Heterogeneous Uptake of Nanoparticles in Mouse Models of Pediatric High-Risk Neuroblastoma

Liposomal chemotherapeutics are exemplified by DOXIL® are commonly used in adult cancers. While these agents exhibit improved safety profile compared to their free drug counterparts, their treatment response rates have been ~ 20%, often attributed to the heterogeneous intratumoral uptake and distribution of liposomal nanoparticles. Non-invasive and quantitative monitoring of the uptake and distribution of liposomal nanoparticles in solid tumors could allow for patient stratification and personalized cancer nanomedicine. In this study, the variability of liposomal nanoparticle intratumoral distribution and uptake in orthotopic models of pediatric neuroblastoma was investigated using a liposomal nanoprobe visualized by high-resolution computed tomography (CT). Two human neuroblastoma cell lines (NGP: a MYCN-amplified line, and SH-SY5Y a MYCN non-amplified line) were implanted in the renal capsule of nude mice to establish the model. Intratumoral nanoparticle uptake was measured at tumor ages 1, 2, 3 and 4 weeks post implantation. The locations of uptake within the tumor were mapped in the 3-dimensional reconstructed images. Total uptake was measured by integration of the x-ray absorption signal over the intratumoral uptake locations. Both tumor models showed significant variation in nanoparticle uptake as the tumors aged. Observation of the uptake patterns suggested that the nanoparticle uptake was dominated by vascular leak at the surface/periphery of the tumor, and localized, heterogeneous vascular leak in the interior of the tumor. Slow growing SH-SY5Y tumors demonstrated uptake that correlated directly with the tumor volume. Faster growing NGP tumor uptake did not correlate with any tumor geometric parameters, including tumor volume, tumor surface area, and R30 and R50, measures of uptake localized to the interior of the tumor. However, uptake for both SH-SY5Y and NGP tumors correlated almost perfectly with the leak volume, as measured by CT. These results suggest that the uptake of nanoparticles is heterogeneous and not governed by tumor geometry. An imaging nanoprobe remains the best measure of nanoparticle uptake in these tumor models.