Preparation of human serum albumin nanoparticles for cancer therapy

Abstract

Targeting tumour microenvironment (TME) is an emerging strategy to fight cancer. In TME, cancer cells exhibit abnormal vasculature and altered metabolic states (anaerobic respiration instead of aerobic respiration) to cope with their high oxygen and nutrient demands. Remoulding TME via normalizing vasculature and preventing lactic acid transport contributes to the inhibition of tumour development. Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), which can remodel the chaotic vascular system in TME toward normalized vasculature via nitric oxide (NO) synthesis. The normalized blood system could increase drug perfusion, which sensitizes cancer cells to drug treatment, thus enhancing therapeutic efficacy. AZD3965, a selective monocarboxylate transporters 1 (MCT1) inhibitor, showed antitumour effects by inhibiting lactic acid transport to modulate tumour cell metabolism. As BH4 is easily oxidized and AZD3965 is toxic to the heart, the two drugs were separately encapsulated into human serum albumin nanoparticles (HSA NPs) to improve their efficacy and safety profile.

Initially, to load our drugs into the optimal human serum albumin (HSA) nanoparticles, empty HSA NPs were prepared by the desolvation technique. The effects of parameters in the formulation were systematically investigated. The physicochemical properties of the prepared HSA NPs (size, polydispersity, and zeta potential) were evaluated. The optimized desolvation method demonstrated that the size of HSA NPs can be controlled between 100 and 200 nm, with a narrow polydispersity and negative surface charge.

Then, BH4-loaded HSA NPs were prepared using the desolvation method. However, the encapsulation efficiency of BH4 was low. Therefore, further work is needed to improve BH4 loading into HSA NPs.

Finally, nonosized AZD3965-loaded HSA NPs with 28% encapsulation efficiency were successfully prepared using the desolvation method, enabling in vitro and in vivo testing. Promisingly, extracellular lactate levels were significantly reduced in cancer cells after treatment. In vitro testing, the intravenous injection of AZD3965 or AZD3965-loaded HSA NPs inhibited tumour growth in mic. 

Thesis is embargoed until 31 December 2026.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Vicky Kett (Supervisor) & Wafa Al-Jamal (Supervisor)