MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle

Abstract

In oncological research, there is a great need for imaging techniques that specifically identify angiogenic blood vessels in tumors on the basis of differences in the expression level of biomolecular markers. In the angiogenic cascade, different cell surface receptors, including the alphavbeta3-integrin, are strongly expressed on activated endothelial cells. In the present study, we aimed to image angiogenesis by detecting the expression of alphavbeta3 in tumor bearing mice with a combination of magnetic resonance imaging (MRI) and fluorescence microscopy. To that end, we prepared MR-detectable and fluorescent liposomes, which carry approximately 700 alphavbeta3-specific RGD peptides per liposome. RGD competition experiments and RAD-conjugated liposomes were used as controls for specificity. In vivo, both RAD liposomes and RGD liposomes gave rise to signal increase on T1-weighted MR images. It was established by the use of ex vivo fluorescence microscopy that RGD liposomes and RAD liposomes accumulated in the tumor by different mechanisms. RGD liposomes were specifically associated with activated tumor endothelium, while RAD liposomes were located in the extravascular compartment. This study demonstrates that MR molecular imaging of angiogenesis is feasible by using a targeted contrast agent specific for the alphavbeta3-integrin, and that the multimodality imaging approach gave insight into the exact mechanism of accumulation in the tumor.

cNGR: A Novel Homing Sequence for CD13/APN Targeted Molecular Imaging of Murine Cardiac Angiogenesis In Vivo

“…Conjugating QDs to gadolinium renders them useful in magnetic resonance imaging. 20 Hence, we show that QD decorated with peptide homing sequences are a useful tool for obtaining proof of principle targeted optical imaging. In the near future cNGR-binding to angiogenic vessels might be shown noninvasively by conjugating cNGR to either radioprobes or paramagnetic particles such as gadolinium.…”

“…Several studies in different angiogenic vascular beds have been performed using an RGD conjugated contrast agent. Both radiolabeled RGD in a canine MI model 19 and magnetic resonance-focused paramagnetic-tagged RGD in a mouse tumor model 20 have been used to image neovascularization noninvasively in vivo.…”

Enhanced tumor MR imaging with gadolinium‐loaded polychelating polymer‐containing tumor‐targeted liposomes

“…However, the longevity of these liposomes alone makes such agents more suitable for blood pool imaging (7). Previous attempts to target contrast liposomes to tumors for enhanced imaging through the use of targeting moieties include antibodies against the transferrin receptor (13) or RGD peptides (14). Although promising data have been obtained, these approaches are restricted only to those tumors that overexpress the transferrin receptor (15), or only to tumor endothelium since the RGD peptide specifically binds endothelial integrins (16).…”

Prevention of Contrast Medium Induced Nephropathy by Liposome Encapsulation

“…2) Surface modification of liposome with active targeting agents (antibody……etc.) can increase the tumor enhancement of encapsulated CM, such as overcoming the low relaxivity by higher accumulation for MRI [18], or with cell-targeted markers can aid visualization of pathological process [19]. 3) High capacity of payload encapsulation and high flexibility of formula or surface modification allow CM included liposome to evolve as multi-model tools for both diagnosis and therapy [19]- [21].…”

“…can increase the tumor enhancement of encapsulated CM, such as overcoming the low relaxivity by higher accumulation for MRI [18], or with cell-targeted markers can aid visualization of pathological process [19]. 3) High capacity of payload encapsulation and high flexibility of formula or surface modification allow CM included liposome to evolve as multi-model tools for both diagnosis and therapy [19]- [21]. 4) The extending circulation lifetime of liposome in vivo allows incorporated CM for prolonged tumor enhancement or revelation of pathological index [21], [22].…”