Elsevier

Ceramics International

Volume 40, Issue 4, May 2014, Pages 5117-5127
Ceramics International

Development of a dual-functional Pt–Fe-HAP magnetic nanoparticles application for chemo-hyperthermia treatment of cancer

https://doi.org/10.1016/j.ceramint.2013.09.137Get rights and content

Abstract

Lung cancer is a harmful form of cancer; chemotherapy is the main methodology for treating it, despite continuing problems such as severe side effects. For the reduction of side effects, hydroxyapatite (HAP) has been investigated as a drug carrier recently. Moreover, hyperthermia has been reported to be an effective cancer treatment modality. In order to develop an effective agent for lung cancer treatment, dual-functional nanoparticles made from HAP with iron and platinum ions incorporation (Pt–Fe-HAP) were developed for chemo-hyperthermia application.

Variant HAP were synthesized and analyzed in this study. The crystallization and chemical composition were examined by X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy. Fe2+ and Pt2+ content was determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES). The biocompatibility and anticancer effects of Pt–Fe-HAP were assessed using 3T3 cells via a WST-1 assay. The effect of hyperthermia on the treatment of Sprague Dawley (SD) rat fibroblast and human lung adenocarcinoma (A549) cells under a magnetic field was evaluated by a lactate dehydrogenase (LDH) assay.

Overall, we have determined Pt–Fe-HAP could be prepared by a co-precipitation method with Fe2+/Pt2+ incorporation. The platinum and iron contents were 3.69 wt% and 12.20 wt%, respectively. The hysteresis curves showed that the Pt–Fe-HAP possessed ferromagnetic properties at low magnetic fields. The water temperature could be raised to 46 °C when the Pt–Fe-HAP suspension was treated in a magnetic field for 6 min. We also confirmed that the extraction solution of Pt–Fe-HAP was nontoxic, but the direct culture of 3T3 cells with these nanoparticles was harmful. Finally, the results of the LDH assay revealed Pt–Fe-HAP was highly toxic to A549 cells after magnetic field treatment under hyperthermia but no damage to fibroblast cells was observed. The magnetic Pt–Fe-HAP nanoparticles show the potential to be a dual agent to treat cancer cells by chemo-hyperthermia therapy.

Introduction

The mortality of lung cancer patients is the highest of all cancer types. The long-term survival rate of lung cancer patients treated by conventional modalities, such as surgical resection, radiation, and chemotherapy, remains far from satisfactory [1], [2]. Systemic drug delivery is rarely successful because only limited dosages of the chemotherapeutic drugs target the lung tumor sites, even when administered at a high doses [3]. Most chemotherapeutic drugs act on normal cells, inhibiting their growth; this makes the patient extremely weak and can even result in death [2]. Recently, several methods have been tested for cancer treatment, such as targeted therapy alone or in combination with systemic chemotherapy, but chemotherapeutic therapy is still the main method used to treat lung cancer.

The encapsulation of anticancer drugs in nanoparticles can protect the integrity of drugs during their transport in blood circulation, and can also protect the normal nontargeted tissues from the toxicity of the drug [4]. Recently, various inorganic hybrid composites have emerged as an imperative class of drug delivery systems in the biomaterials field. Bioceramics, such as bioglass or calcium phosphates, represent another class of materials suitable for use as a carrier of drugs, nonviral gene delivery, antigens, enzymes, and proteins [5], [6], [7]. The localized drug release from these bioceramic-based controlled release systems was found to minimize the high concentration of drugs typically required in the bloodstream and other organs to achieve therapeutic outcomes [8]. Hydroxyapatite [HAP, Ca10(PO4)6(OH)2] has a chemical structure similar to bone mineral, and hence has excellent biocompatibility and bioactivity [9], and has also high affinity for proteins, DNA, chemotherapy drugs, and antigens [10], [11]. The HAP carriers also provide a means to minimize unnecessary systemic toxicity and reduce the need for the repeated dosing often required for most drugs. Magnetic HAP with iron addition can be used as a thermal seed by magnetically induced hyperthermia, killing cancer cells at temperatures of approximately 45 °C for bone cancer treatment [12]; in fact, a previous study confirmed that iron-containing HAP is a good material for hyperthermia therapy [10].

Hyperthermia induced by magnetic nanoparticles is used in conjunction with other modalities of cancer treatment, with the objective of improving the effect of antineoplastic drugs [13], [14], [15], [16]. Metals and metal compounds, such as bismuth (antiulcer), gold (antiarthritic), iron (antimalarial), silver (antimicrobial), and platinum (anticancer), have been extensively used in medicine in the treatment of various diseases [17]. The first platinum-containing complex to be used in cancer treatment was cisplatin [2], [18]. Approximately 3000 platinum derivatives were tested against cancer cells, but only 4 are currently in clinical use: cisplatin, carboplatin, oxaliplatin, and nedaplatin. The commonality of these drugs is that they all contain platinum, which can form a large number of adducts with DNA, thereby inhibiting DNA synthesis and consequently causing cell death [17], [19]. The presence of platinum in those metal compounds causes toxic effects on the treated cancer cells. However, chemotherapy using cisplatin is associated with severe side effects such as anemia, nausea, vomiting, neurotoxicity, and nephrotoxicity [15], [20]. Therefore, the use of a carrier such as HAP containing platinum may produce anticancer effects with lower toxicity.

In this study, a dual-functional carrier, HAP with Fe2+ and Pt2+ incorporation (Pt–Fe-HAP), was designed and prepared for lung cancer treatment. HAP is stable in a neutral environment but relatively unstable in low-pH endosomes. Therefore, drugs carried by HAP could be stabilized during transport and then dissolved in lysosomes (pH 4), where the osmotic pressure could increase their concentration. As a result, endosomes could be broken causing the release of Pt2+ into the cytoplasm. Furthermore, a magnetic field could be applied for hyperthermia treatment to exploit the presence of iron in the HAP carrier. We predict that this dual agent (Pt–Fe-HAP) with chemo-hyperthermia properties will reach the goal of combining two therapies in a single carrier and will be applied in the future clinical treatment of lung cancer (Fig. 1).

Section snippets

Reagent and chemicals

Chemicals were of analytical grade from commercial sources, and were used as received without further purification. Calcium hydroxide [Ca(OH)2] and 85% phosphoric acid (H3PO4) were obtained from Riedel-de Haën (St. Louis, MO, USA). Ferrous chloride 4-hydrate (FeCl2·4H2O) and K2PtCl4 were purchased from J.T. Baker (Phillipsburg, NJ, USA). Ammonium hydroxide (NH4OH) was acquired from TEDIA (Fairfield, OH, USA). Calcium, iron, and platinum standard solutions for ICP-AES analyses were obtained from

Results

A schematic description of HAP with iron (Fe) and platinum (Pt) incorporation is presented in Fig. 1. Pt–Fe-HAP was prepared by the chemical co-precipitation method through FeCl2·4H2O and K2PtCl4 addition. Pt–Fe-HAP was formed via an ion exchange reaction of Pt2+ and Fe2+ with the Ca2+ contained in HAP. Finally, HAP crystals doped with Fe and Pt were obtained as dual function nanoparticles with hyperthermia and chemotherapy agent properties.

Discussion

The notable findings of this work were that hydroxyapatite (HAP) with Fe2+ and Pt2+ incorporation could become a thermal seed when immersed in a magnetic field, causing A549 cell death. Additionally, the incorporation of Pt2+ into HAP could provide the release of the metal to form DNA complexes to abolish cell proliferation. HAP is widely applied in the biomedical field for bone filling, cell scaffolding, or gene/drug delivery. Ion exchange is commonly observed in HAP structure; the calcium

Conclusions

HAP with iron and platinum incorporation was successfully prepared in this study. We determined via XRD and FT-IR analysis that the phase of calcium phosphate was HAP. Fe2+ and Pt2+ ions were incorporated into HAP, and the platinum and iron contents were determined to be 3.69 wt% and 12.20 wt%, respectively. From the hysteresis curves it was concluded that Pt-Fe-HAP has magnetic properties. The magnetic Pt–Fe-HAP under an AC magnetic field could release heat and raise the water temperature to

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