Development of a dual-functional Pt–Fe-HAP magnetic nanoparticles application for chemo-hyperthermia treatment of cancer
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
References (44)
- et al.
Biodegradable calcium phosphate nanoparticle with lipid coating for systemic siRNA delivery
Journal of Controlled Release
(2010) - et al.
Inorganic nanoparticles as carriers for efficient cellular delivery
Chemical Engineering Science
(2006) - et al.
Gelatin stabilized iron oxide nanoparticles as a three dimensional template for the hydroxyapatite crystal nucleation and growth
Materials Science and Engineering C
(2008) - et al.
Hyperthermia – description of a method and a review of clinical applications
Reports of Practical Oncology and Radiotherapy
(2007) - et al.
Surface structure and composition of calcium hydroxyapatites substituted with Al(III), La(III) and Fe(III) ions
Colloids and Surfaces A
(2000) - et al.
Intrinsic magnetism and hyperthermia in bioactive Fe-doped hydroxyapatite
Acta Biomaterialia
(2012) - et al.
Effect of iron on enamel demineralization and remineralization in vitro
Archives of Oral Biology
(2011) - et al.
Calcium phosphate apatites with variable Ca/P atomic ratio I. Synthesis, characterisation and thermal stability of powders
Biomaterials
(2002) - et al.
In vitro feasibility study of the use of a magnetic electrospun chitosan nanofiber composite for hyperthermia treatment of tumor cells
Acta Biomaterialia
(2012) - et al.
The synthesis and magnetic properties of nanosized hematite (α-Fe2O3) particles
Journal Colloid Interface Science
(2002)
Platinum folate nanoparticles toxicity: cancer vs. normal cells
Toxicology in Vitro
Catalytic nanomedicine: A new field in antitumor treatment using supported platinum nanoparticles. In vitro DNA degradation and in vivo tests with C6 animal model on Wistar rats
European Journal of Medicinal Chemistry
Drug therapy of lung cancer
Australian Prescriber
Recent clinical trials using cisplatin,carboplatin, and their combination chemotherapy drugs
Oncology Reports
Paclitaxel liposome aerosol treatment induce inhibitoin of pulmonary metastases in murine renal carcinoma model
Clinical Cancer Research
Biocompatible core-shell nanoparticles for biomedicine
Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy
Expert Review of Molecular Diagnostics
A ceramic-based anticancer drug delivery system to treat breast cancer
Journal of Materials Science: Materials in Medicine
Modification of apatite materials for bone tissue engineering and drug delivery carriers
Current Medicinal Chemistry
A novel biomagnetic nanoparticle based on hydroxyapatite
Nanotechnology
Mitochondria-dependent apoptosis induced by nanoscale hydroxyapatite in human gastric cancer SGC-7901 cells
Biological and Pharmaceutical Bulletin
Effect of local hyperthermia on blood flow and microenvironment
Cancer Research
Cited by (40)
Optimization of FDM for Fabrication of PLA-HAp-CS Based Functional Prototypes/Scaffolds Using Matrix Co-Relation
2022, Encyclopedia of Materials: Plastics and PolymersZirconium doped hydroxyapatite nanoparticle as a potential design for lung cancer therapy
2021, Ceramics InternationalCitation Excerpt :Among 72 out of 118 elements in periodic table successfully incorporated into HAp, zirconium is one of the less studied ion doped into HAp [14]. Because of its biocompatibility and low toxic property [17], most of zirconium doped HAp study were focussed for implant application and small number of paper studied about its antimicrobial and anticancer properties [11–13,15,18]. Similar characteristic was found on the study of zirconium apart from HAp, most of zirconium compound used for anticancer study were acted as drug delivery system, especially in the form of metal organic framework (MOF) and zirconium nanoplatelets [19–22], or other form of nanoparticles such as hollow and mesoporous nanoparticles [23–25].
Magnetic hydroxyapatite nanocomposites: The advances from synthesis to biomedical applications
2021, Materials and DesignMagnetic particle targeting for diagnosis and therapy of lung cancers
2020, Journal of Controlled Release