Multimodal In Vivo Imaging Exposes the Voyage of Nanoparticles in Tumor Microcirculation

Abstract

Tumors present numerous biobarriers to the successful delivery of nanoparticles. Decreased blood flows and high interstitial pressures in tumors dictate the degree of resistance to extravasation of nanoparticles. To understand how a nanoparticle can overcome these biobarriers, we developed a multimodal in vivo imaging methodology, which enabled the non-invasive measurement of microvascular parameters and deposition of nanoparticles at the microscopic scale. To monitor the spatiotemporal progression of tumor vasculature and its vascular permeability to nanoparticles at the microcapillary level, we developed a quantitative in vivo imaging method using an iodinated liposomal contrast agent and a micro-CT. Following perfusion CT for quantitative assessment of blood flow, small animal fluorescence molecular tomography was used to image the in vivo fate of cocktails containing liposomes of different sizes labeled with different NIR fluorophores. The animal studies showed that the deposition of liposomes depended on local blood flow. Considering tumor regions of different blood flow, the deposition of liposomes followed a size-dependent pattern. In general, the larger liposomes effectively extravasated in fast flow regions, while smaller liposomes performed better in slow flow regions. We also evaluated whether the tumor retention of nanoparticles is dictated by targeting them to a receptor overexpressed by the cancer cells. Targeting of 100-nm liposomes showed no benefits at any flow rate. However, active targeting of 30-nm liposomes substantially increased their deposition in slow flow tumor regions (~12-fold increase), which suggested that targeting prevented the washout of the smaller nanoparticles from the tumor interstitium back to blood circulation.

Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts

“…In addition to differences in total uptake, early variations in intratumoral localization were clearly visible and were probably caused by perfusion differences (24,25). For example, MDA-MB-231 showed a clear uptake in certain regions of the tumor periphery, whereas other regions remained clear.…”

Targeted nanotechnology for cancer imaging

“…Another study found that a nanoparticle’s size dictates the extent to which blood flow affects its transport. A threefold increase in blood flow resulted in a 100-fold elevated intratumoral deposition of PEGylated liposomes with a hydrodynamic diameter of 100 nm [30] (Fig. 3).…”

“…While nanoparticle CT agents are excellent blood pool agents [30, 154], the development of targeted CT probes has been limited due to the low contrast sensitivity of the X-ray imaging technique. The majority of targeted CT probe development has been pursued using metal-based nanoparticles due to their high atomic weight and therefore increased X-ray attenuation compared to the conventional iodine moiety.…”

Online open-tubular fractionation scheme coupled with push–pull perfusion sampling for profiling extravasation of gold nanoparticles in a mouse tumor model

“…It has been reported that NMs having HDs in the sub-100-nm range possess higher tendency toward extravasating into tissue extracellular space [8,16,[45][46][47][48][49] by virtue of their sizes matching those of the pores on the vascular wall and as a result of microvascular permeability [13]. When administered AuNPs in the blood stream are extravasated into tumor extracellular space, endocytosis and clearance of the extracellular AuNPs in the tumor extracellular space would be initiated.…”