A NIR heptamethine dye with intrinsic cancer targeting, imaging and photosensitizing properties
Introduction
The personalized therapeutic strategy has been considered significantly critical to the success of cancer therapy and the improvement of patients’ survival rates [1], [2]. There is an urgent need for the development of multifunctional theragnostic agents to integrate tumor targeting, real-time monitoring (or imaging), and selective killing activities [3]. Current strategy for achieving simultaneous tumor specific detection and therapeutics is generally explored through the chemical conjugation among functional agents or materials, such as tumor targeted ligands, contrast agents and anti-tumor drugs, etc [4], [5], [6]. Despite the above strategy has demonstrated some efficacy, there is still considerable debate about their delivery, specificity and therapeutic potential [7], [8], [9].
Very recently, we have identified a unique near infrared (NIR) heptamethine indocyanine dye, IR-780, which has preferential tumor accumulation without the need of chemical conjugation to tumor specific ligands [10]. This dye is a lipophilic agent and has been found to selectively retain in the mitochondria of tumor cells but not normal cells in multiple tumor xenografts as well as chemically induced tumors in mice [10]. The fluorescent signal from tumors of this dye can reach a contrast index value over 20, while such a contrast index in a tumor of more than 2.5 was regarded as substantial accumulation [11], suggesting that this dye may represent an attractive agent for tumor targeted imaging.
It has been reported that some of cyanine dyes have photosensitizing characteristics [12], [13], which could be potentially employed in photodynamic therapy (PDT) for cancer patients. For instance, indocyanine green (ICG), a classic cyanine dye approved by FDA almost for over 50 years for evaluating blood flow and clearance, recently has hotly been investigated as a potential photosensitizer by many research groups [14], [15]. However, IR-780 has been reported without photocytotoxic or anti-proliferative activities on tumor cells [12]. So, we hypothesize that certain IR-780 analogs may have tumor photosensitizing activity. To test this hypothesis, we have designed, synthesized and screened a series of IR-780 analogs. Here, we describe the chemical synthesis and biological characterization of an analog, termed as IR-808, which not only possesses tumor targeting and imaging properties, but also has significant photodependent cytotoxic activity.
Section snippets
Chemicals
6-bromohexanoic acid (98%), cyclohexanone (99.8%), 1,2-dichlorobenzene (1,2-C6H4Cl2, 99%) and 2,3,3-trimethyl-3H indole (98%) were purchased from ACROS (via Chemgogo web in China). Except specific mention, all reagents and solvents were used without further purification. Rhodamine 123 (2-(6-Amino-3-imino-3H-xanthen-9-yl) benzoic acid methyl ester) was purchased from Sigma–Aldrich (MO, USA). These dyes were dissolved in dimethylsulfoxide (DMSO) diluted with appropriate vehicles and stored
Chemical synthesis and structure characterization of IR-808
The synthesis of IR-808 was initially described by Chen et al to study the structure and photostability relationship of some heptamethine dyes [16]. Here, we have developed a modified procedure for the chemical synthesis of IR-808 to improve the overall yield for potential large-scale preparation. As shown in Fig. 1, the use of dichloromethane was discarded in the first step which usually was employed as a solvent in literatures [29], [30]. This modification provided homogeneous reaction when
Discussion
Currently, most common strategy for the development of multifunctional agents for cancer targeted imaging and therapy has been employed through multistep chemical conjugation. For example, tumor-homing chitosan-based nanoparticles was labeled with Cy5.5, a near infrared fluorescent dye, and also conjugated with paclitaxel, an anticancer drug, for simultaneously cancer diagnosis and treatment [33]. Recently there has been reported magnetic nanoparticles conjugated with a photosensitizer
Conclusion
In this study, we have identified a near infrared fluorescent heptamethine dye, IR-808, which exhibits intrinsic preferential tumor accumulation and photosensitizing activities without the need of chemical conjugation with tumor specific ligands and photosensitizers. This dye has favorable optical and pharmacokinetic properties, as well as good biocompatibility. In addition, we have also developed a modified procedure for the chemical synthesis of IR-808 to improve the product yield. These
Acknowledgments
This work was supported by National Key Basic Research Development Program (2012CB518103), National Natural Science Foundation Programs of China (81072523 and 81130026), Chongqing Municipal Natural Science Foundation Program (CSTC2009BA5043).
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These authors contributed equally to this work.