Title: Long-acting surface-engineered nanocarrier system for codelivery of temozolomide with polyunsaturated fatty acid for the improved treatment of glioblastoma multiforme
Funder: The Academy of Medical Sciences

Abstract: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour with extremely poor prognosis and median survival of approximately 12 to 18 months. Till date, surgical removal followed by radiotherapy and concurrent administration of chemotherapeutic agent has only shown improvement in the quality of life in GBM patients with negligible impact on the mortality rate. Temozolomide, the only approved drug and first-line treatment often suffers from a number of challenges such as limited access of the drug to the tumour due to poor blood-brain barrier permeation, extremely fast elimination half-life (1.8 hours), along with chances of tumour recurrence, drug resistance and high cost of therapy. Additionally, single agent therapy creates therapy resistant subpopulations of GBM cells due to heterogenicity of the tumour. In this context, the present research proposes to develop combined delivery of temozolomide and gamma linolenic acid, a polyunsaturated fatty acid which has shown promising activity against GBM acting on completely different targets than TEM for improving the treatment outcomes. My fellowship on this interdisciplinary project at the interface of Nanomedicine and Cancer biology will take at University of Central Lancashire (Prof Singh, Dr Alder) and University of Hyderabad (Prof Babu) and will focus on design development of blood brain barrier (BBB) penetrating long-acting nanoparticles loaded with temozolomide in combination with gamma linolenic acid and surface engineered with a cell penetrating peptide for favourable intra-tumoral distribution of the drugs. The present investigation proposes to use human serum albumin (HSA) nanocarrier because of its proven safety and improve its BBB permeability by making hybrid nanostructures with biolipids. The nanoparticles will be completely characterised for critical quality parameters. Transport of nanoparticles across BBB and BBTB will be assessed using in-vitro 3-D models. Cytotoxicity and cellular internalization studies will be conducted on GBM cells and short-term cultures from patient-derived cells. Proof-of-concept in-vivo studies will be done in experimental GBM rat model. Progress to completion will be reviewed by a Research and Professional Development Plan which will provide me with both discipline-specific and complementary technical training and generic and complementary transferable skills (e.g. intellectual property, leadership skills, motivation skills, communication skills, regulatory affairs). I will benefit from Prof Singh’s academic industry-clinician partnership and Prof Babu’s vast neuro-oncology network. This training will facilitate me to achieve my future career goals of achieving a position of professional maturity, diversity and independence and enabling me to translate innovative therapeutic interventions to the clinic setting.

Lay abstract: Glioblastoma multiforme (GBM) is an aggressive brain tumour with median survival rate of only 12-18 months. Radiotherapy is highly challenging in GBM due to the location of tumour in brain and the success rate with the only available chemotherapeutic drug, temozolomide is very limited (<​25%). This is due to limited access of the drug at the tumour-site due to its poor permeability across the blood-brain barrier (BBB), tumour recurrence due to therapy resistant subpopulations of tumour cells and intolerance to chemotherapy, which all lead to poor prognosis of the disease. Hence, there is an urgent need for novel multiple therapy interventions required for augmenting the efficacy of temozolomide. PUFAs especially gamma linolenic acid has shown distinct antiproliferative effect on GBM and can boost the temozolomide therapy. My fellowship on an interdisciplinary project at the interface of Nanomedicine and Cancer biology will take at University of Central Lancashire (Prof Singh, Dr Alder) and University of Hyderabad (Prof Prakash) and will focus on development of BBB penetrating long-acting nanoparticles loaded with temozolomide in combination with gamma linolenic acid surface engineered with a cell penetrating peptide for efficient tumour targeting. Such multifunctional approach has promise to deliver chemotherapeutics to brain, improve the quality of patients suffering from GBM and extend their life span. This fellowship will not only facilitate to train me to achieve my future career goals of achieving a position of professional maturity, diversity and independence but empower me to translate transformative therapeutic interventions to the clinic setting.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS