Abstract
Rhodamine derivatives have been widely investigated for their mitochondrial targeting and chemotherapeutic properties that result from their lipophilic cationic structures. In previous research, we have found that conversion of Rhodamine 6G into nanoGUMBOS, i.e., nanomaterials derived from a group of uniform materials based on organic salts (GUMBOS), led to selective chemotherapeutic toxicity for cancer cells over normal cells. Herein, we investigate the chemotherapeutic activity of GUMBOS derived from four different rhodamine derivatives, two bearing an ester group, i.e., Rhodamine 123 (R123) and SNAFR-5, and two bearing a carboxylic acid group, i.e., rhodamine 110 (R110) and rhodamine B (RB). In this study, we evaluate (1) relative hydrophobicity via octanol–water partition coefficients, (2) cytotoxicity, and (3) cellular uptake in order to evaluate possible structure–activity relationships between these different compounds. Intriguingly, we found that while GUMBOS derived from R123 and SNAFR-5 formed nanoGUMBOS in aqueous medium, no distinct nanoparticles are observed for RB and R110 GUMBOS. Further investigation revealed that the relatively high water solubility of R110 and RB GUMBOS hinders nanoparticle formation. Subsequently, while R123 and SNAFR-5 displayed selective chemotherapeutic toxicity similar to that of previously investigated R6G nanoGUMBOS, the R110 and RB GUMBOS were lacking in this property. Additionally, the chemotherapeutic toxicities of R123 and SNAFR-5 nanoGUMBOS were also significantly greater than R110 and RB GUMBOS. Observed results were consistent with decreased cellular uptake of R110 and RB as compared to R123 and SNAFR-5 compounds. Moreover, these results are also consistent with previous observations that suggest that nanoparticle formation is critical to the observed selective chemotherapeutic properties as well as the chemotherapeutic efficacy of rhodamine nanoGUMBOS.
Highlights
Lipophilic rhodamine derivatives have been widely investigated for chemotherapeutic applications due to their hydrophobic structures and cationic properties [1,2,3]
In order to understand the role of cation structure of rhodamine derivatives on selective chemotherapeutic toxicity, our studies reported here provide data for evaluation and comparison of therapeutic properties for GUMBOS derived from two ester derivatives, rhodamines (R123 and SNAFR-5) [32], and two zwitterion rhodamines (R110 and rhodamine B (RB))
While both parent dyes [Rhodamine 123 (R123)][Cl] and [SNAFR-5][OH] had slight toxicity towards normal cells, nanoGUMBOS from of these compounds led to selective toxicity toward cancer cells for these dyes under the conditions investigated
Summary
Lipophilic rhodamine derivatives have been widely investigated for chemotherapeutic applications due to their hydrophobic structures and cationic properties [1,2,3]. While cationic dyes such as R123 serve as strong imaging agents for mitochondria and mitochondria-targeting therapeutic agents, the zwitterion structures of RB and R110 reduce use for imaging and chemotherapeutic applications Nanocarrier systems such as liposomes, polymers, and micelles have been investigated as intracellular delivery systems for enhancing internalization of hydrophobic drugs [19,20,21,22]. In order to understand the role of cation structure of rhodamine derivatives on selective chemotherapeutic toxicity, our studies reported here provide data for evaluation and comparison of therapeutic properties for GUMBOS derived from two ester derivatives, rhodamines (R123 and SNAFR-5) [32], and two zwitterion rhodamines (R110 and RB) Relative hydrophobicities of these GUMBOS were characterized using octanol–water partition coefficients. These studies provide further insight into an approach for rapid synthesis of selective nanomaterials for direct use as cationic drugs to minimize systemic toxicity
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