Figure 2.

(A) Summary of the proposed mechanisms of the tumor-specific accumulation of HMCD-drug derivatives from the circulation. HMCDs travel through the circulation as unbound or albumin-bound molecules toward the bulk tumor through the EPR effect. HMCDs may exist as covalently or non-covalently bound to albumin in the plasma, or as free molecules. (B) Describes the proposed mechanism of uptake of HMCD-drug conjugates into tumor cells. Albumin-bound HMCDs bind to caveloin-1 associated Gp60 receptors, triggering caveolae-mediated transcytosis across the endothelium, which is then deposited in the tumor interstitium. The unbound HMCDs are transferred across the endothelium through the polarized expression of OATPs. SPARC is secreted from the tumor cells into the interstitium and entraps albumin and albumin-bound HMCD, which is likely taken up through SPARC or albumin-triggered endocytosis or macropinocytosis. Albumin-bound HMCDs are internalized by the tumor through caveolae-mediated endocytosis, but rather than being transcytosed, caveolae fuse with lysosomes, resulting in lytic degradation of albumin and the subsequent release of the HMCDs. OATP also play a role in the uptake of free HMCD from the tumor interstitium.