Abstract
Background: In the past decade, researchers have focused on developing new biomaterials for cancer therapy that combine imaging and therapeutic agents. In our study, we use a new biocompatible and biodegradable polymer, termed poly(glycerol malate co-dodecanedioate) (PGMD), for the synthesis of nanoparticles (NPs) and loading of near-infrared (NIR) dyes. IR820 was chosen for the purpose of imaging and hyperthermia (HT). HT is currently used in clinical trials for cancer therapy in combination with radiotherapy and chemotherapy. One of the potential problems of HT is that it can up-regulate hypoxia-inducible factor-1 (HIF-1) expression and enhance vascular endothelial growth factor (VEGF) secretion.Results: We explored cellular response after rapid, short-term and low thermal dose laser-IR820-PGMD NPs (laser/NPs) induced-heating, and compared it to slow, long-term and high thermal dose heating by a cell incubator. The expression levels of the reactive oxygen species (ROS), HIF-1 and VEGF following the two different modes of heating. The cytotoxicity of NPs after laser/NP HT resulted in higher cell killing compared to incubator HT. The ROS level was highly elevated under incubator HT, but remained at the baseline level under the laser/NP HT. Our results show that elevated ROS expression inside the cells could result in the promotion of HIF-1 expression after incubator induced-HT. The VEGF secretion was also significantly enhanced compared to laser/NP HT, possibly due to the promotion of HIF-1. In vitro cell imaging and in vivo healthy mice imaging showed that IR820-PGMD NPs can be used for optical imaging.Conclusion: IR820-PGMD NPs were developed and used for both imaging and therapy purposes. Rapid and short-term laser/NP HT, with a low thermal dose, does not up-regulate HIF-1 and VEGF expression, whereas slow and long term incubator HT, with a high thermal dose, enhances the expression of both transcription factors.
Highlights
The synthesis and development of novel polymers and their use for nanoparticle (NP) synthesis has been an important focus of materials science research in the past decade
Our previous study investigated the effect of HT on cancer cells in a thermal dose-dependent manner, and the results showed that heat shock protein 70 (HSP70) was inhibited by indocyanine green (ICG)-induced rapid heating after exposure to laser, so that the thermal protective mechanism of the cells was not initiated [23]
The shape and size of IR820-poly(glycerol malate co-dodecanedioate) (PGMD) NPs were confirmed with scanning electron microscopy (SEM) imaging
Summary
The synthesis and development of novel polymers and their use for nanoparticle (NP) synthesis has been an important focus of materials science research in the past decade. An additional advantage of NPs is that they are passively targeted to tumor sites because of the enhanced permeability and retention (EPR) effect This effect occurs as a result of a combination of factors, including increased pore sizes of tumor vasculature, fast tumor angiogenesis from increased secretion of vascular endothelial growth factor (VEGF), and poor lymphatic clearance from tumor sites [4]. Because of these advantages, we synthesized a new formulation of polymeric NPs for image-guided therapy based on the polymer poly(glycerol malate co-dodecanedioate) (PGMD) developed in our lab. One of the potential problems of HT is that it can up-regulate hypoxia-inducible factor-1 (HIF-1) expression and enhance vascular endothelial growth factor (VEGF) secretion
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