Diffusive Flux Analysis of Tumor Vascular Permeability for 3-Helix-Micelles in Comparison to Other Nanoparticles

Abstract

Understanding the complex interplay of factors affecting nanoparticle accumulation in solid tumors is a challenge that must be surmounted to develop effective cancer nanomedicine. The tumor microenvironment is unique in comparison to healthy tissue, possessing elevated interstitial pressure that limits convective transport, hence leaving diffusive processes to predominate especially in the tumors necrotic core. Certain tumor types such as glioblastoma multiforme and pancreatic tumor are known to be poorly permeable, making them less accessible for nanoparticle drug delivery. Evidence indicates that small and long-circulating nanoparticles are ideal for taking advantage of the enhanced permeability and retention effect, even in such intractable tumor models. Three-helix-micelle (3HM) self-assembled nanoparticles possess these characteristics, and previous studies have shown that 3HM can achieve more favorable tumor accumulation and penetration than liposomes in several tumor models. The reason for its superior performance had yet to be determined, and thus we sought to examine its passive transport into tumors. In this paper we present a simple mathematical model based on diffusive flux to describe particle accumulation in tumors with respect to particle plasma pharmacokinetics. Fitting the diffusive flux equation to in vivo particle tumor concentration yields the particle effective permeability value, which for 3HM is 2.31 {+/-} 0.18 x 10-8 cm/s in U87MG glioblastoma and 4.25 {+/-} 0.91 x 10-8 cm/s in HT29 colon cancer murine models. Applying this diffusive flux model to other nanoparticles reported in literature enables the effect of plasma half-life to be decoupled from particle permeability in influencing tumor accumulation, reinforced trends reported in the field regarding the impact of particle size, and provided a semi-quantitative means of comparing various tumor models. This work is also the first demonstration, to the best our knowledge, of extracting particle permeability values from bulk biodistribution data obtained via positron emission tomography, as opposed to laborious tumor optical window intravital microscopy experiments. As such the analysis provided here presents a simple and accessible tool to further enhance nanomedicine development.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC=\"FIGDIR/small/708263v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (26K):\norg.highwire.dtl.DTLVardef@5981e5org.highwire.dtl.DTLVardef@5ef928org.highwire.dtl.DTLVardef@137edceorg.highwire.dtl.DTLVardef@dd9b17_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG