Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation.

ABSTRACT

Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-ß inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-ß inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-ß inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-ß inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms.