Responsive alginate-cisplatin nanogels for selective imaging and combined chemo/radio therapy of proliferating macrophages

Abstract

Atherosclerosis is a major global health concern. Targeting macrophages is hypothesized as an alternative treatment for atherosclerosis. We synthesized alginate-based cisplatin-loaded nanogels (TANgel) as a pH-responsive drug-releasing theranostic nanoplatform for macrophage cells. Carboxylic acid groups of alginic acid were modified with iminodiacetic acid (IDA) to enhance chelation of platinum ions. The near infrared (NIR) fluorophore ATTO655 was conjugated to the modified alginic acid. Cisplatin was used as an antiproliferation drug and as a crosslinking agent between alginate molecules to form TANgel. Release behavior of cisplatin from TANgel was analyzed under different pH conditions. Cellular uptake and therapeutic efficacy of TANgel were tested in the macrophage cell line J774A.1 and normal human cell lines such as HDMVECn. The nanogel had a narrow size distribution of approximately 100 nm. The nanogel showed highly pH-responsive drug release behavior. All incorporated cisplatin was released at pH 5 within 48 h, while less than 15% was released at pH 7.4. The nanogel was preferentially taken up by J774A.1 cells compared to normal human cells, enabling selective NIR fluorescence imaging and chemotherapy of macrophage cells. In addition, the nanogel formulation lowered the therapeutic concentration of the drug with and without low dose radiation therapy (RT) compared to the free drug form. This nanogel system may have potential utility for selective NIR fluorescence imaging and combined chemo/radio therapy of proliferating macrophage cells in atherosclerotic regions, allowing for reduction of systemic toxicity.