Modular nanoparticle drug delivery systems for treating multiple types of cancer

Abstract

Cancer is the leading cause of death globally and a major limitation of conventional treatments is toxicity to normal tissues, restricting the dose deliverable to patients. There has been enormous interest in the application of nanotechnology towards therapeutics for cancer, as many of these therapeutics lack specificity and in some cases, efficacy due to limitations in delivering a therapeutic dose. With the hypothesis that delivering increased therapeutic doses specifically to tumour cells will increase the efficacy of treatment, the aim of this thesis is to develop and evaluate targeted therapies for different types of cancer. Initially, the development of targeted magnetic hyperthermia was examined and demonstrated some of the challenges encountered when working with magnetic iron oxide nanoparticles for this application. This highlighted the need for better control of aggregation under clinically relevant conditions. Next, a modular strategy for targeting a clinically-approved liposomal formulation of doxorubicin towards epidermal growth factor receptor on lung cancer cells, prostate specific membrane antigen on prostate cancer cells and disialoganglioside (GD2) on neuroblastoma cells via bispecific antibodies was developed. Targeting resulted in increased internalisation, apoptosis and cytotoxicity in vitro. While initial in vivo experiments were inconclusive, potential reasons for this are discussed. With insights gained regarding nanoparticle properties for targeting, and to broaden the number of payloads that can be effectively targeted towards cancer cells, novel cross-linked poly amino acid micelles were developed and covalently loaded with several payloads including monomethyl auristatin E, a potent anti-microtubule drug. Micelles had a hydrodynamic diameter of 37 nm and were uniform in size with a polydispersity index of 0.1. When applied with bispecific antibodies, the system demonstrated a remarkable increase in internalisation of payload by cancer cells, microtubule inhibition, G2/M cell cycle arrest, radiosensitisation and significantly enhanced cytotoxicity in both monolayer and 3D spheroid models. These findings broaden our understanding of active targeting with bispecific antibodies. Targeted micellar system may have broad clinical potential as it could be used to deliver a wide array of payloads to various antigens overexpressed by cancer cells.