Advances in drug treatments for
brain metastases of
breast cancer have improved progression-free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate
brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic
metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access:
transferrin receptor (TfR)
peptide,
low-density lipoprotein receptor 1 (LRP1)
peptide,
albumin. Each was far-red labeled, injected into two hematogenous models of
brain metastases, circulated for two different times, and their uptake quantified in
metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in
metastases, while LRP1 was poorly distributed.
Albumin distributed to virtually all
metastases in both model systems, significantly greater than in uninvolved brain (P < 0.0001). Further experiments revealed that
albumin entered both macrometastases and
micrometastases, the targets of treatment and prevention translational strategies.
Albumin uptake into
brain metastases was not correlated with the uptake of a paracellular probe (
biocytin). We identified a novel mechanism of
albumin endocytosis through the endothelia of
brain metastases consistent with
clathrin-independent endocytosis (CIE), involving the
neonatal Fc receptor,
galectin-3, and
glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human
craniotomies. The data suggest a reconsideration of
albumin as a translational mechanism for improved drug delivery to
brain metastases and possibly other central nervous system (CNS)
cancers.In conclusion,
drug therapy for brain
metastasis needs improvement. We surveyed three transcytotic pathways as potential delivery systems in brain-tropic models and found that
albumin has optimal properties.
Albumin used a novel endocytic mechanism.