Enhanced Delivery of Thermoresponsive Polymer-Based Medicine into Tumors by Using Heat Produced from Gold Nanorods Irradiated with Near-Infrared Light.

Abstract

Simple SummaryTo establish a therapy targeting scattered tumors throughout the body, we propose a novel drug delivery system using a thermoresponsive polyoxazoline (POZ) as a drug carrier in combination with gold nanorods (GNR), which produce heat when irradiated with near-infrared (NIR) light. After the tumor was irradiated with NIR light, where GNR was accumulated in advance, the radiolabeled POZ was intravenously injected. As a result, a marked tumor uptake was achieved via self-aggregation of POZ by sensing heat yielded from the GNR. Because the POZ would be chemically modified with various anti-tumor drugs including therapeutic radionuclides, remarkable anti-tumor effects can be expected by enhancing delivery of POZ-based medicine into scattered tumors throughout the body.The aim of this study was to establish a drug delivery system (DDS) for marked therapy of tumors using a thermoresponsive polymer, polyoxazoline (POZ). The effectiveness of the following was investigated: (i) the delivery of gold nanorods (GNRs) to tumor tissues, (ii) heat production of GNR upon irradiation with near-infrared (NIR) light, and (iii) high accumulation of an intravenously injected radiolabeled POZ as a drug carrier in tumors by sensing heat produced by GNRs. When the GNR solution was irradiated with NIR light (808 nm), the solution temperature was increased both in a GNR-concentration-dependent manner and in a light-dose-dependent manner. POZ, with a lower critical solution temperature of 38 °C, was aggregated depending on the heat produced by the GNR irradiated by NIR light. When it was intratumorally pre-injected into colon26-tumor-bearing mice, followed by NIR light irradiation (GNR+/Light+ group), the tumor surface temperature increased to approximately 42 °C within 5 min. Fifteen minutes after irradiation with NIR light, indium-111 (111In)-labeled POZ was intravenously injected into tumor-bearing mice, and the radioactivity distribution was evaluated. The accumulation of POZ in the tumor was significantly (approximately 4-fold) higher than that in the control groups (GNR+/without NIR light irradiation (Light–), without injection of GNR (GNR–)/Light+, and GNR–/Light– groups). Furthermore, an in vivo confocal fluorescence microscopy study, using fluorescence-labeled POZ, revealed that uptake of POZ by the tumor could be attributed to the heat produced by GNR. In conclusion, we successfully established a novel DDS in which POZ could be efficiently delivered into tumors by using the heat produced by GNR irradiated with NIR light.