and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME.Such nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment,leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models.Furthermore,combining the nanovaccine with simultaneous?PD-1 treatment leads to a long-term tumor inhibition.This research provides a new strategy for the development of efficient cancer immunotherapy.