Biocompatible Fe³⁺–TA coordination complex with high photothermal conversion efficiency for ablation of cancer cells

Highlights

• Fe³⁺–TA complex was synthesized rapidly by a one-step method with natural reagents.

• Fe³⁺–TA complex exhibited a photothermal conversion efficiency as high as 77.3%.

• Fe³⁺–TA complex showed excellent photothermal stability and ultralow cytotoxicity.

• The photothermal ablation efficacy of Fe³⁺–TA is adequate to photothermal therapy.

Abstract

Near-infrared (NIR) light absorbing nanomaterials, which can convert light to heat energy, have great prospects in biomedical applications. In the current work, Fe³⁺–TA (Tannic Acid) coordination complex formed by simple mixing of tannic acid and FeCl₃ solutions was explored as a novel photothermal agent. Due to the strong absorbance in the near-infrared region induced by the coordination effect between TA molecule and Fe³⁺ ion, the as-prepared Fe³⁺–TA complex exhibited excellent photothermal performance with high photothermal conversion efficiency of 77.3% and high photothermal stability. Upon the exposure to Fe³⁺–TA aqueous dispersions with a concentration of 0.125 mg/mL, the cell mortality of HeLa cells was more than 85% after being irradiated for 10 min under NIR light (808 nm, 6 W cm⁻²). Besides, the Fe³⁺–TA complex exhibited ultralow cytotoxicity since only biocompatible tannic acid and iron ions were used as raw materials. Therefore, the merits of simple and convenient fabrication method, high photothermal conversion efficiency and excellent biocompatibility endow the high potential of Fe³⁺–TA complex as a photothermal agent for biomedical applications.

Introduction

The current clinical cancer treatments include surgical resection, chemotherapy, radiotherapy and their combinations. However, surgical resection cannot completely remove tumors and is limited to highly accessible tissues. In addition, chemotherapy and radiotherapy can also bring severe side effects to patients, due to the insufficient selectivity of drugs or radiation applied during the therapy process [1,2]. Thermal therapy based on the electromagnetic technology has been developed since the 1990s [3,4]. According to the temperature range and time requirements, thermal therapy can be generally categorized into three modalities, respectively, diathermia, hyperthermia and thermal ablation, which are applied to different kinds of treatments in accordance with the extent of initial tissue necrosis. Diathermia (heating tissues up to 40–41 °C for 6–72 h), which can accelerate tissue repair, has been applied to physiotherapy for rheumatism treatment, and hyperthermia (heating tissues up to 42–45 °C for 15–60 min) can lead to cell death after a relatively long heating duration, which can contribute to radiation therapy. Correspondingly, thermal therapy (heating tissues above 48 °C for 4–6 min) is much more efficient than the other two thermal technologies because it can generate irreversible tissue necrosis in a short duration [4]. Unfortunately, the conventional thermal therapy methods mentioned above are still far from satisfactory because they are mainly induced by radio-frequency or microwaves, having limited ability to focus on tumors [[4], [5], [6]], their applications restricted to small local tumors or the supplement of radiotherapy and chemotherapy. Human tissues have weak absorption in the near-infrared (NIR) regions called “biological windows”, including the first NIR window (650–950 nm) and the second NIR window (1000–1350 nm), thus having a deep penetration through the tissue of approximate 1.1–3.6 mm [[7], [8], [9]]. As a result, NIR light can allow for relatively deep tissue treatment and minimize damage to the surrounding healthy tissues in the meanwhile, which offers significant advantages for thermal therapy applications.

Different from conventional thermal therapy, photothermal therapy (PTT), an emerging cancer treatment technique, utilizes photothermal conversion materials to destroy tumor cells by imposing heat converted from NIR light energy on target sites [[10], [11], [12], [13]]. Compared with conventional therapy approaches, PTT has received great attention in recent years because it reveals comparable strengths contributed by its rapid heating ability, such as minimal invasiveness, high specificity, less complicated operation and efficient ablation performance [14,15]. Nanomaterials can accumulate at targeted tumor sites passively by virtue of the enhanced permeability and retention (EPR) effect, in which the macromolecules and nanoparticles present greater permeability through tumor vessels and longer retention in tumor interspace than in normal tissues [1,16,17]. Due to the EPR effect, the area affected by photothermal conversion can be determined by the specific distributions of NIR light-absorbing nanomaterials, inducing rapid temperature to rise at tumor sites without damaging normal tissues.

In response to the demand of PTT, more and more attention has been paid to the research of NIR photothermal conversion agents. Currently, a variety of nanoscale photothermal conversion agents in the first NIR window have been widely explored, including noble metal nanoparticles (e.g., gold nanospheres/rods/cages [[8], [18], [19], [20], [21]]), Cu-based nanoparticles (e.g., CuS [22], Cu₉S₅ [13] and Cu₂Se nanocrystals [23]), carbon-based nanostructures simple (e.g., carbon nanotubes [24] and graphene [25]) and organic polymers (e.g., porphysome nanovesicles [26] and polypyrrole nanoparticles [11,12]), among which the organic nanoparticles are generally preferred due to their high biocompatibility. For example, polypyrrole nanoparticles show better photothermal performance than gold nanorods in terms of photothermal stability [11]. Very recently, some natural biomaterials and their analogues, including melanin nanoparticles [27], melanin-like polydopamine nanoparticles [28], porphysome nanovesicles [26] and melanoidins [29], have gained great attention due to their relatively high biocompatibility. However, previous studies have shown that compared with the first NIR window, the second one is more suitable for PTT since it produces less background noise caused by auto-fluorescence and has greater penetration depth in the tissue, thereby treating deeply embedded tumors more effectively [30,31]. Recently, new photothermal conversion agents applicable to the second NIR window have been reported, such as a new type of Au nanorods [32,33], Au-Cu₉S₅ [34] and Ag₂S quantum dots [35]. However, these photothermal agents are still plagued by complex synthesis methods or side effects during the fabrication process [28,29]. Hence, it will be highly desirable and valuable to develop novel organic photothermal agents with simple fabrication methods, high biocompatibility and excellent photothermal performance. As new photothermal agents develop, new assessment methods of photothermal performance are also investigated. In addition to the common time constant method [18], a simpler and faster determination method of photothermal conversion efficiency though an integrating sphere was reported recently [36].

With multiple ortho-phenolic hydroxyl structures, tannic acid (TA) can chelate with various metal ions as a multi-ligand to form stable organometallic complexes, among which the complex of ferric ion (Fe³⁺) and TA (Fe³⁺–TA) has been substantiated to be cytocompatible and versatile in biomedical applications because tannic acid widely exists in plants, and iron is an essential micronutrient widely distributed in the human body, mostly in blood [37,38]. Fe³⁺–TA coordination complex can form nano-coating with adjustable thickness on the surface of a vast majority of materials, including macroscopic blocks, nanoparticles and biointerfaces [37,39,40]. Furthermore, Fe³⁺–TA can form self-assembled capsules which can be applied to cell nanoencapsulation, drug delivery, magnetic resonance imaging and catalysis, by virtue of its diverse merits such as pH-responsive disassembly, selective permeability and thermal stability [39,42,43]. In addition, the Fe³⁺–TA complex exhibits strong NIR light absorption, which suggests great potential for PTT applications.

In this work, the Fe³⁺–TA complex was synthesized by simply mixing tannic acid and FeCl₃ solutions. The obtained Fe³⁺–TA complex revealed a strong absorbance in the NIR region, and it was then explored as a novel photothermal agent for the first time. Remarkably, it was found that the photothermal conversion efficiency was up to 77.3%, and more than 85% of HeLa cells were killed by the photothermal effect after exposure to the Fe³⁺–TA complex solution under laser irradiation. In addition, the as-prepared complex exhibited ultralow cytotoxicity, indicating the potential for biomedical applications.