Development of novel peptide hydrogel therapies for endometriosis and endometrial cancer

Endometrial cancer and endometriosis are common gynaecological disorders, which arise from the uterine lining. Cancer develops by glandular cell differentiation, whilst implantation and growth of endometrial-like tissue in endometriosis induces a chronic inflammatory reaction causing pain and infertility. Existing surgical and medical interventions are limited by systemic side effects, cost and short-term relief of chronic symptoms. A sophisticated class of hydrogel scaffolds has emerged as a powerful tool for the generation of new biomaterials with adherent gelation properties. Design of these nanostructured peptides can be tailored for potential application to mucosal surfaces for local drug delivery.
Our hypothesis is that local placement of a drug delivery system at the time of surgery will prevent disease return and reduce the risk of systemic side effects.

Aims:
To develop a hydrogel formulation of promising new and repurposed drugs for targeted delivery to disease sites.
To examine the therapeutic value of hydrogels using in vitro and in vivo models.

Methods
This project offers a unique experience at leading industrial and academic research sites.

Optimising hydrogel formulations: Manchester BIOGEL's bespoke peptide-based scaffolds will be tailored for therapeutic application within the pelvic cavity. These hydrogels will be optimised for suitable composition, adhesion and stability with long-acting drug release profiles without appreciable lag or burst effects. Structural and physical properties will be assessed using rheometry, TEM and HPLC-UV.

In vitro and in vivo hydrogel assessment: Prototype drug-loaded and blank hydrogel formulations will initially be evaluated using mouse and human endometrial cells. The effect of drug treatments (novel and known oestrogen suppressors) on cell viability, prostaglandin production and steroidogenesis will be assessed using metabolic response assays, lipidomic analysis and ELISAs. Efficacy of these hydrogel implants will also be examined in vivo with the primary measured end point being a reduction in endometrial lesion or tumour size.

Potential impact: biotechnology for health
Understanding the design and biological effects of drug-loaded hydrogels should lead to development of a new treatment moiety to prevent recurrence of endometriosis and endometrial cancer. It provides an exciting opportunity to accelerate the proposed novel hydrogel technology into clinical evaluation. This aligns with BBSRC's mission to advance knowledge and technology through world-class discovery research.

Laurence will be trained in a variety of cross-cutting skills, which include:
Formulation science to design, manufacture and assess biocompatible materials (TEM, HPLC, FTIR and rheometry).
In vitro pharmacology to assess drug and hydrogel effects on the steroid, lipid and inflammatory microenvironment (histology, immunostaining, primary cell culture, microscopy, lipidomics, ELISA, molecular biology).
Excellent quantitative skills required to evaluate in vitro and in vivo outputs for translation of findings into the clinic.
Integrative mammalian biology: high quality experimental design, animal handling, surgery, in vivo drug delivery, whole animal physiology & pathophysiology (drug metabolism and pharmacokinetics), required for pre-clinical evaluation of new medicines.