<p>Noninvasive Molecular Imaging of the Enhanced Permeability and Retention Effect by ⁶⁴Cu-Liposomes: In vivo Correlations with ⁶⁸Ga-RGD, Fluid Pressure, Diffusivity and ¹⁸F-FDG</p>

Abstract

Background The accumulation of liposome encapsulated chemotherapy in solid cancers is dependent on the presence of the enhanced permeability and retention (EPR) effect. Positron emission tomography (PET) imaging with a liposome encapsulated radioisotope, such as liposome encapsulated Cu-64 ( 64 Cu-liposome) may help to identify tumors with high liposome accumulation, and thereby stratify patients based on expected benefit from liposomal chemotherapy. However, intravenous administration of liposomes without a cytotoxic content is complicated by the accelerated blood clearance (ABC) phenomenon for succeeding therapeutic liposome dosing. Alternative markers for assessing the tumor’s EPR level are therefore warranted. Materials and Methods To increase our understanding of EPR variations and to ultimately identify an alternative marker for the EPR effect, we investigated the correlation between 64 Cu-liposome PET/CT (EPR effect) and 68 Ga-RGD PET/CT (neoangiogenesis), 18 F-FDG PET/CT (glycolysis), diffusion-weighted MRI (diffusivity) and interstitial fluid pressure in two experimental cancer models (CT26 and COLO 205). Results 64 Cu-liposome and 68 Ga-RGD SUV max displayed a significant moderate correlation, however, none of the other parameters evaluated displayed significant correlations. These results indicate that differences in neoangiogenesis may explain some EPR variability, however, as correlations were only moderate and not observed for SUV mean , 68 Ga-RGD is probably insufficient to serve as a stand-alone surrogate marker for quantifying the EPR effect and stratifying patients.

Liposomes: Biomedical Applications

“…Børresen et al 64 recently investigated the correlation between the degree of the EPR effect ( 64 Cu-liposome) and tumor neoangiogenesis ( 68 Ga-RGD), fluid pressure, glycolytic activity ( 18 F-FDG) and diffusivity (diffusion-weighted MRI) to identify potential biomarkers suitable for prediction of the EPR effect in cancer models. The researchers determined that 64 Cu-liposome and 68 Ga-RGD uptake were moderately correlated, and the authors ultimately concluded only that 68 Ga-RGD does not qualify as a surrogate marker, and that 18 F-FDG (metabolic activity) and 64 Cu-liposome uptake were not correlated. Lee et al 65 introduced 64 Cu-MM-DX-929 (untargeted, no-drug PEGylated liposome) as a universal companion diagnostic agent to prospectively select patients for liposomal therapeutics.…”

“…The researchers determined that 64 Cu-liposome and 68 Ga-RGD uptake were moderately correlated, and the authors ultimately concluded only that 68 Ga-RGD does not qualify as a surrogate marker, and that 18 F-FDG (metabolic activity) and 64 Cu-liposome uptake were not correlated. Lee et al 65 introduced 64 Cu-MM-DX-929 (untargeted, no-drug PEGylated liposome) as a universal companion diagnostic agent to prospectively select patients for liposomal therapeutics.…”

Advanced Nanoparticle-Based Drug Delivery Systems and Their Cellular Evaluation for Non-Small Cell Lung Cancer Treatment

“…Nanoliposomes could also enhance the stability of the incorporated drugs in vivo, prolong the drug circulation, and readily modify the size and surface to improve the drug’s therapeutic index [ 32 ]. In addition, the EPR effect of radioisotope-loaded liposomes has been clinically proven in metastatic breast cancer patients using positron emission tomography (PET) imaging [ 23 , 33 ]. The advantageous pharmacological properties of liposomal formulations and their clinical applications have been extensively reviewed by Beltran-Gracia et al [ 34 ].…”

“…Within nanomedicine, a nanoparticle drug delivery system (NDDS) is a potential solution for overcoming the limitations of anti-cancer drugs, as it can improve the effectiveness of the drugs by increasing the stability and bioavailability, improving transport across the biological barriers and disease targeting, prolonging circulation and blood concentration, reducing enzyme degradation, and reducing the toxicity and immunogenicity of the drugs [ 21 , 22 ]. Nanoparticles are also advantageous to augment the accumulation of therapeutic agents in the cancer tissues via an enhanced permeability and retention (EPR) effect [ 23 , 24 , 25 ]. Many types of nanoparticles have been formulated for the delivery of anti-cancer agents, although only a handful has reached the clinical stage.…”

Impact of Liposomal Drug Formulations on the RBCs Shape, Transmembrane Potential, and Mechanical Properties

“…These beneficial effects are a result of a phenomenon referred to as Enhanced Permeability and Retention (EPR). EPR is based on the fact that nanodrugs, such as liposomal forms of active substances tend to selectively accumulate in the tissues of solid tumors due to the special properties of blood vessels supplying neoplasms with blood [ 11 , 12 , 13 ].…”