The Antitumor Activity Study Of Novel Water-soluble Fulvestrant In Breast Cancer

Part 1: Data analysis of injection site reactions caused by flulvestrant injection based on FAERS databaseObjective: To analyze the distribution of injection site reactions caused by intramuscular injection of fulvestrant in the treatment of breast cancer,and to strengthen the understanding of the adverse reactions caused by fulvestrant.Expect to provide reference for clinical medication and nursing.Methods: The injection site reactions events caused by fulvestrant injection were collected from the FARES database from May 2012 to June 2021,and descriptive statistics were used to analyze the patient’s reporting year and specific ISR adverse event.Results: A total of 10344 data items related to fulvestrant were extracted,of which 552(5.34%)recorded ISR adverse events,and a total of 874 ISR adverse events.The most common ISR were pain(50.36%),mass(12.86%),erythema(10.14%).There were necrosis(5.25%),abscess(2.72%),ulcer(1.45%)and other serious adverse events.The number of reported ISR adverse events of fulvestrant has been increasing year by year.Conclusions: The most commonly reported ISR adverse events of fulvestrant included pain,mass,erythema,etc.,and there are more serious adverse events such as necrosis,abscess,and ulcer.When fulvestrant is used clinically,patients should be monitored and appropriate measures should be taken to reduce the incidence of adverse reactions.It is of great significance to solve the problem of water solubility of fulvestrant and develop new dosage forms.Part 2: Preparation of a novel water-soluble fulvestrant and its anti-tumor effect on breast cancer cellsObjective: Based on the synthesis of a novel water-soluble fulvestrant,systematic in vitro evaluation was carried out,including drug toxicity,induction of tumor cell apoptosis,inhibition of tumor cell invasion and related mechanisms,so as to provide basis for its application as anti-breast tumor drugs.Methods: Firstly,a novel water-soluble fulvestrant was synthesized and prepared.Secondly,CCK-8,Ki-67 immunofluorescence staining,Hoechest33258 immunofluorescence staining,flow cytometry apoptosis assay,scratched assay and Transwell assay were used to explore the effect of the novel water-soluble fulvestrant on the basic functions of breast cancer cells in vitro.Western blot was used to detect the expression of related proteins and explore its anti-tumor mechanism preliminarily.Finally,CCK-8 assay was used to detect its toxicity to normal cells.Results: A novel water-soluble fulvestrant was prepared and synthesized.The inhibition of proliferation of two breast cancer cells was verified by CCK-8 assay and confirmed by immunofluorescence staining with proliferation-related antigen Ki-67.Afterwards,Hoechest 33258 immunofluorescence and flow cytometry assay proved that it could promote the apoptosis of breast cancer cells.Scratch test and Transwell test confirmed that it could inhibit the invasion and metastasis of breast cancer cells.Western blot assay confirmed that its anti-tumor mechanism is similar to fulvestrant.As an ERα antagonist and ERβ agonist,it could induce the activation of tumor cell apoptosis pathway and exert its anti-tumor effect.The results of CCK-8 indicated that it has no obvious toxicity to normal renal epithelial cells.Conclusion: In this experiment,a novel water-soluble fulvestrant has been successfully constructed,which has good anti-tumor effects.The anti-tumor effect and mechanism were equivalent to fulvestrant.And it has good biological safety,which lays the foundation for clinical application.Part 3: Anti-tumor effect of the novel water-soluble fulvestrant in the animal model of breast cancerObjective: To investigate the effect of the novel water-soluble fulvestrant in vivo,detect its anti-tumor activity and biological safety,and explore the therapeutic effect of intraductal administration of breast.Methods: Construct a SD rat breast cancer model induced by intraductal injection of MNU,and verify the effect of the water-soluble fulvestrant in vivo through tumor volume changes,tumor-free survival time,ER and Ki-67 antigen immunohistochemical analysis,etc..Local skin reaction,rat body weight and liver,kidney and lung pathology were used to verify its safety.The efficacy and safety of the two administration methods were compared by intraductal injection and conventional intramuscular injection.Results: The novel water-soluble fulvestrant was equivalent or better than fulvestrant in terms of tumor volume,time of occurrence,pathological results and other aspects,and had no obvious local adverse reactions and systemic toxicity.Intraductal administration could enhance this effect.Conclusion: The novel water-soluble fulvestrant still maintained its activity and anti-tumor effect in vivo,and its effect was superior to or equal to fulvestrant.And effectively avoided local adverse reactions such as skin damage caused by the oil.Intraductal administration of fulvestrant could enhance its anti-tumor effect,laying a foundation for clinical application.