Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts

Abstract

Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with 111 In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation. Al most all nanocarriers, including liposomes (1), and many other anticancer drugs rely on the enhanced permeability and retention (EPR) effect for accumulation in tumor tissue. The EPR effect is defined as the process of extravasation of large molecules from leaky tumor vasculature, leading to accumulation in tumor tissue (2). The EPR effect is dependent on many biological parameters, with the development of the abnormal tumor vasculature playing a major role, although other parameters such as the composition of the surrounding stroma, absence of functional lymphatics, and presence of tumor infiltrating macrophages also play an important role (3). Abnormally upregulated growth factors affect the vasculature of the tumor (4) and lead to large endothelial junctions at the luminal surface, resulting in a leaky vasculature (5). In addition, vessels lack smooth muscle cell layers and supporting cells (6), and the fast recruitment of blood vessels results in tumor neovasculature that is not hierarchically organized, causing a heterogeneous spatial distribution (4,7,8). Finally, tumors overexpress many permeability-enhancing factors, which contribute to an enhanced EPR effect (9). These observations suggest that most tumors may be susceptible to nanoparticle treatment, but thus far such particles show only a limited effect in vivo due to various barriers such as the mononuclear phagocyte system, extracellular matrix, low pH, low oxygenation, and high interstitial fluid pressure (10-12)....

Cholesterol-Containing Nuclease-Resistant siRNA Accumulates in Tumors in a Carrier-free Mode and Silences MDR1 Gene

“…It should be noted that the kidney filtration limit for nucleic acids was found to be 20–40 kDa 54 . Slowing excretion by the kidneys allows improved siRNA accumulation in the tumor because of the enhanced permeability and retention (EPR) effect, and in other organs through the endothelium vasculature depending on capillary pore size 55 . Our data showed that Ch-siRNA distribution in mouse internal organs does not depend on the presence or absence of a tumor (Figures 2 and 3) and apparently depends only on the conjugate nature, concentration of siRNA, and its circulation time in the bloodstream.…”

In vitro and in vivo evaluation of macromolecular prodrug GC-FUA based nanoparticle for hepatocellular carcinoma chemotherapy

“…Furthermore, according to the literatures, the favorable permeability and good retention (EPR) effect are paramount for nanocarriers (including polymeric nanoparticles (Kawaguchi, 2000), liposomes (Zong et al, 2016), micelles (Sutton et al, 2007) and nanogels (Jung et al, 2008)) to accumulate in tumor tissues (Anitha et al, 2014;Bolkestein et al, 2016). Alternative formulations of free 5-Fu (such as microspheres, NPs, micelles and liposomes) (Udofot et al, 2015) could prolong retention time (Onishi & Machida, 2008;Huang et al, 2010;Li et al, 2014), reduce side effects (Wigmore et al, 2010;Noori et al, 2014) and improve bioavailability.…”

Acidic pH-Targeted Chitosan-Capped Mesoporous Silica Coated Gold Nanorods Facilitate Detection of Pancreatic Tumors via Multispectral Optoacoustic Tomography

“…44–45, 61 Subcutaneous tumors also have abnormally high vascularity, artificially high leakiness and immunogenicity, and have decreased metastatic potential; such a model does not translate to clinical application. 12, 44 The use of iv injection verifies that our particles in fact target a model tumor, as opposed to relying on the less translationally relevant environment of a subcutaneous tumor or attributing particle targeting to diffusion after direct tumor injection. 34–35, 60 Orthotopic tumors using the cancer cell type of interest provide a more reliable model for testing clinical translation of new nanotechnologies.…”