Magnetic Heating Stimulated Cargo Release with Dose Control using Multifunctional MR and Thermosensitive Liposome

Abstract

Rationale: Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. In this setting, real-time monitoring of therapy and tumor site would give the clinicians a handle to observe therapeutic response and to quantify drug amount to optimize the treatment. In this work, we developed a liposome-based cargo (cancer drugs) delivery strategy that could simultaneously monitor the real-time alternating magnetic field-induced cargo release from the change in MRI relaxation parameter R 1 and the location and condition of liposome from the change in R 2 . The tumor site can then be monitored during the cargo release because liposomes would passively target the tumor site through the enhanced permeability and retention (EPR) effect. Physical insights from the experimental results and corresponding Monte Carlo spin dynamics simulations were also discussed. Methods: Superparamagnetic iron oxide (SPIO) nanoparticles, diethylenetriaminepentaacetic acid gadolinium(III) (Gd(III)-DTPA), and a model cancer drug (fluorescein) were co-loaded in PEGylated thermosensitive liposomes. The liposomes were characterized by transmission electron cryo-microscopy (cryoTEM), dynamic light scattering (DLS), and inductively coupled plasma optical emission spectrometry (ICP-OES). Alternating magnetic field (AMF) was used to create controlled mild hyperthermia (39-42°C) and facilitate controlled cargo (fluorescein) release from the thermosensitive liposomes. MRI relaxation parameters, R 1 and R 2 , were measured at room temperature. The temporal variation in R 1 was used to obtain the temporal profile of cargo release. Due to their similar sizes, both the gadolinium and cargo (model cancer drug fluorescein) would come out of the liposomes together as a result of heating. The temporal variation in R 2 was used to monitor SPIO nanoparticles to enhance the tumor contrast. Monte Carlo spin dynamics simulations were performed by solving the Bloch equations and modeling SPIO nanoparticles as magnetized impenetrable spheres. Results: TEM images and DLS measurements showed the diameter of the liposome nanoparticle ~ 200 nm. AMF heating showed effective release of the model drug. It was found that R 1 increased linearly by about 70% and then saturated as the cargo release process was completed, while R 2 remained approximately constant with an initial 7%-drop and then recovered. The linear increase in R 1 is consistent with the expected linear cargo release with time upon AMF heating. Monte Carlo spin dynamics simulations suggest that the initial temporal fluctuation of R 2 is due to the plausible changes of SPIO aggregation and the slow non-recoverable degradation of liposomal membrane that increases water permeability with time...

Comparison Study of the Effects of Cationic Liposomes on Delivery across 3D Skin Tissue and Whitening Effects in Pigmented 3D Skin

“…NA is considered to be incorporated into the aqueous core of the liposomes without any precipitation because the core was observed to be clear. [18] When we evaluated diffusional transport across the synthetic membrane, no significant difference between the liposomes was observed, where the amount of the penetrated NA ranged from 20.43 to 22.89 µg cm −2 (Figure 4). Although a Franz diffusion cell is a model widely employed to compare the permeation of cosmetic products, previous reports indicated that several issues are under controversy because of the structural inconsistency to the skin tissue.…”

“…NA is considered to be incorporated into the aqueous core of the liposomes without any precipitation because the core was observed to be clear. [ 18 ]…”

Droplet Microfluidics for Tumor Drug‐Related Studies and Programmable Artificial Cells

“…[181] Tumor angiogenesis visualization using MRI imaging was achieved though the passive or active delivery of magnetic liposomes. [181,182] Li et al also proposed a combined approach (PDT, MRI imaging and immunotherapy), using IR dye, MRI contrast agent, and anti-EGFR antibody on liposomes for targeting, treating and imaging colorectal tumors. [183] Figure 4c summarizes the possible modifications to produce functional and stimuli responsive liposomes, in order to encapsulate and deliver drugs effectively.…”

“…[ 181 ] Tumor angiogenesis visualization using MRI imaging was achieved though the passive or active delivery of magnetic liposomes. [ 181 , 182 ] Li et al. also proposed a combined approach (PDT, MRI imaging and immunotherapy), using IR dye, MRI contrast agent, and anti‐EGFR antibody on liposomes for targeting, treating and imaging colorectal tumors.…”

Imaging Beyond Seeing: Early Prognosis of Cancer Treatment

“…[ 37 ] In other studies, Gd 3+ ‐based complexes were loaded into nanoparticles along with drug molecules to report drug release. [ 38 ] The effect of paramagnetic metal complexes is to increase the longitudinal and transverse relaxation rate of nearby water protons. Due to the fact that MRI contrast agents (especially T 1 ‐weighted MRI) depend on the access of freely diffusing water molecules, paramagnetic species inside or outside a nanocarrier provide different MRI signals for assessing drug release.…”