Patel, Shiv Vinod; (2024) Cathepsin B-degradable, NIR-responsive nanoparticles for intraoperative imaging and treatment of pancreatic cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

As it stands, surgical intervention still proves to be the best course of action to improve patient survival and is still regarded as the only potentially curative option for pancreatic cancer patients. But despite that, post-operative local and systemic recurrence is high due to the inability in establishing clear resection margins. Microscopic residual disease is often left behind. However, the development of an intraoperative NIR fluorescence imaging technique could help to better visualise the tumour mass and margins, and therefore assist the surgical team in achieving a true R0 resection. Moreover, a theranostic platform that could then also be used to intraoperatively treat the tumour bed after tumour removal would further ensure no malignancy is left behind. This kind of technology would aid significantly in reducing recurrence rates. The investigations in this thesis aimed to fill this unmet clinical need by developing ICG- and IR808DB-polymeric nanoparticles based on a phospholipid-polyglutamate conjugate (DOPE-PGA) that could target distinct features of the tumour microenvironment. For example, the overexpression of proteases like cathepsin B and low acidic pH. PGA, itself, is a well-known biodegradable polymer and DOPE was integrated onto the polymer chain as a way of enhancing both drug entrapment and photostability of NIR dyes. Indeed, the formulated nanoparticles were capable of strong cathepsin Bdependent elevation in fluorescence. In fact, the level of fluorescence being observed was higher than the reference nanoparticle formulation, ICG PGA NPs, which lacked the DOPE conjugation. The addition of endogenous cathepsin B increased the fluorescence of nanoparticles while E64, a cathepsin B inhibitor, showed a clear reduction in fluorescence in 2D cell models. Nanoparticle photocytotoxicity was even found to be pH selective and was significantly enhanced in pH 6.4 environments, which further demonstrates its preference for characteristics of the tumour microenvironment. Finally, while therapeutic efficacy dropped off in 3D spheroid models, they still maintained their pH preference and they were able to visualise spheroids clearly. More optimisation is required, but these findings lay out a good foundation for further work on this technology.

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