Application of ultrasound for enhanced delivery of biological therapeutics into solid tumours

Thesis

Drug development for cancer is heading towards increased use of highly-targeted and complex biological therapeutics. As the complexity and costs of drug development increase, the importance of ensuring good tumoural delivery and distribution of these drugs is paramount.

The tumour microenvironment, which possesses many characteristics distinguishing it from healthy tissue, presents both challenges to and opportunities for drug delivery. Countless novel nanoscale formulations or reformulations of existing drugs have been created to harness the potential of the ‘enhanced permeability and retention’ of tumours. The scale of this effect has, however, come under recent scrutiny, and a clear role for alternative delivery mechanisms has emerged.

Ultrasound-mediated cavitation has been evaluated as a non-invasive external stimulus to improve delivery of drugs to solid tumours. Cavitation nuclei can be used to seed cavitation at relatively low pressures to achieve cavitation levels capable of enabling enhanced drug transport, without safety concerns, suggesting a path for clinical translation.

In this thesis, the effects of ultrasound-mediated cavitation on the delivery of a range of therapeutic drug classes to solid tumours was investigated: a cancer-targeting antibody (cetuximab), an actively targeted nanoparticle (cetuximab-GNP), and an oncolytic virus (ColoAd). Two classes of cavitation nuclei were employed: a microbubble ultrasound contrast agent (SV) and sonosensitive gas-entrapping nanoparticles (SSPs).

Ultrasound-mediated cavitation was shown to enhance the delivery of all therapeutics tested here, though the scale of the effect varied. Cavitation activity achieved with SV or SSPs in vivo showed different characteristics, with SSPs demonstrating more sustained cavitation. Delivery of a long-circulating antibody was significantly more enhanced with SSPs than with SV, but the two cavitation nuclei provided a comparable benefit to the shorter-circulating targeted nanoparticle and oncolytic virus. Furthermore, site-specific density-modification of ColoAd was investigated, in an attempt to further enhance its cavitation-mediated transport, though the conclusion of this work was that the proposed modification strategy was not viable.

The work presented in this thesis highlights the challenge of achieving effective tumoural delivery of systemically administered biological therapeutics, and provides compelling evidence for the further investigation of ultrasound-mediated cavitation as an effective tool for enhancing the delivery of biological therapeutics into tumours.

Authors: Grundy, M

• DOI: 10.5287/ora-zbmp5dg2p
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford