Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer

Abstract

Background: Improvements in drug delivery to brain metastases are needed. We hypothesized that albumin transcytosis would demonstrate widespread distribution in experimental brain metastases of breast cancer. Methods: The metastatic and uninvolved brain localization of five transcytotic pathways was determined in two hematogenous models of breast cancer brain metastasis. Albumin was compared to distribution of a Biocytin-TMR, which uses paracellular permeability. An in vitro model for transcytosis of albumin across a blood-tumor barrier (BTB) was developed and characterized for modes of endocytosis. Human craniotomy specimens were stained for endocytic proteins. Results: Albumin transcytosis occurred in virtually all metastases, including micrometastases; distribution was greater than, and independent of paracellular permeability. Albumin uptake into the normal brain parenchyma was negligible. Using an in vitro assay that permits albumin transcytosis through a BTB, albumin used a form of macropinocytosis with features of clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor (FcRn), Galectin-3 and membrane sphingolipids. Human craniotomy specimens demonstrated FcRn and Galectin-3 staining. Conclusions: The data identify CIE as a pathway with optimal features for drug delivery into brain metastases.