Targeted Nanomedicines for Breast and Metastatic Brain Cancers

Project code - PHBM3020217

Nearly 140 women are diagnosed daily with breast cancer, the most common type of cancer in the UK. Although mortality has been reduced by almost 20% in recent years, on average 30 women still die daily in UK, with metastasis being a major cause (the total incidence of brain metastasis amongst breast cancer patients is about 30%). As a direct result of ongoing improvements in controlling systemic diseases (e.g. successful use of Trastuzumab) leading to an extended life span, the incidence of brain metastases is increasing in breast cancer patients, with the current systemic medication (including Trastuzumab) unable to penetrate the blood-brain barrier (BBB) in significant amounts. Currently, nanotechnology appears as the only promising approach in successfully delivering actives across relevant biological barriers (the BBB, the tumour blood vessel walls and the cancer cells membrane).

This project focuses on developing targeted delivery strategies for both primary breast and secondary brain tumours. The proposed work aims to develop specifically engineered cellulose nanocrystals as state-of-the-art vehicles for the targeting of breast and brain metastatic tumour cells. Nanocrystals derived from cellulose, a unique natural polysaccharide found in all plant cell walls, have been recently shown to target brain tumour cells with no cytotoxicity. By specifically tailoring the cellulose molecular weight and hydrophilic character, decorating the particle surface with ligands specific for the low density lipoprotein (LDL) receptor (overexpressed in the BBB, breast tumour and brain metastatic tumour cell membranes), and simultaneously loading chemotherapeutics while cross-linking the cellulose nanocrystals with peptidic linkers that are cleavable by specific proteases (abundant in the extracellular tumour microenvironment), the proposed nano constructs are expected to selectively target breast/brain cancer cells and enable the release of the cytotoxic drug cargo to the tumour site in a selective manner, thus avoiding the unwanted side-effects of the normally administered current chemotherapeutics.

The project is positioned at the interface between biomaterial nano-engineering, drug delivery and cellular medicine, and addresses specific challenges in relation to metastatic breast-brain tumours and drug permeation across the BBB. The successful candidate will gain experience in polymer engineering and nanomaterial characterisation, solid-phase peptide synthesis/characterisation, physicochemical/morphological characterisation of nanomedicines, receptor binding assays, permeability studies across all-human in vitro BBB models (collaboration with Synvivo), efficacy studies in human breast and brain metastatic tumour cells. The successful technology could be further tested in pharmacokinetic and proof of concept studies using orthotopic xenograft rat models (in collaboration with Prof Bjerkvig, Norway).