Abstract
The endothelial phenotype of tumor blood vessels differs from the liver and forms an important base for endothelium-specific targeting by antibody-coated nanoparticles. Although differences of shear stress and ligand avidity can modulate the nanoparticle binding to endothelium, these mechanisms are still poorly studied. This study analyzed the binding of antibody-coated nanoparticles to tumor and liver endothelium under controlled flow conditions and verified this binding in tumor models in vivo. Binding of anti-CD146-coated nanoparticles, but not of antibody was significantly reduced under increased wall shear stress and the degree of nanoparticle binding correlated with the avidity of the coating. The intravascular wall shear stress favors nanoparticle binding at the site of higher avidity of endothelial epitope which additionally promotes the selectivity to tumor endothelium. After intravenous application in vivo, pegylated self-coated nanoparticles showed specific binding to tumor endothelium, whereas the nanoparticle binding to the liver endothelium was very low. This study provides a rationale that selective binding of mAb-coated nanoparticles to tumor endothelium is achieved by two factors: higher expression of endothelial epitope and higher nanoparticle shearing from liver endothelium. The combination of endothelial marker targeting and the use of shear stress-controlled nanoparticle capture can be used for selective intratumoral drug delivery.
Highlights
IntroductionIn contrast to singlemolecule applications, one nanoparticle can carry a high amount of different imaging or therapeutic substances
Advances in nanotechnology enabled the development of nanoparticles with specific functional properties that address the shortcoming of traditional diagnostic and therapeutic agents
This study investigates the interrelationship of three individual factors: shear stress, avidity of endothelial epitope and nanoparticle coating, and their influence on nanoparticle binding to tumor endothelium in vitro and in vivo
Summary
In contrast to singlemolecule applications, one nanoparticle can carry a high amount of different imaging or therapeutic substances Nanoparticle therapeutics such as immunoliposomal drugs and magnetic nanocarriers represent a rapid developing area in cancer therapy and some successful efforts in their clinical application have been achieved. Immunoliposomal doxorubicin formulation is clinically approved and used in treatment of different human cancer types [1, 2] Superparamagnetic nanoparticles represent another class of nanoparticles that have been developed for diagnostic aims. These nanoparticles have been initially used only for magnetic imaging via passive tumor targeting, but recent advances have opened new opportunities for tumor-specific targeting and drug delivery [3]. The additional coating of nanoparticles with tumor-specifc mAb increases specific drug delivery into the tumor [4]
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