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PVP-stabilized arsenic sulfide [As.sub.4][S.sub.4] nanocomposites probed with positron annihilation lifetime spectroscopy.


The promising anticancer functionality of arsenic sulfide [As.sub.4][S.sub.4] polymorphs has been in a sphere of tight interests in biomedicine because of versatile angiogenesis inhibition effect on a row of human malignancies [l, 2]. To overcome negative feedback of poor bioavailability (due to limited solubility in water), these compounds (arsenicals) are often used as mediated to a nanosize [3], Being subjected to nanostructurization through mechanochemical milling in solutions with some biocompatible polymers such as polyvinylpyrrolidone (PVP), that is, polyvinylpyrrolidone [([C.sub.6][H.sub .9]ON).sub.n], the arsenic sulfide polymorphs form nanocomposites possessing an excellent medicinal efficacy due to DNA damage and apoptosis-induced cellular effect on a number of human cancer cell lines |4-6]. The PVP has been widely used in pharmaceuticals industry as high-efficient nonionic stabilizer, dispersant, and delivery agent in the production of many drugs [7, 8], This polymer possesses a unique ability to stabilize highly interactive chemical systems, preventing them from agglomeration and segregation, the property, which is important for nanostructurized pharmaceuticals [9]. Enhanced antitumor activity of PVP-directed assembly of water-soluble As sulfides mediated by milling to nanosize was shown to exhibit anticancer autophagy and apoptosis in a number of human malignances [10, 11]. Undoubtedly, the improved biomedical functionality of such objects benefit from both atomic-specific (nearest interatomic arrangement, atomic and molecular clusters, polyhedral building blocks, network-forming units, etc.) and atomicdeficient nanostructure (low electron- and atomic-density entities like vacancies, vacancy-type clusters, free-volume voids, interfacial junctions, etc.). The latter are very important in various biomedical applications tailoring nanospace (i.e., directly related to space-filling host-guest chemistry [12]) owing to characteristic free-volume entities accessible to be occupied by different atomistic species.

In this work, the positron annihilation lifetime (PAL) spectroscopy, the method which can be recognized as advanced instrumentation tool efficiently exploring nanospace at atomistic and sub-atomistic length scales [12-16], is employed to characterize atomic-deficient nanostructurization in composites based on [As.sub.4][S.sub.4] polymorphs prepared by high-energy milling in a wet mode.


Nanocomposite Preparation Procedure

Nanocomposites were prepared using three types of coarsegrained [As.sub.4][S.sub.4] milled in laboratory mill MiniCer (Netzsch, Germany) in the presence of 300 mL of 0.5% PVP solution as nonionic stabilizer. The PVP with average molecular weight [M.sup.w] = 40,000 g [mol.sup.-1] was purchased from Sigma-Aldrich Co. LLC (St. Louis, MO). We used (1) commercial arsenic(II) sulfide (Sigma-Aldrich. USA), (2) mineral realgar from Allchar locality (R. Macedonia), (3) mineral realgar subjected to partial transformation into pararealgar due to sunlight, the sample batches being respectively marked as REA1, REA2, and REA3. The milling was performed with 5 g of arsenical under 85% loading of milling shaft with yttrium-stabilized Zr[O.sub.2] balls (0.6 mm in a diameter). After filtration through sterile 0.22-[micro]m filter, the separated solid phase was dried at 70[degrees]C and pelletized under applied pressure of 0.7 GPa. This route was identical for all samples, thus the pellets being 6 mm in a diameter and 1 mm in a thickness. Nanoparticles (NPs) sizes in dried pellets were close to ones proper to as-prepared suspensions (100-200 nm in a diameter [6]). In a similar manner, the pelletized samples of pure PVP were prepared to be used as reference in further research [17].

PAL Spectroscopy

Experimental PAL spectra were recorded with fast-fast coincidence system (ORTEC) of 230 ps resolution at the temperature of 22[degrees]C and relative humidity of 35% [15]. To ensure precise lifetime measurement, each PAL spectrum was recorded in normal-measurement statistics (~[10.sup.6] coincidences). The channel width of 6.15 ps allows total number of channels to be 8000. The [sup.22]Na isotope of low ~50 kBq activity prepared from aqueous [sup.22]NaCl solution (wrapped by Kapton[R] foil of 12 [micro]m thickness and sealed) was used as positron source sandwiched between two identical nanocomposite pellets. The best fitting of PAL spectra was achieved under decomposition into three single exponents (three-term x3-decomposition under normalized intensities [I.sub.1] + [I.sub.2] + [I.sub.3] = 1), covering channels from positrons annihilating in defect-free bulk, trapped in extended free-volume defects and forming bound positron-electron (positronium, Ps) state. This procedure was performed by processing the raw PAL spectra with LT 9.0 program [18]. The error-bar in positron lifetimes [[tau].sub.i] and intensities [I.sub.i] was not worse [+ or -]0.005 ns and 0.5%, respectively.

Positron Trapping within x3-x2-Coupling Decomposition Algorithm

In many inhomogeneous molecular substances such as polymers or composites, positron-electron annihilation is expected through mixed positron-Ps trapping channels [16, 19]. These channels are mutually interconnected, so that interplay between them essentially complicates meaningful interpretation of the measured PAL spectra. The formalism of separated positron and Ps trapping cannot be further explored as quite realistic signature of annihilation because of uncompensated admixture in the first component arising from para-Ps (p-Ps) state [16. 19]. In such a case, additional supposition on mixed positron-Ps trapping is needed to separate annihilation modes unambiguously.

In this research, we explore the developed x3-x2-coupling decomposition algorithm [16] concerning substitution positronPs trapping, for example, process, which occurs as conversion of ortho-Ps (o-Ps) traps in pure host matrix into positron trapping sites in the NP-modified host-guest matrix. This procedure is applied for both host matrix and NP-modified host-guest composite [19], Additional positron trapping input with lifetime [[tau]] and intensity [] due to guest NP is resolved in the second component of generalized x2-decomposed PAL spectrum of host-guest matrix, the compensating ([[tau].sub.n], [I.sub.n]) input in the first channel being found under equilibrium between channels. Thereby, the full parameterization of NP-related trapping sites is achieved by accepting ([[tau].sub.n], [I.sub.n]) and ([[tau]], []) as first and second components in the x2-decomposed PAL spectrum.

Thus, by transferring the x3-term decomposed PAL spectra of host PVP matrix and host-guest PVP-stabilized [As.sub.4][S.sub.4] nanocomposites in the generalized x2-term form in respect to algorithm [16], we extract just this additive part, which directly corresponds to NP-related traps. The positron traps can be imagined as pseudogap holes at the interface between outer surface layer of guest NPs and innermost layer of surrounding host PVP matrix (as it was well outlined in Ref. 19). The bulk positron lifetime ib calculated with respect to ([[tau].sub.b], [I.sub.n]) and ([[tau]], []) components with respect to known formalism of two-state trapping model [13-15] can be attributed to defect-free positron lifetime of distinct NPs. In case of highly monolith NPs, this [[tau].sub.b] tends toward bulk lifetime of substance, while in more loose aggregates of many NPs, it is higher reflecting their reduced compactness. In general, the [[tau]], lifetime, as well as its difference and ratio with bulk lifetime can be attributed to geometrical size and nature of positron trap, the trapping rate being estimated via two-state model [13-15].


The raw PAL spectra of pure PVP and [As.sub.4][S.sub.4]-PVP nanocomposites parameterized in terms of minimal statistically weighted least-squares deviation between experimental points and theoretical curve built of three single negative exponentials evolving inputs from both positron and Ps trapping channels are depicted in Fig. 1. To clarify the nature of NP-related void evolution in [As.sub.4][S.sub.4]-PVP nanocomposites, the PAL data for REA1,2,3 were also treated within x3-x2-coupling decomposition algorithm [16] in respect to x3-component fitting parameters of reference PVP [17], the results being presented in Table I.

Nearly the same [[tau].sub.b] [congruent to] 0.24 ns for [As.sub.4][S.sub.4]-PVP pellets determined within this algorithm for ([[tau].sub.n], [I.sub.n]) and ([[tau]], []) as components of generalized x2-term decomposed PAL spectra, but which is evidently above bulk positron lifetime of 0.224 ns proper to realgar [alpha]-[As.sub.4][S.sub.4] crystal [20], testifies that positron trapping sites concern rather loosely-packed arsenic sulfide crystallites composing distinct NP. The values of defect-related lifetimes [[tau]] [congruent to] 0.37-0.39 ns show that NP-related interfacial voids have free volumes approaching ~100 [[Angstrom].sup.3] (near ~0.3 nm in radius in spherical approximation), as it follows from semiempirical estimation for S-rich environment [21, 22]. This conclusion agrees well with difference ([[tau].sub.2] - [[tau].sub.b]) [congruent to] 0.15 ns and ratio [[tau].sub.2]/[[tau].sub.b] = 1.6 as fingerprints of triplet-quadruple vacancies in chalcogenide-type chemical compounds [13].

These findings are well reflected in atomic-deficient void structure of REA1 pellet, composed of high-temperature /?[As.sub.4][S.sub.4] polymorph (the source chemical arsenical from Sigma Aldrich, USA), owing to typical values of [[tau]] = 0.389 ns and [[tau].sub.b] = 0.240 ns. The most densified free-volume structure is character for REA2, composed of [alpha]-[As.sub.4][S.sub.4] polymorph (mineral realgar as a source for milling). The corresponding lifetimes are minimal in this nanocomposite ([[tau]] [congruent to] 0.368 ns and [[tau].sub.b] = 0.233 ns) because of smallest free volumes associated with agglomerated isocompositional NPs. If we will accept that both REA1 and REA2 nanocomposites are characterized by the same building blocks (cage-like [As.sub.4][S.sub.4] molecules possessing [D.sub.2d] symmetry and nearly ~ 14.8 [[Angstrom].sup.3] self-closed volume, composed by two AsAs bonds in opposite orthogonal configurations interlinked via four As-S-As bridges [20]), this enhanced atomic compactness can be reasonably connected to better anticancer activity of REA2 suspension [6]. Thus, the [IC.sub.50] parameter (which is 50% concentration of arsenical corresponding to the inhibition effect) on H460 human lung cell is twice reduced with transition from REA1 (0.066 [micro]g/mL) to REA2 suspension (0.033 [micro]g/mL) [6], thus reflecting positive impact of local As concentration on this cancer cell.

The largest values of [[tau]] = 0.396 ns and [[tau].sub.b] = 0.244 ns are proper to REA3 pellet having most complicated phase composition (~75 wt% of realgar and ~19 wt% of pararealgar [As.sub.4][S.sub.4] with intermediate [chi]-phase [23]). This nanocomposite is built of most loosely packed NPs with largest positron trapping voids. Nevertheless, the corresponding nanosuspension demonstrates well-expressed anticancer activity in respect to [IC.sub.50] = 0.031 [micro]g/ mL [6], which evidently follows from its chemistry enriched on pararealgar [As.sub.4][S.sub.4] phase. Positive effect of densified local As environment in this case is realized due to specificity of pararealgar molecules of [C.sub.s] symmetry and nearly ~ 15.7 [[Angstrom].sup.3] self-closed volume having three As atoms forming two adjacent As-As bonds in As-S neighboring environment [24]. Comparing positron trapping modes gathered in Table 1 for this REA3 with REA2 (where [alpha]-[As.sub.4][S.sub.4] realgar phase is also dominant), we conclude that most perfect structure of [As.sub.4][S.sub.4] polymorphs composing NPs corresponds to smallest free volumes associated with them.

So at the basis of these findings, the microstructure model of mixed positron-Ps trapping in the studied [As.sub.4][S.sub.4]-PVP nanocomposites (REA1,2,3) can be recognized as it is illustrated in Fig. 2. Each pellet represents NPs of relatively large sizes (above hundred nanometers like in suspensions [6]) composing of a few smaller [As.sub.4][S.sub.4] crystallites, these NPs being more or less uniformly embedded in PVP environment. Since geometrical sizes of these nanostructurized entities are smaller than positron diffusion lengths (no more than a few tens of nm in typical semiconductors [13]), the thermali/.ed positrons will contribute to annihilation outside them tending the overall process of positron trapping toward saturation. Positron trapping dominates in PVP environment at interfacial free-volume holes created by neighboring NPs and/or [As.sub.4][S.sub.4] crystallites. These NPs are rather loosely composed of [As.sub.4][S.sub.4] crystallites (as it follows from enlarged bulk lifetimes in Table 1), packing efficiency being defined by crystallographic perfectness of arsenic sulfide polymorphs (decaying in [alpha]-[As.sub.4][S.sub.4]-[beta]-[As.sub.4][S.sub.4]-pararealgar row, corresponding to REA2-REA1-REA3 sequence).


The method of positron-electron annihilation in lifetime measuring mode is employed to study atomic-deficient nanostructurization in composite systems like those based on arsenic sulfide [As.sub.4][S.sub.4] polymorphs subjected to high-energy mechanochemical ball milling in polyvinylpyrrolidone (PVP) solution as nonionic stabilizer. The collected PAL spectra of pure PVP and composite [As.sub.4][S.sub.4]-PVP pellets reconstructed from unconstrained x3-term fitting procedure testify in a favor of mixed positronpositronium trapping. The modified x3-x2-coupling decomposition algorithm applied in addition to conventional x3decomposition allows to parameterize expectcd annihilation channels in host-guest [As.sub.4][S.sub.4]-PVP in respect to host PVP matrix. Interfacial free-volume voids between neighboring nanoparticles composed of arsenic sulfide crystallites embedded in PVP environment are defined as most favorable positron trapping sites, they being rather loosely packed in respect to variety of crystallographic polymorphs used for milling. The microstructure model of mixed positron-positronium trapping in the studied [As.sub.4][S.sub.4]-PVP nanocomposites is developed.


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O. Shpotyuk, (1,2) A. Ingram, (3) Y. Shpotyuk, (4,5) Z. Bujnakova, (6) P. Balaz (6)

(1) Department of Structural Studies and Medical Physics, Institute of Physics, Jan Dlugosz University in Czestochowa, Czestochowa 42200, Poland

(2) Department of Optical Glasses and Ceramics, Vlokh Institute of Physical Optics, Lviv 79005, Ukraine

(3) Department of Physics, Opole University of Technology, Opole 45370, Poland

(4) Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, Faculty of Mathematics and Natural Sciences, University of Ftzeszow, Rzeszow 35-310, Poland

(5) Department of Sensor and Semiconductor Electronics, Ivan Franko National University of Lviv, Lviv 79017, Ukraine

(6) Department of Mechanochemistry, Institute of Geotechnics of Slovak Academy of Sciences, Kosice 04001, Slovakia

Correspondence to: O. Shpotyuk; e-mail: Contract grant sponsor: Slovak Research and Development Agency; contract grant number: APVV-14-0103; contract grant sponsor: bilateral project SKUA-2013-0003; contract grant sponsor: SAIA within National Scholarship Program of the Slovak Republic.

DOI 10.1002/pen.24503

Caption: FIG. 1. Raw PAL spectra of pure PVP (a) and pelletized [As.sub.4][S.sub.4]-PVP nano-composile REA1 (b) reconstructed from x3-term fitting at the general background of source contribution (bottom insets show statistical scatter of variance) inputs from both positron a. [Color figure can be viewed at]

Caption: FIG. 2. Schematic illustration depicting expected channels of positron annihilation in [As.sub.4][S.sub.4]-PVP nanocomposites: (a) distinct NPs, (b) [As.sub.4][S.sub.4] crystallites, (c) interfacial positron-trapping free-volume void is illustrated in Fig. 2. [Color figure can be viewed at]
TABLE 1. Positron trapping in [As.sub.4][S.sub.4]-PVP nanocomposites
treated within x3-x2-coupling decomposition algorithm in respect to
pure PVP.

                    First component

Sample   [[tau].sub.n] (ns)   [I.sub.n] (a.u.)

REA1           0.207               0.427
REA2           0.199               0.409
REA3           0.211               0.445

                    Second component

Sample   [[tau]] (ns)   [] (a.u.)

REA1            0.389                 0.181
REA2            0.368                 0.199
REA3            0.396                 0.180

                      Positron trapping modes

Sample   [[tau].sub.av]    [[tau].sub.b]        [K.sub.d]
              (ns)              (ns)          ([ns.sup.-1])

REA1          0.261            0.240               0.68
REA2          0.253            0.233               0.74
REA3          0.264            0.244               0.64

Sample    [[tau]]-      [[tau]]/
         [[tau].sub.b] (ns)   [[tau].sub.b] (a.u.)

REA1            0.15                  1.62
REA2            0.14                  1.58
REA3            0.15                  1.62
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Author:Shpotyuk, O.; Ingram, A.; Shpotyuk, Y.; Bujnakova, Z.; Balaz, P.
Publication:Polymer Engineering and Science
Article Type:Report
Date:Jun 1, 2017
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