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Title: Development of a novel controlled release pelvic drug delivery system to manage endometriosis
Author: Santorelli, Sara
ISNI:       0000 0005 0289 7816
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Endometriosis is a debilitating, chronic disease which affects an estimated 176 million women around the globe (10% of reproductive aged women), characterised by the growth of ectopic endometrial cells and tissue outside the uterine cavity. Despite being such a widespread disease, a totally resolving cure for endometriosis is yet to be found. All the treatments currently prescribed (progestogens, gonadotropin-releasing hormone (GnRH) agonists) carry several side effects that limit their clinical usefulness. The aims of the projects were to develop an animal model to resemble the hormonal and pathophysiological abnormalities that occur in the human disease, to evaluate and compare the therapeutic efficacy of AZD4547, a novel Fibroblast Growth Factor Receptor Inhibitor (FGFRI), with the gold standard progestin, etonogestrel (ENG), administered either systemically or locally, towards the development and size of the ectopic endometrial implants. Endometriosis was induced by transplanting uterine fragments from a donor mouse in the stage of proestrus into the peritoneal cavity of recipient mice. AZD4547 and ENG were administered systemically starting either from the day of endometriosis induction or 2 weeks after surgery (when the endometriotic lesions were already developed). After 20 days of treatment, the lesions were harvested, their size and weight were measured and examined by H&E staining. LC/ESI-MS/MS for lipidomic analysis of eicosanoids and hydroxy fatty acids was performed on lesions, uteri and lesion fluids. Successively, the most effective doses of each drug were loaded on hydrogels and inserted in the peritoneal cavity of mice subjected to endometriosis induction on the same day. After 20 days, lesions were harvested, and their weight and size were measured. When the two drugs were administered systemically, analysis of lesions weight, volume and histological examination demonstrated 25mg/kg being the most effective dose of AZD4547 in counteracting lesion growth and inducing lesion weight regression either from the day of surgery or 2 weeks after surgery; whereas, the dose of 0.08mg/kg of ENG was the most effective dose in reducing lesion volume, and percentage of lesions filled with fluid when administered from 2 weeks after surgery. LC/ESI-MS/MS showed these two doses induced the highest reduction of pro-inflammatory mediators in the lesions. However, the dose of 0.08mg/kg of ENG was associated with partial oestrous cycle disruption and hyperaemia of the uteri. When AZD4547 and ENG were administered loaded on hydrogels, lesion volume was smaller compared to the systemic administration. The group treated with the hydrogel loaded with AZD4547 showed lower percentage of lesions filled with fluid, moreover, with no evidence of glandular structure or blood vessels in the endometrial compartment, suggesting not well developed and viable implants. In the group treated with the hydrogel loaded with ENG neither partial cycle interruption nor hyperaemia of the uteri was observed. In conclusion, AZD4547 and ENG were demonstrated to be effective in reducing the size of endometriotic lesions when administered systemically but AZD4547, in particular, caused no oestrous cycle disturbance, compared to the impairment of the cycle induced by ENG. Therefore, FGFR inhibition is worthy of further investigation as a new target for endometriosis therapy. Moreover, based on the promising results in reduction of lesions volume and inhibition of fluid filled cysts development, and, the avoidance of the anti-fertile activity seen when AZD4547 and ENG were respectively delivered locally, hydrogels confirmed to be safe and compatible drug delivery systems, enlarging the spectrum and route of administration of therapies currently available.
Supervisor: Harris, Lynda ; Marshall, Kay ; Fischer, Deborah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: endometriosis ; FGFR ; Etonogestrel ; Hydrogel