Novel theranostic liposomal-based nanoparticles for cancer treatment.

'Theranostic' nanotechnology aims to use the same drug and delivery system to achieve diagnostic imaging and therapy simultaneously¹. We will develop novel gadolinium-chelate labelled, drug-loaded liposomal nanoparticles that are MRI-visible, as well as capable of delivering and releasing drugs when activated by a localising technique such as focused ultrasound (FUS, Fig. 1). We have shown how incorporation of gadolinium chelate-conjugated lipids in liposomes has enabled these nanoparticles to be MRI-visible². In this study, we will design and synthesise a novel liposome formulation, rendered MRI-visible by incorporation of gadolinium-chelate conjugated lipids that can encapsulate and deliver drugs to be released on heat exposure by FUS.

Chelating ligands were conjugated to the lipid, N,N-distearylamidomethylamine prior to chelation of Gd³⁺. Image-guided thermosensitive PEGylated liposomal (ITLs) nanoparticles were prepared and loaded with doxorubicin. For near-infrared fluorescence (NIRF) imaging, lipids conjugated to a near-infrared fluorophore were also incorporated into the ITLs.

ITLs were characterised in vitro by T1-MRI relaxometry at 7T and NIRF imaging with FUS-induced drug release determined by fluorescence imaging. ITLs were visualised in vivo by MRI and NIRF imaging following intravenous injection into mice bearing human xenograft tumours on both flanks, with one flank being exposed to short-term heating by FUS.

In vitro: The novel ITLs were visible by NIRF imaging (Fig. 2a). Doxorubicin itself is also fluorescent (Fig. 2b) and its fluorescence increased when released from liposomes by FUS (Fig. 2c). T1-weighted MRI shows positive enhancement of the liposomal formulation compared to water (Fig. 2d and e).

In vivo: NIRF imaging confirms the accumulation of ITLs in the xenograft tumours following administration but significantly higher in the tumours exposed to FUS (Fig. 3). This is consistent with the greater signal enhancement by T1-weighted MRI of the FUS-exposed tumour (Fig. 4). Note, FUS was not purely localised to the tumour and underlying tissue structures including the hind legs were also exposed and signal enhancement is also observed.

We have shown our novel ITLs are indeed visible by MRI and that they can be targeted by FUS to deliver and release a cytotoxic drug, paving the way for their theranostic applications in cancer therapy.