Long-acting surface-engineered nanocarrier system for codelivery of temozolomide with polyunsaturated fatty acid for the improved treatment of glioblastoma multiforme

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.