Image-based analysis of the size- and time-dependent penetration of polymeric micelles in multicellular tumor spheroids and tumor xenografts

While the heightened tumor accumulation of systemically administered nanomedicines relative to conventional chemotherapeutic agents has been well established, corresponding improvements in therapeutic efficacy have often been incommensurate. This observation may be attributed to the limited exposure of cancer cells to therapy due to the heterogeneous intratumoral distribution and poor interstitial penetration of nanoparticle-based drug delivery systems. In the present work, the spatio-temporal distribution of block copolymer micelles (BCMs) of different sizes was evaluated in multicellular tumor spheroids (MCTS) and tumor xenografts originating from human cervical (HeLa) and colon (HT29) cancer cells using image-based, computational techniques. Micelle penetration was found to depend on nanoparticle size, time as well as tumor and spheroid cell line. Moreover, spheroids demonstrated the capacity to predict relative trends in nanoparticle interstitial transport in tumor xenografts. Overall, techniques are presented for the assessment of nanoparticle distribution in spheroids and xenografts and used to evaluate the influence of micelle size and cell-line specific tissue properties on micelle interstitial penetration.

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