Study On Hierarchical Structured Polymer Fiber Carrier For Breast Cancer Treatment

Worldwide,breast cancer has become the most common cancer among women and threatens the survival benefit of patients seriously.The types and pathogenesis of breast cancer are complex,but the inherent feature of solid tumor with vascularization,invasiveness and immunosuppression are relatively fixed.The current treatment of breast cancer based on systemic or local drug delivery systems has been effective in pre-clinical studies.However,sophisticated structural modifications of these drug delivery systems make it difficult in fabrication,circulation,and quality control.How to maximize the synergy between different drugs and minimize the side effects when delivering multiple drugs sequentially in a single system is still a challenge.This thesis is devoted to design and fabricate a local drug delivery system based on hierarchical structured electrospun fibers to improve the"abnormal"microenvironment of breast tumor tissue.Thus,the therapeutic effect of breast cancer would be improved while the systemic toxicity caused by drugs would be reduced.In view of the high vascularization degree of breast tumor and the challange to achieve time-programmed administration of therapeutic agents.An implantable trilayer structured fiber device was developed in the second chapter to achieve time-programmed release of combined drugs for synergistic treatment of breast cancer.The fiber device was prepared by a triaxial-electrospinning technique.The glycerol solution containing chemotherapeutic agent doxorubicin hydrochloride(DOX·HCl)formed the internal periodic cavities of the fiber,and poly(L-lactic acid)(PLA)and poly(ε-caprolactone)(PCL)containing the angiogenesis inhibitor Apatinib(APA)formed the interlayer and matrix of the fiber.A rapid release of DOX·HCl could be obtained by adjusting the wall thickness of the cavities,meanwhile sustained release of APA was achieved through the slow degradation of the fiber matrix.After the fiber device was implanted subcutaneously near to the implanted solid tumor of mice,an excellent synergistic therapeutic effect was achieved through timeprogrammed release of the combined dual drugs.In view of the high recurrence and metastasis risk of breast cancer after surgery and a clear survival benefit has not been established by existing postoperative adjuvant chemotherapy methods,on the previous reserch of tri-layer structured fiber,the third chapter of this article optimized the fiber structure and developed an implantable hierarchical structured ultrafine fiber device with a time-programmed drug release function for the local postoperative adjuvant chemotherapy of breast cancer.The periodically distributed chambers in fiber device formed by polyethylene glycol(PEG)with different molecular weight(Mw)to encapsulate Doxorubicin hydrochloride(DOX·HCl).The fiber matrix is composed of poly(D,L-lactic acid)(PLA),which is used to carry the hydrophobic matrix metalloproteinase 2(MMP-2)inhibitor disulfiram(DSF).By simply changing the Mw of PEG,the rapid release behaviors of DOX·HCl from the internal chambers can be achieved and the recurrence of tumor can be inhibited by killing the residual micro tumors in a short period.The DSF from the fiber matrix was released sustainably with the degradation of fiber matrix to inhibite the activity of MMP-2 and further prevent the distant metastasis of tumor.The fiber device implanted in tumor-bearing mice after a surgical tumor reduction displays excellent therapeutic efficacy by preventing both recurrence and metastasis.The mechanism investigation of tumor invasion through the type II collagen immunofluorescence analysis reveals that the decrease of the activity of MMP-2 plays a key role in this process.In the last chapter,since the immunosuppressive microenvironment of breast tumor and the existing drug carriers are difficult to achieve dual targeting of tumor cells and tumor-associated macrophages(TAMs)in a single system,we further prepared an implantable fiber device based on hierarchical structured polymer fibers with graded-targeting ability to simultaneously achieve active-targeted killing tumor cells and passive-targeted reprogramming TAMs in one system which enhanced the antitumor immunotherapy effect.The internal chamber of fiber device is formed by the mixed solution of glycerin and DOX loaded chondroitin sulfate-poly(β-amino ester)(CS-PBAE)micelles.The matrix of the fiber is made by a degradable poly(Lactic-co-glycolic acid)(PLGA)with low Mw and the agonist of toll-like receptor 7(TLR-7)Imiquimod(R837).Benefit from the rupturable chambers and the low Mw of PLGA matrix,the encapsulated DOX-loaded micelles can be released as the chamber ruptures and actively targeted to induce immunogenic cell death(ICD)of tumor cells,due to the high affinity effect of chondroitin sulfate in micelles to the overexpressed CD44 receptor in breast cancer cells.On the other hand,as the hydrolysis process of fiber matrix progresses,the rod-like microparticles with the length under 3μm were phagocytized by TAMs but cannot be internalized by tumor cells.After the rod-like microparticles were phagocytosed by TAMs,R837 would releasing intracellularly and stimulates the TLR-7 to polarize M2-like TAMs into M1 phenotype,thereby alleviating immunosuppression in tumor microenvironment and achieving the selectively-targeted reprogramming of TAMs.In vivo experiment revealed that the fiber device can enhance the effect of anti-tumor immunotherapy through the actively targeted killing of tumor cells and the selectively targeted reprogramming of TAMs.In addition,an anti-tumor immune cascade can be triggered in vivo and the infiltration amount of CD8~+T cell in tumor tissues increased,under the combined effects of tumor cell ICD and TAMs reprogramming.