Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizer
Graphical abstract
Introduction
One of the major challenge in nanomedicine is the development of systems for targeted substance delivery, which requires understanding of fundamental biochemical processes such as cellular uptake mechanisms [1], [2] or intracellular transport [3], and also the intelligent design of adequate carriers [4], [5], [6]. An effective matrix for such a delivery system is calcium carbonate (CaCO3) [7], [8], [9], [10]. CaCO3 exists in three different anhydrous crystalline polymorphs: calcite, aragonite, and vaterite. Under standard conditions for temperature and pressure, calcite is the stable phase, while aragonite and vaterite are the metastable forms that readily transform into the stable phase. Vaterite is an ideal candidate for a drug delivery system because it has large porosity, large surface area, and can decompose rapidly under relatively mild conditions [10], [11]. Vaterite is the least stable phase of CaCO3 since in contact with water it slowly dissolves and recrystallizes to form calcite. Previous studies described the possibility of synthesizing spherical mono-dispersed vaterite particles in the size range from 2 to 10 μm [11] and from 400 nm to 2.4 μm [12]. Vaterite containers allow for different substance loading methods such as adsorption [13], [14], [15] and co-precipitation [8], [14]. A release mechanism based on a crystal phase transition has recently been demonstrated [12], [15], [16]. Cytotoxicity and influence on cell viability have been excluded in cell culture studies with 400 nm vaterite containers. Apart from this efficient cellular uptake of substance-loaded containers was observed [15].
To exploit vaterite containers as a drug delivery system in photodynamic therapy (PDT), photosensitizers have to be incorporated, delivered to the target, and released within the cells. Exposure to light at the photosensitizers absorbance wavelength then induces singlet oxygen generation, a photochemical reaction of type II [17], [18]. The singlet oxygen can oxidize cellular macromolecules like lipids, nucleic acids, and amino acids leading to cancer cell apoptosis [19].
So far, the main negative side effect of PDT is caused by its insufficient selectivity of action: a high concentration of photosensitizer is required for cancer treatment at the tumor site, but causes incidental toxicity in healthy tissue. This side effect could be strongly reduced by targeted delivery to the region of interest. The proposed delivery system will achieve this exploiting a pH-dependency of the carrier degradation dynamics.
Section snippets
Materials
Calcium chloride, sodium carbonateacetic acid, and sodium hydroxide were purchased from Sigma-Aldrich and used without further purification. The photosensitizer Photosens, a mixture of sulfonated aluminum phthalocyanines AlPcSn, with n = 2, 3 or 4 (the mean n = 3.1), was obtained from the Organic Intermediates and Dyes Institute (Moscow, Russia). It has strong absorption bands with a maximum at 675 nm wavelength [20], and can be activated at 100 J/cm2 light power [21]. It is applied in clinical
Particle loading
To study the influence of the carrier size on the loading efficiency, two lines of the vaterite particles were synthesized: vaterite containers with an average size of 650 ± 30 nm (hereafter referred to as “small”) and of size 3.6 ± 0.5 μm (hereafter referred to as “big”). In 5 mg of small particles 0.067 ± 0.007 mg of Photosens could be incorporated, which amounts to 1.4 ± 0.4% (w/w). For big particles the uptake was 0.047 ± 0.003 mg, corresponding to 0.9 ± 0.2% (w/w). The loading efficiencies of big and small
Acknowledgments
Bogdan Parakhonskiy acknowledges funding by the Provincia autonoma di Trento (Marie Curie Actions, Trentino COFUND). Yulia Svenskaya acknowledges funding from the EU Erasmus Mundus Action 2 MULTIC Programme. Work was partially supported by RFBR, research projects no. 12-03-33088 mol_a_ved.
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