Evaluation of therapeutics in two mice models yields different response based on the tumor architecture

Despite the phenomenon of Enhanced Permeability and Retention (EPR) effect that led to major investments and research in the field of nanomedicine, there have been few nanoparticles that saw therapeutic success in clinical settings. The difference in outcomes in different patients has been assigned to the absence of EPR effect in some patients or tumor types. In our current work, we developed robust mice 3D spheroid model by implantation of pre-formed mini-tumors in contrast to the routinely used 2D model wherein single cells are injected en masse. The two models differ characteristically with respect to blood vasculature (CD31+) and carcinoma associated fibroblasts (alpha Smooth Muscle Actin+) cells and the ensuing tumor microenvironment (TME) dynamics. Representatives of drug, nanoparticle and an antibody- Doxorubicin, Doxil and Avastin, were tested in the two tumor models, either alone or in combination. Overall, Doxorubicin seemed to show more anti-tumor effects in 2D model (2 fold smaller tumors than non-treated); Doxil showed promising results both with or without Avastin (~5 & 10 times smaller tumor than non-treated) in 3D spheroid model whereas in 2D model, Doxil worked only when administered with Avastin (~2 fold smaller than non-treated). This study gives an insight into the role of tumor histopathology and supporting non-cancer cells of TME in deciding the fate of the nanocarriers. Evidently, testing on relevant tumor models and patient stratification prior to clinical testings will warranty superior outcomes.