Effect of an Endothelin B Receptor Agonist on the Tumor Accumulation of Nanocarriers.

Enhancing blood flow to tumors is a prominent strategy for improving the tumor accumulation of macromolecular drugs through the enhanced permeability and retention (EPR) effect. IRL-1620 is an agonist of the endothelin B receptor, and is a promising molecule to enhance tumor blood flow by activating endothelial nitric oxide synthase. However, contradictory effects on tumor blood flow modulation have been reported because the effects of IRL-1620 may differ in different animal models. Here, we examined for the first time the effect of IRL-1620 on the EPR effect for PEGylated liposomes in a CT-26 murine colon cancer model. Co-injection of IRL-1620 at an optimum dose (3 nmol/kg) nearly doubled the tumor accumulation of liposomes compared with controls, indicating that IRL-1620 enhanced the EPR effect in the present colon cancer model. Co-injection of IRL-1620 is a promising strategy to improve the therapeutic effects of macromolecular drugs while reducing their side effects.

Evoking Photothermy by Capturing Intramolecular Bond Stretching Vibration-Induced Dark-State Energy.

Development of highly effective approaches to desirable photothermal conversion agents is particularly valuable. Herein, we report a concept, namely, bond stretching vibration-induced photothermy, that serves as a mechanism to construct advanced photothermal conversion agents. As a proof-of-concept, two compounds (DCP-TPA and DCP-PTPA) with donor-acceptor (D-A) structures were synthesized. The bond stretching vibration of the pyrazine-containing unit in these molecules is vigorous and insensitive to the external environmental restraint, which efficiently transforms the absorbed photons to dark-state heat energy. The nanoparticles (NPs) of DCP-TPA and DCP-PTPA show rather high photothermal conversion efficiency (52% and 59%) and stronger photoacoustic (PA) signal than commercial methylene blue and reported high-performance semiconducting polymer nanoparticles. The DCP-PTPA NPs perform better than DCP-TPA NPs in terms of photothermal conversion, PA signal production, and in vivo PA tumor imaging because of the increased bond stretching vibration in the former molecule.

Rapid and continuous accumulation of nitric oxide-releasing liposomes in tumors to augment the enhanced permeability and retention (EPR) effect.

The modulation of blood flow to tumors is a prominent strategy for improving the tumor accumulation of nanomedicines, resulting from the enhanced permeability and retention (EPR) effect. We previously reported a promising EPR enhancer-a nitric oxide (NO) donor-containing liposome (NO-LP)-which showed enhanced accumulation in tumor tissue. Herein, we study NO-LP in greater detail to clarify its practical use as an EPR enhancer. NO-LP was found to have advantages as a NO donor, including the ability to maintain NO donation over long periods of time, and a constant rate of NO-release irrespective of the environmental pH. NO-LP showed rapid accumulation in tumor tissue after injection (1 h), and then accumulation was continuously enhanced until 48 h. Enhanced NO-LP accumulation was observed specifically in tumor, while the accumulation in other organs remained relatively unchanged. The results obtained show the promising features of NO-LP as an EPR enhancer.