Abstract 554: The impact of matrigel on the evaluation of nanomedicines in a mouse model of human breast adenocarcinoma

Abstract

Abstract There exists a disparity in the literature on the use of matrigel, a mouse tumor derived basement protein scaffold solution, in the establishment of orthotopic mouse models of human breast cancer. Whether or not a tumor model requires matrigel is rarely, if ever, discussed, and whether or not matrigel has any confounding effects on the assessment of nanomedicines in these models has not been determined. To this end, the effects of matrigel on the assessment of a potential nanoparticle carrier in an orthotopic model of human breast cancer was evaluated. Bilateral human enhanced green fluorescent protein-expressing MDA435 breast tumors were established in the inguinal mammary fat pads of Nude mice with (left side, M+) or without (right side M-) co-injection of Matrigel. To determine if M- or M+ breast tumors resulted in altered retention of near-infrared emitting solid lipid nanoparticles (SLN), SLN were injected intratumorally and the tumor-retained near-infrared fluorescence was tracked over time. Lymphatic flow was tracked in a caudal-to-rostral direction through the subcutaneous injection of indocyanine green into the tail interstitium lateral to the ventral caudal artery. Tumor and lymph node morphologies were assessed with high frequency ultrasound imaging, and local perfusion of these structures was measured with destruction-replenishment of microbubbles. There was a significant difference in the retention time of SLN within M+ and M- tumors, with the retention of SLN in M- tumors beyond 6 hours but near total SLN clearance from M+ tumors within 2 hours of administration. Anatomical interrogation of the M+ and M- tumor growth with fluorescence imaging revealed occlusion and overgrowth of the inguinal lymph nodes by M+ tumors, whereas M- tumors neither occluded nor overgrew the lymph node, but rather grew in its periphery. Corroboration of these findings was achieved using ultrasound imaging, demonstrating the reduction of lymph node area by the overgrowing M+ tumors that was not seen with M- tumors. M+ and M- tumors also differed physiologically both in lymphatic flow rates and lymph node blood perfusion rates, where the M+ associated lymphatics showed significantly greater lymphatic flow and lymph node perfusion relative to the M- associated lymphatics. The alteration of both anatomical and physiological parameters of lymphatic flow and lymph node perfusion by M+ orthotopic breast tumors relative to M- tumors and the effect of these alterations on the performance (i.e. retention) of nanomedicines warrant scrutiny of the use of matrigel in the establishment of tumor models for nanomedicine evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 554. doi:10.1158/1538-7445.AM2011-554