The release of Doxorubicin from liposomes monitored by MRI and triggered by a combination of US stimuli led to a complete tumor regression in a breast cancer mouse model

Abstract

The work aimed at developing a novel MRI-based theranostic protocol for improving the anticancer efficacy of a Doxil-like liposomal formulation. The goal was achieved stimulating the intratumor release of the drug from the nanocarrier and favoring its diffusion in the lesion by the sequential application of low-intensity pulsed ultrasound. The protocol was tested on mice bearing a syngeneic breast cancer model. The combination of acoustic waves with different characteristics allowed for: i) the release of the drug and the co-encapsulated MRI agent (Gadoteridol) from the liposomes in the vessels of the tumor region, and ii) the extravasation of the released material, as well as intact liposomes, in the tumor stroma. The MR-T1 contrast enhancement measured in the tumor reported on the delivery and US-triggered release of Doxorubicin. The developed protocol resulted in a marked increase in the intratumor drug concentration that, in turn, led to the complete regression of the lesion. The protocol has a good clinical translatability because all the components of the theranostic agent (Doxorubicin, liposomes, Gadoteridol) are approved for human use. MRIJbased% procedure% for% the% in$ vivo% visualization% of% the% release% of% an% anticancer% drug% (Doxorubicin)% from% liposomes% stimulated% by% the% local% application% of% pulsed% lowJintensity% planar% ultrasound.% First,% we% investigated% the% in% vitro% release% properties% of% several% nanovesicular% carriers% under% US% application% and% demonstrated% that% the% release% was% i)% caused% by% the% mechanical% characteristics% of% the% US% stimulus,% ii)% very% sensitive% to% the% composition% of% the% particle% membrane,% and% iii)% MRI% detectable% (Giustetto% et$ al.,% J.$ Med.$ Imaging$Health$Inf.%3,%356J366%(2013)).%Next,%the%MRI%potential%of%the%method%was%demonstrated%in$vivo%on%a% mouse%model%of%melanoma% (Rizzitelli%et$al.,%Nanomedicine%10,%901J904%(2014)).%More%recently,%the%theranostic% protocol% was% implemented% by% the% encapsulation% of% Doxorubicin,% and% both% the% MRI% performance% and% the% therapeutic% benefits% associated% with% the% USJtriggered% intratumor% release% of% the% drug% on% a% mouse% model% of% breast%cancer%were%reported%(Rizzitelli%et$al.,%J.$Control.$Release%202,%21J30% (2015)).% In%the%submitted%paper,%we%further%improved%the%performance%of%the%method%through%the%sequential% application%of%two%different%low%intensity%US%stimuli,%one%inducing%a%permeabilization%of%the%tumor%vascular% endothelium,%and%the%other%stimulating%the%release%of%the%drug%from%the%nanocarrier.%The%synergy%between% the%two%short%stimuli%(only%3%minutes%in%total)%allowed%for%a%complete%tumor%regression%in%a%mouse%model%of% breast%cancer.%Furthermore,%also%the%MRI%detectability%of%the%process%was%improved.%% Though% several% examples% dealing% with% the% use% of% US% (but% mostly% focused% with% highJintensity)% for% triggering% drug% release% can% be% found% in% literature,% this% is,% to% our% knowledge,% the% case% with% the% highest% therap...

Molecular Imaging with 68Ga Radio-Nanomaterials: Shedding Light on Nanoparticles

“…For this purpose, liposomes are either labeled or loaded with both, the therapeutic agent and the imaging probe. Visualization of liposomes with T 1 -weighted MRI [115,116] and T 2 -weighted MRI [117], PET [118][119][120] and OI [121], among others, has been achieved in several studies.…”

Recent advances in the preparation and application of multifunctional iron oxide and liposome-based nanosystems for multimodal diagnosis and therapy

“…CTRL no LIPO refers to a group of mice that was not injected with liposomes. Adapted from [121]. As previously mentioned, the synergistic effect of more than one therapy can greatly improve the efficacy of the cancer defeat.…”

Magnetic Resonance Imaging and Spectroscopy in Cancer Theranostic Imaging

“…28 Pulsed low intensity non-focused US are pulsed planar acoustic waves with intensity lower than 10 W/cm 2 and US frequencies ranging from 20 kHz to 1-3 MHz. 29 The release of DOX results from mechanical interaction between the acoustic waves and the particles. These nanocarriers were tested in a syngeneic breast tumor model, and the results showed that MRI was useful for both confirming the drug delivery and assessing the efficacy of the treatment.…”

“…28 To further improve treatment efficacy, two sequential pulsed US treatments are applied. 29 The first releases the drug from the liposomes circulating in the tumor blood vessel, and the second increases the vessel permeability, facilitating the diffusion of the drug in the tumor stroma. 29 These modified liposomes were tested in a mammary carcinoma model in BALB/C mice using TS/A cells.…”