Enhanced Antimetastatic Activity of the Ruthenium Anticancer Drug RAPTA‐C Delivered in Fructose‐Coated Micelles

Abstract

(HER-2) has been utilized as a targeting site for the Trastuzumab drug delivery system. Trastuzumab is a humanized monoclonal antibody and has been widely used for HER2-positive metastatic breast cancer. [2] In the case of triplenegative breast cancer, [3] which is lacking the expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER-2/neu), other targeting mechanism are sought after. Interestingly, an overexpression of fructose transporter GLUT5 could be observed in cell lines such as MCF-7 and MDA-MB-231. [4] Glucose transporters (GLUTs) are transmembrane proteins, which participate in the cellular uptake of carbohydrates in order to provide energy for cellular metabolism. [5] This possible targeting mechanism has been investigated by Zhang et al. who have successfully applied fructose pendants on phosphorescent metal complexes to increase the cellular uptakes of the complexes. [6] The ruthenium complex-dichlororuthenium (II) (p-cymene) (1,3,5-triaza-7-phosphaadamantane) (RAPTA-C)-has shown to be remarkably effective at suppressing the growth of solid tumor metastases. However, poor delivery efficacy and the lack of targeting ability of the common drug delivery system pose significant obstacles to maximize the therapeutic benefit of RAPTA-C. Inspired by the overexpression of GLUT5 transporter on the surface of breast cancer tissues but not the healthy mammary tissues, the use of d-fructose as the targeting moiety of the drug carrier can significantly improve the cellular uptake of nanoparticles, thus further enhancing the therapeutic efficiency of RAPTA-C. In this work, fructose-micelles and 2-hydroxyethyl acrylate (HEA)-micelles are prepared to investigate the difference in cellular uptake. It is found that glycopolymer leads to an increased uptake by breast cancer cells, while the HEA-micelles show less uptake. This behavior is also reflected by the slightly faster movement of fructose-coated micelles in MCF-7 tumor spheroid models using light sheet microscopy as analytical tool. The incorporation of RAPTA-C into micelles can enhance the inhibitory effect of the ruthenium drug demonstrated using invasion, chemotaxis, and haptotaxis assays. As a result, fructose-coated nanoparticles can be a promising drug delivery platform of RAPTA-C for the treatment of metastatic breast cancer.

Recent advances in metallopolymer-based drug delivery systems

“…It should also be noted the use of polymer micelles for the delivery of Pt(II) and Ru(II) complexes to cancer cells. 140 Palladium catalysts were used to catalyze intracellular reactions by uncaging various model prodrugs, including the doxorubicin (DOX) prodrug (pro-DOX), for the effective tumor treatment in vivo. 141 The Pd(II) catalysts were encapsulated in the micellar core of diblock amphiphilic copolymers poly(lactic acid-co-glycolic acid) (PLGA)-PEG, which were intravenously delivered to various tumor cell models using the enhanced permeability and retention (EPR) effect.…”

From Polymers to Functional Biomaterials

“…Next, Martina Stenzel and co‐workers report the application of fructose‐coated micelles to overcome the poor delivery efficiency of the ruthenium complex dichlororuthenium (II) p ‐cymene (1,3,5‐triaza‐7‐phosphaadamantane) in tumor spheroid models and invasion assays. The reported results demonstrate the potential of polymeric micelles to enhance bioavailability of poorly soluble drugs and underline the role of carbohydrates for enhancing cellular uptake …”

Sialic acid-binding lectin-modified fructose-coated nanoparticles: a promising targeted therapeutic synthetic for breast cancers

“…5 Recently, glycopolymer-coated nanoparticles have attracted great interest due to the specific binding between them and carbohydrate receptors located on the cancer cell surface, suggesting that these synthetics are potential to deliver agents into tumor cells in a targeted way [13]. Several studies have addressed that the intake of FCN can be substantially observed in tumor cells but rarely in healthy cells [13,41], which is correlated to the overexpressed GLUT5 found on the surface of tumor cells [42,43]. Of note, nanoparticles that are coated with hydrophilic shell manufactured by long polymer chains with high fructose density have great affinity to tumor cells [14].…”