In Situ Drug-Loading Platform For Preventing Postoperative Tumor Recurrence And Metastasis Through Combination Of Chemotherapy And Tumor Microenvironment Remodeling

Malignant tumors severely threat to human health.Surgical resection,as one of the main treatments of solid tumor,still has many disadvantages.Postoperative residual tumor cells usually lead to tumor recurrence and metastasis.Meanwhile,the postoperative tumor microenvironment,including platelet activation,tumor angiogenesis and cancer-related adipocytes,can promote tumor progression and adversely affect the prognosis of patients.How to eliminate these unfavorable factors to improve the postoperative prognosis of malignant tumor patients still remains a challenge.Chemotherapeutic drugs can effectively kill residual tumor cells.However,monotherapy usually faces problems such as less drug accumulation at the resection site,high toxicity and side effects,as well as having a window of administration after surgery,resulting in minimal therapeutic effects.In this study,in situ drug loading platforms were constructed to simultaneously load chemotherapeutic drugs and microenvironmentregulating drugs(such as metformin for inhibiting adipocyte function and angiogenesis,and aspirin for inhibiting platelet activation).After implantation into the tumor resection sites after surgery,these drugs were slowly released locally and highly accumulated at the tumor sites.These in situ drug loading platforms achieved the synergy of chemotherapy-induced residual tumor cell killing and tumor microenvironment remodeling,efficiently inhibiting tumor recurrence and metastasis after surgery.The main research contents and results are as follows:(1)An adhesive hydrogel implant combining chemotherapy and tumor microenvironment remodeling for preventing postoperative recurrence and metastasis of breast cancerDopamine and 3-Aminobenzeneboronic acid were grafted onto hyaluronic acid by one pot method to prepare HDP hydrogels with good rheological and bioadhesive properties.Doxorubicin hydrochloride(DOX)and metformin hydrochloride(Met)were then loaded to HDP hydrogels to construct DOX/Met@HDP.DOX/Met@HDP exhibited p H-responsive drug release profiles under the acidic tumor microenvironment.The released DOX effectively killed residual tumor cells,while the released Met effectively inhibited the function of adipocytes and adipocyte-promoted proliferation and migration of tumor cells.In addition,the residual Met efficiently inhibited the tubule formation and migration of human umbilical vein endothelial cells.After implanting DOX/Met@HDP to the tumor surgical cavity,HDP significantly enhanced the retention of loaded drugs in the tumor resection sites.DOX/Met@HDP effectively inhibited tumor recurrence and metastasis after surgery with good biosafety,and reduced adipocyte function and tumor angiogenesis.(2)Biodegradable electrospun nanofibrous platform integrating antiplatelet therapychemotherapy for preventing postoperative tumor recurrence and metastasisBiodegradable Poly(DL-lactide-co-glycolide)nanofiber membranes loaded with aspirin(ASA)were prepared by electrospinning technology to obtain ASA@NF.Cancer stem cell-derived microparticles loading DOX(DOX-MPs)were then loaded into ASA@NF through a syringe injection to construct DOX-MPs/ASA@NF,in which ASA was located inside the NF nanofibers while DOX-MPs were located on the surface.The different spatial distributions enabled DOX-MPs to exhibit faster drug release behavior than ASA.DOX-MPs/ASA@NF could effectively kill tumor cells,inhibit platelet aggregation and granule secretion induced by arachidonic acid and tumor cells,and weaken the proliferation and migration of tumor cells induced by the activated platelets.Implantation of DOX-MPs/ASA@NF into the tumor resection cavity could increase the accumulation of DOX-MPs at the resection site.DOX-MPs/ASA@NF significantly reduced the platelet activation and inhibited tumor recurrence and metastasis with good biosafety in orthotopic4T1 breast tumor-and subcutaneous H22 liver tumor-bearing mice after surgery,and has good biological safety.In summary,this study developed in situ drug loading platforms integrating chemotherapy and tumor microenvironment remodeling,which effectively inhibited tumor recurrence and metastasis after surgery.These in situ platforms exhibited clinical application prospects to some extent.