Preparation Of Two Kinds Of Drug-loaded Thermosensitive Gel And Its Application In The Treatment Of Vaginal Tumor In Mice And Dog

Vaginal neoplasmas is a tumor which seriously threats the health of animals,remaining problematic in clinic.Cisplatin and doxorubicin which have been widely applied in human clinic against vaginal neoplasmas usually cause serious toxic and side effects by intravenous injection for systemic chemotherapy.Therefore,the research have made rapid advance relating to increasing drug accumulation in the tumor site by using polymer as drug carriers.By directly implanting drug-loaded polymer carrier into tumor,anti-cancer drug can be mainly accumulated in the tumor,leading to increased curative effect and reduced toxic compared with systemic chemotherapy.Among various local drug delivery systems,thermosensitive gel has aroused public attention due to its unique property.In contrast to other hydrogel,thermosensitive gel enjoys the advantage of temperature-dependent reversible sol-gel transition,presenting a liquid state at lower temperature and a solid gel at higher.As drug carrier,thermosensitive gel can achieve an effective vaginal drug delivery.Few researches,however,have been reported regarding its application in the treatment of vaginal neoplasmas in animal.The present study is aimed at exploring the efficacy of vaginal neoplasmas in mice by the local chemotherapy of cisplatin-loaded thermosensitive gel or local thermalchemotherapy of doxorubicin and indocyanine co-loaded thermosensitive gel.We firstly prepared cisplatin-loaded poloxamer gel,characterized by rheology,in vitro erosion and in vitro drug release.The results showed that the optimal prescription is 22%(wt)of P407,18% P188 and 1% cisplatin,which has good thermosensitivity and drug sustained release.Then we evaluated the retention of fluorescence-labelled gel in the vagina of mice,and the local and systemic drug distributio n after the infusion of gel into the mice vagina.The results showed that poloxamer gel can effectively remain in the vagina without leakage,resulting in sustained drug accumulation in the vagina and elimination of drug diffusion into other organs such as heart,liver,spleen,lung and kidney.We prepared orthotopic cervix/vagina tumor model in mice by using murine cervical carcinoma U14 cells,followed by the infusion of cisplatin-loaded poloxamer gel into the vagina of tumor-bearing mice and the evaluation of the inhibition effect of drug-loaded gel against murine cervix/vagina cancer.The results showed that the inhibition rate was as high as 63.1% by vaginal delivery of cisplatin-loaded poloxamer gel,with much greater systemic safety than intravenous i njection of cisplatin.Then we prepared doxorubicin and indocyanine green co-loaded mesoporous silica nanoparticles,which were characterized by transmission electron microscopy,dynamic light scattering,ultraviolet absorption spectrum,heating curve and so on.The results showed that the encapsulation rate of indocyanine green and doxorubicin were 95.5% and 88.5% respectively,and drug loading rate 6.4% and 2.95% respectively.The particle size of nanoparticles was about 30 nm.Under the near infrared laser irradiation of 808 nm,temperature of nanoparticles could raise 15.4 ? within 5 minutes,which was better than that of small molecule of indocyanine green.In vitro cells experimental results showed that thermochemotherapy synergy effects are better tha n the pure chemotherapy whether nanoparticles or the mixture of doxorubicin and indocyanine green were adopted.Nanoparticles were similar to small molecules in the case of the inhibition rate of tumour cells.Then nanoparticles-loaded thermosensitve poloxamer gel was prepared and was infused the vagina of mice,followed by fluorescence imaging of all organs at different time points.The results showed that composite gel can effectively deliver the two drugs to the vagina at the same time,and the drugs can mainly accumulated in the vagina for a long time rather than other organs.Then we evaluated the curative effect of the composite gel-based thermochemotherapy against vaginal tumor in mice.The results showed that inhibitory rate of the local thermochemotherapy can reach 91.2%,which was much better than the pure chemotherapy(45%).At last we tried applying composite gel-based thermochemotherapy to a vaginal tumor-bearing pet dog.The tumor size dramatically decreased after two-time treatments and the life quality of the dog greatly improved.The above results showed that the composite gel-based local thermochemotherapy synergy is an effective new way for the treatment of animal vaginal tumor.