MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice

Abstract

Rationale: Image-guided, triggerable, drug delivery systems allow for precisely placed and highly localised anti-cancer treatment. They contain labels for spatial mapping and tissue uptake tracking, providing key location and timing information for the application of an external stimulus to trigger drug release. High Intensity Focused Ultrasound (HIFU or FUS) is a non-invasive approach for treating small tissue volumes and is particularly effective at inducing drug release from thermosensitive nanocarriers. Here, we present a novel MR-imageable thermosensitive liposome (iTSL) for drug delivery to triple-negative breast cancers (TNBC). Methods: A macrocyclic gadolinium-based Magnetic Resonance Imaging (MRI) contrast agent was covalently linked to a lipid. This was incorporated at 30 mol% into the lipid bilayer of a thermosensitive liposome that was also encapsulating doxorubicin. The resulting iTSL-DOX formulation was assessed for physical and chemical properties, storage stability, leakage of gadolinium or doxorubicin, and thermal-or FUS-induced drug release. Its effect on MRI relaxation time was tested in phantoms. Mice with tumours were used for studies to assess both tumour distribution and contrast enhancement over time. A lipid-conjugated near-infrared fluorescence (NIRF) probe was also included in the liposome to facilitate the real time monitoring of iTSL distribution and drug release in tumours by NIRF bioimaging. TNBC (MDA-MB-231) tumour-bearing mice were then used to demonstrate the efficacy at retarding tumour growth and increasing survival. Results: iTSL-DOX provided rapid FUS-induced drug release that was dependent on the acoustic power applied. It was otherwise found to be stable, with minimum leakage of drug and gadolinium into buffers or under challenging conditions. In contrast to the usually suggested longer FUS treatment we identified that brief (~3 min) FUS significantly enhanced iTSL-DOX uptake to a targeted tumour and triggered near-total release of encapsulated doxorubicin, causing significant growth inhibition in the TNBC mouse model. A distinct reduction in the tumours' average T1 relaxation times was attributed to the iTSL accumulation. Conclusions: We demonstrate that tracking iTSL in tumours using MRI assists the application of FUS for precise drug release and therapy.

Phase-shift nanodroplets as an emerging sonoresponsive nanomaterial for imaging and drug delivery applications

“…PET, MR and fluorescence imaging have great potential to be used in these studies. Fluorescence imaging can be used for short-term realtime biodistribution imaging in small animals 123 whereas PET imaging has clinical translatability for large animals and human. Besides, PET allows treatment monitoring and planning.…”

Physically stimulus-responsive nanoparticles for therapy and diagnosis

“…In another study, gadolinium- and DOX-loaded liposomes were activated upon HIFU exposure, in which they release about whole encapsulated MRI contrast and anticancer contents. The MDA-MB-231 tumor-bearing mice treated with the liposomes and HIFU experienced a significant inhibition in tumor growth ( Amrahli et al, 2021 ).…”

Theranostics for MRI‐guided therapy: Recent developments

“…A more recent study reported a Gd-labeled thermoresponsive liposome that can be concentrated in a tumor. 71 A subsequent burst of focused US (3 minutes) caused it to release a DOX payload, thus allowing highly targeted treatment. The accumulation of liposomes at the tumor site also caused a reduction of the T 1 relaxation time.…”

“…This was found able to act as a radiofrequency thermal therapy agent, which can trigger the release of DTX as observed in T 2 ‐weighted MRI and eradicate the cancer cells by heat energy generated from radiofrequency irradiation. A more recent study reported a Gd‐labeled thermoresponsive liposome that can be concentrated in a tumor 71 . A subsequent burst of focused US (3 minutes) caused it to release a DOX payload, thus allowing highly targeted treatment.…”