Title: Neuro-oncological precision nanomedicines
Funder: Engineering and Physical Sciences Research Council

Abstract: According to the world health organisation, the incidence of brain tumours has been rising steadily (up to forty percent) since the late 1970s. World-wide deaths in 2012 were recorded as 189,382 and are predicted to rise by a further twenty-five percent by 2020. Brain tumours are the most common solid tumour in children and the second most common cancer after leukaemia representing twenty-five percent of all primary paediatric tumours, the leading cause of cancer death. Despite the advances in imaging and multi- modality therapy with neurosurgery, radiotherapy and conventional cytotoxic chemotherapy, outcomes for high-risk brain tumours have improved little in the last two decades. When treatments are effective, they are associated with both acute and long-term significant treatment-related side effects. One of the chief obstacles hindering effective therapy for brain tumours is that the brain is very much isolated from the rest of the body with well-gated barriers controlling the trafficking of molecules and macromolecules in and out. In particular, the interface between the circulatory system and the brain tissues, (the blood-brain barrier (BBB) is the largest barrier by surface area, and allows short distance between blood and neural tissue. On top of this, one of the most critical limitations for cancer therapy is our inability to direct anticancer drugs to cancerous cells maximising killing and minimising side effects (often worse than the disease itself). This is due to the fact that cancer cells are the same healthy cells gone wrong and hence share many similarities with the good cells complicating detection and targeting.We propose here the design of ultra-small carriers (as small as a virus and 100 times smaller than cancer cells) that will be equipped with unique chemical signature to target almost exclusively the BBB, cross it, and target brain cancer cells. These nanocarriers will also be able to carry different drugs and deliver them right inside the cells where the drug is most effective.

Lay abstract: Poor and inefficient drug delivery is a major reason for therapeutic failure in childhood brain tumours. The integrity of the blood-brain barrier (BBB) may render some paediatric tumours (e.g. diffuse midline gliomas) effectively completely resistant to drug therapy and even in those tumours with a partially disrupted BBB (e.g. medulloblastoma and ependymoma) require intensive and high doses of systemic chemotherapy resulting in significant and dose limiting side effects. Therefore, improving drug transport across the BBB in a tumour specific manner could potentially result in both improved survival and also reduce systemic toxicity. We propose here the design and development of a super-selective carrier equipped to target selective passage across the BBB, follow glucose gradients, bind to neoplastic cells, and with the ability to deliver combinations of anticancer drugs. We will do so by the molecular engineering of synthetic vesicles known as polymersomes made of biodegradable materials. We will validate BBB crossing targeting both Low-density lipoprotein receptor-related protein 1 (LRP1) and Glucose transporters (GLUT1) combined with tumour specific targeting motifs to create super-selective binding initially in paediatric diffuse gliomas. It is proposed to design and develop super-selective polymersomes composed of biodegradable materials which are already undergoing pre-clinical development (in Somanautix). The objectives of this project are therefore 1. To equip polymersomes to target: (i) receptors that can pass across the BBB and (ii) receptors that distinguish neoplastic cells from healthy ones. 2. To apply super-selective rules to target specific cell populations whose phenotypic signature is the result of appropriate stratification of the somatic tissues as well as patient-to-patient variability. 3. To combine super-selectivity with combination therapy to augment cancer reduction and minimise drug resistance emergence. 4. To develop work-flow protocols based patient derived induced pluripotent stem cells (IPS) so to both validate the personalised approach and optimise combination therapy.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS