RESUMO
In this study, we developed an extremely small-sized water-soluble hyaluronate dot (dHA) conjugated with cyclic RGD (cRGD) and cleavable doxorubicin (DOX, as a model antitumor drug), named cRGD@dHA-c-DOX. This dot with HA moieties (as specific ligands to tumor CD44 receptors) and cRGD moieties (as specific ligands to tumor integrin αvß3) was designed to enable multivalent tumor targeting. In particular, the imine bonds, linking the DOX and dHA, can exhibit cleavage performance at endosomal pH, resulting in pH-triggered DOX release from cRGD@dHA-c-DOX. We demonstrated that cRGD@dHA-c-DOX resulted in highly improved cellular uptake and cell death in MDA-MB-231 tumor cells (CD44+, integrin αvß3+) compared to those in Huh7 tumor cells (CD44-, integrin αvß3-). In vivo studies using MDA-MB-231 tumor-bearing mice revealed that cRGD@dHA-c-DOX enhanced the tumor inhibition efficacy. These results suggest that cRGD@dHA-c-DOX can be utilized as a promising multivalent tumor-targeting drug carrier for highly efficient tumor treatment.
Assuntos
Antineoplásicos , Doxorrubicina , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Camundongos , Peptídeos CíclicosRESUMO
We report here the use of near-infrared fluorescent dye-labelled hyaluronate (HA) dot named HDFc for tumor imaging. We took advantage of the unique auto-quenching characteristic that occurs when the fluorescent dye molecules are in close proximity to one another under ordinary conditions. However, when the HDFc is located in tumor cells, the tumor cell-specific enzyme (e.g., hyaluronidase: HAase) affects the structure of the HDFc, followed by the transition from auto-quenched dye molecules to dequenched dye molecules, resulting in the identification of the tumor cells. For this purpose, HDFcs were synthesized, characterized, and exogenously treated with HAase to demonstrate the enzyme-dependent HDFc photoactivity. Specifically, confocal microscopy and flow cytometry confirmed the efficient cellular internalization and fluorescence production of HDFc in CD44+ and HAase-abundant tumor cells. Collectively, this study opens the door for utilizing polymeric dots to visualize tumor cells by introducing biocompatible HA and tumor cell-on photoluminescent dye.
Assuntos
Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Imagem Óptica/métodos , Endocitose , Humanos , Hialuronoglucosaminidase/metabolismo , Células MCF-7RESUMO
pH-Responsive drug vehicles targeting the specific extracellular pH of tumors have served as potent tools to overcome the limitation (e.g., low tumor seletivity) in antitumor drug delivery system. Here, we describe the advantage of pH-responsive extracellular vesicles (HDEA@EVs) containing the hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA) and a model antitumor drug, doxorubicin (DOX). We demonstrated their physicochemical characteristics through in vitro cell endocytosis, in vitro tumor cell toxicity, in vivo biodistribution, and in vivo tumor regression efficacy experiments. Because the HDEA@EVs efficiently responded to extracellular tumor pH (pH 6.5) and actively bound to CD44 receptors on HCT-116 tumor cells, the EVs selectively inhibited CD44+ tumor cell growth in vitro, and CD44+ tumor development in vivo. From these results, we conclude that HDEA@EVs can help in designing effective strategies for pharmacologic intervention in tumor therapy.