Abstract 5219: Relationship between intratumoral drug distribution and tumor microenvironment
Authors: Pathak Arvind P. , Donato Kristin , Benoit Nicole E. , Kato Yoshinori 
Published: February 2011

Abstract
Purpose: Anticancer agents released from nanocarriers have to reach cancer cells in order to demonstrate their cytotoxic activity. The distribution pattern of anticancer agents can be affected by the tumor microenvironment which varies among different types of tumors. The purpose of this study is to delineate the relationship between drug transport and tumor microenvironmental factors, such as extracellular matrix (ECM) integrity. Such studies provide insight into the factors that hinder the accessibility of cargo molecules to cancer cells.
Hypothesis: In tumors with a “permissive” ECM, small molecules are likely to diffuse farther after release from nanocarriers, while they are likely to be hindered in the tumors with denser ECM. Non-invasive monitoring of drug release and subsequent intratumoral distribution of the released drug can be visualized using a dual MR contrast technique capable of distinguishing between released and intact molecules in vivo.
Methods: GdDTPA was used as a surrogate tracer for a water-soluble, small molecular-weight drug. Liposomes were used as the model nanocarrier in this study. Xenografts derived from the highly-invasive and metastatic MDA-MB-231 human breast carcinoma cell line, and weakly-metastatic MCF-7 human breast carcinoma cells were used. Liposomes encapsulating GdDTPA, iron particles, and rhodamine (Lip-Gd/Fe/Rho) were prepared using a sonication method, followed by extrusion. Orthotopic xenografts were grown in female SCID mice by injecting 3×106 of cancer cells into the mammary fat pad of the animal. All MR studies were carried out on a horizontal bore Bruker Biospec 9.4T spectrometer. MR images were acquired before, 30 min, and 23 hrs post-i.v. administration of Lip-Gd/Fe/Rho. To identify iron particles, a 3D fast low-angle shot (FLASH) sequence was used, while a 3D fast spin echo (RARE: Rapid Acquisition with Relaxation Enhancement) sequence with an effective echo time of 50 ms and five different repetition times was acquired to track GdDTPA released from liposomes. After completion of the MRI study, tumors were excised, fixed and were cut into 10μm sections for imaging with second harmonic generation multiphoton microscopy. Region of interest analysis were carried out on the MRI data.
Results/Discussion: In vivo MRI results demonstrated that a decrease in T1 of the tumors was observed following i.v. administration of the Lip-Gd/Fe/Rho, indicating successful delivery and degradation of liposomes in the tumor. The comparison of differences in liposome delivery and its correlation with collagen-I density in the ECM of MDA-MB-231 and MCF-7 tumors is currently underway. Our results demonstrate the feasibility if using complementary imaging techniques to characterize the factors affecting intratumoral distribution of drug molecules after a release from nanocarriers.
Acknowledgment: Supported by NIH grant R21 EB008162 (YK).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5219.