Remodeling Extracellular Matrices Of Tumors By Controlled Release Of Drugs From Intratumorally Injected Short Fibers

Cancer is a global health problem,which is a common threat to mankind.Currently,themain method of cancer treatment include surgical treatment,radiotherapy and chemotherapy.But the therapeutic effect of these treatments is not ideal and there are great side effects.Therefore,the drug delivery system has been extensively studied.However,the transport of nanoparticles will be subject to many obstacles and collagen in the extracellular matrix is the most important barrier to the penetration and distribution of nanoparticles in tumor tissues.So the collagen content in tumor tissue determines the penetration and distribution of nanoparticles in tumor tissue.In this study,micelles-loaded fibers containing losartan(Los)or telmisartan(Tel)were designed to improve the penetration and distribution of micelles in tumor tissues.The releases of Los,Tel,camptothecin(CPT)and micelles from fiber fragments were investigated via in vitro release assay at different pH.In vitro cell experiments were performed to investigate cellular uptake,cytotoxicity and apoptosis of 4T1 cells,and the content of collagen produced by carcinoma-associated fibroblasts(CAF).The distribution of micelles,the changes of oxygen and collagen content in tumor tissues were examined in animal models.The antitumor effect and antitumor metastasis were evaluated to providesa new idea for the research and development of new drug release system.The CPT-conjugtaed hyaluronic acid(HA)via 3,3'-dithiodipropionic acid(HA-CPT)as the promicelle polymers of CPT(PMc),tetraphenylethene(TPE)-conjugtaed HA(HA-TPE)as the promicelle polymers of TPE(PMT),polylactide conjugates with PMc(PLA-cdm-PMc)or PMT PLA-cdm-PMT via 2-propionic-3-methylmaleic anhydride(CDM)were prepared.The short fibers FMc and FMT were prepared from PLA-cdm-PMc and PLA-cdm-PMT by electrospinning,and the inoculation of Los or Tel in the electorspinning solutions was sued to prepare FMc/Los,FMc/Tel,FMT/Los and FM-r/Tel short fibers.The fiber fragments had a uniform structure with an average diameter of about 1.42 ?m and lengths of about 20 ?m.The results of in vitro release showed that Los was released quickly from the short fiber and Tel,CPT,micelles can be sustainedly released from the polymeric short fiber.The presence of Los or Tel did not affect the release of micelles and CPT from the fibers.In addition,the released micelles are unstable in a reducing environment and can release CPT.CAF experiments show that FMc/Los and FMc/Tel could reduce the collagen content secreted by CAF,whereas FMc did not.The cellular uptake,toxicity and apoptosis of 4T1 cells showed that Los and Tel did not affect cellular uptake of micelles and Los or Tel had little effect on cell viability.The cytotoxicities were mainly from CPT,leading to the effective inhibition of cell growth by FMc/Los,FMc/Tel short fibers.Western blotting,masson's trichrome stain and laser confocal microscopy analysis showed that the fibers containing Los and Tel could reduce the collagen content in the tumor tissue to varying degrees,and increase the distribution and penetration of drug-loaded micelles in tumor tissue.Moreover,the optimal micelle distributionand penetration in the tumor tissues were detected after treatment with mixtures of FMT/Los and FMT/Tel with a 1:2 ratio.The tumor volume,animal survival,and immunohistochemical staining showed that the short fiber containing Los or Tel were able to improve the oxygen delivery and antitumor effect and inhibit lung metastasis.Among the treatment group,the most effective antitumor efficacy was detected for the mixtures of FMT/Los and FMT/Tel with a 1:2 ratio.