Application of mesenchymal stem cells as a tumor-targeting carrier of gold nanoparticles in photothermal cancer therapy

Abstract

Cancer is a major health problem and a leading cause of death worldwide. As nanotechnology has made remarkable progress, nanoparticle-based cancer therapies have been extensively studied. Recently, photothermal cancer therapy has emerged as a new strategy for cancer treatment. Among the photothermal agents, gold nanoparticles (AuNPs) have drawn much attention for their application in photothermal therapy because AuNPs exhibit the high light-to-heat conversion efficiency upon near-infrared (NIR) laser irradiation. However, it remains challenging to improve the tumor-targeting efficiency of AuNPs for the effective photothermal treatment. In this thesis, the application of tumor-tropic mesenchymal stem cells (MSCs) as a carrier for tumor-targeted delivery of AuNPs in photothermal therapy are presented. First, pH-sensitive gold nanoparticles (PSAuNPs) were delivered to tumors by internalized in MSCs. Tumor-tropic MSCs can aggregate PSAuNPs in mildly acidic endosomes, target tumors, and be used for photothermal therapy. The aggregated PSAuNPs showed a higher cellular retention by preventing exocytosis compared to pH-insensitive, control AuNPs (cAuNPs), which is important for the cell-based delivery process. PSAuNP-laden MSCs (MSC-PSAuNPs) injected intravenously to tumor-bearing mice showed higher efficiency in tumor-targeting and heat generation compared to injections of cAuNPs after irradiation, which results in a significantly enhanced anti-cancer effect. Second, hybrid sheets composed of AuNPs and graphene oxide (GO) were delivered to tumor tissues by attached to the MSC surface. There are limitations in loading nanoparticles within cells as the internalized nanoparticles cause cytotoxicity and leak out of the cells via exocytosis. Therefore, we introduced AuNP/GO sheets which stably adhere to the cell surface and exhibit remarkable photothermal effect. To form AuNP/GO sheets in which GO is sandwiched between two AuNP monolayers, AuNPs were coated with α-synuclein protein and subsequently adsorbed onto GO sheets. Attaching AuNP/GO sheets to tumor-tropic MSC surface enhanced the loading efficiency of AuNPs in MSCs by avoiding the cytotoxicity and exocytosis issues. Furthermore, the tight packing of AuNPs on micro-scaled GO sheets enhanced the photothermal effect via strong plasmon coupling between AuNPs. The injection of AuNP/GO sheet-attached MSCs into tumor-bearing mice significantly improved the photothermal therapeutic efficacy by delivering larger amounts of AuNPs to the tumor and generating higher heat at tumor region compared to injection of AuNP-internalized MSCs. The cellular Trojan horse strategy may be an effective platform for delivering anti-cancer agents to tumors. Furthermore, therapeutic effect can be maximized through the interaction between materials and cells. This material- and cell-based anti-cancer therapy may be used in the future for successful cancer treatments.