Nano-engineered Systems for the Targeted Delivery of Oncology Drugs for Breast Cancer

The development of target delivery systems is the single most important focus in healthcare technology for the EPSRC as evidenced by a recent sandpit workshop (Bristol:12/05/17) and the subsequent "Targeted Delivery Strategies" funding call. As such, this project aligns not only with the research priorities of QUB, but the current national strategic focus of the EPSRC and fulfils a 'gap' in the global industrial sector. The industrial partner, Phion Therapeutics, has developed a patented delivery technology, that can be used to deliver nucleoside and nucleotide analogue drugs specifically to solid tumours following intravenous administration in a nano-formulation. This composite peptide based nanoparticle prevents cell entry except in the tumour microenvironment and thus enhances the efficacy of the drug at its intended site. It is now a key priority of Phion Therapeutics to expand the utility of the delivery system to standard of care (SoC) chemotherapies specifically for breast cancer.

Breast cancer is the most common cancer in the UK with over 55,000 cases each year, with approximately 65% of patients receiving chemotherapy. The SoC chemotherapy is an anthracyline based regimem usually consisting of epirubicin (E) and Cyclophosphamide (C), both of which confer debilitating side-effects, resulting in sub-optimal dosing with a reduced clinical efficacy. This PhD project is designed to modify this SoC regimen to be

incorporated into the peptide technology, for targeted efficient delivery to tumours. Each stage of the workplan will help set the parameters for the subsequent step as we optimise the nanoparticle, understand dosing parameters, evaluate pharmacodynamics and -kinetics prior to testing efficacy in vivo.

Objective 1: Development of the nanoparticles (0-12M): Click chemistry will be employed to add non-functional phosphate groups to the EC drugs. Characterisation techniques of drugs and nanoparticles include FTIR, NMR, UV spectroscopy, dynamic light scattering, TEM, stability studies over time, temperatures, salt and phosphate concentrations. The optimal ratios with single drug and combination drugs will be determined alongside development of a manufacturing protocol.

Objective 2: Functionality of the nanoparticles (9-24M): The next step will be in vitro comparison of the nanoparticle formulations in a panel of human and mouse breast cancer cells (e.g. MCF-7, MDA-MB-231 and 4T1). Tests include dose profiling, proliferation assays, 2D clonogenic and 3D spheroid assays. The optimal strategy for lyophilisation of NPs will also be interrogated.

Objective 3: Determination of NP Bio-distribution and PK/PD profiling (18-36M): The nanoparticles will be delivered intravenously and in vivo pharmacokinetic, -dynamic and biodistribution profiles will be determined via HPLC, organ analysis and tissue pathology.

Objective 4: Therapeutic efficacy of the NPs (24-42M): Xenografts (human and mouse models optimised in Objective 2 will be treated with nanoparticles in vivo and therapeutic effect assessed using end-points such as tumour size, survival and inflammatory markers from blood samples. Formulations will also include lyophilisation at a range of doses against appropriate control.