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Antacids are crucial in the treatment of gastro-esophageal reflux disease and peptic ulcers. Antacids based on the calcite phase of bulk calcium carbonate have been the standard for over fifty years. More recent research has shown that nanomaterial forms of such bulk materials often have improved properties. However, the metastable vaterite form of calcium carbonate is particularly difficult to synthesize as a nanomaterial, and thus has not been extensively studied. Here, we describe the synthesis of these particles and investigate them for antacid applications. Experimental and computational approaches show that nanoscale vaterite particles maintain neutral gastric pH values three times longer than commercial antacids.
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Nano-antacids enhance pH neutralization beyond
their bulk counterparts: synthesis and
characterization
Ramesh Raliya,
a
Avik Som,
b
Nishit Shetty,
c
Nathan Reed,
a
Samuel Achilefu
b
and Pratim Biswas*
a
Antacids are crucial in the treatment of gastro-esophageal reux disease and peptic ulcers. Antacids based
on the calcite phase of bulk calcium carbonate have been the standard for over fty years. More recent
research has shown that nanomaterial forms of such bulk materials often have improved properties.
However, the metastable vaterite form of calcium carbonate is particularly dicult to synthesize as
a nanomaterial, and thus has not been extensively studied. Here, we describe the synthesis of these
particles and investigate them for antacid applications. Experimental and computational approaches
show that nanoscale vaterite particles maintain neutral gastric pH values three times longer than
commercial antacids.
1. Introduction
The vaterite phase of calcium carbonate exhibits high dissolu-
tion, dispersivity, and biocompatibility.
1,2
As a widely used
antacid, calcium carbonate has been studied extensively.
36
It
has three common polymorphs: calcite, vaterite, and aragonite.
Calcite is the most stable, while vaterite is the least stable at
room temperature and atmospheric pressure.
7
Vaterite's ther-
modynamic instability converts it to calcite over time under
normal conditions
8
and also makes it dicult to study as an
antacid. Much like other nanomaterials, CaCO
3
has dierent
optical and mechanical properties than its bulk counterpart, as
well as a higher surface area to volume size ratio, and dierent
surface chemical properties. Several attempts have been made
to synthesize the meta-stable vaterite form of calcium
carbonate, however these particles are too big (>few microme-
ters),
911
are not stable for an extended period of time,
12,13
and
have low phase purity.
14,15
This work develops a method for the synthesis of stable and
monodisperse vaterite nanoparticles and investigates their
antacid activity. Results are validated with both computational
and experimental approaches.
2. Materials and methods
2.1. Synthesis and characterization of CaCO
3
nanoparticles
Stable vaterite nanoparticles were synthesized by reacting 0.1 M
calcium chloride dihydrate (CaCl
2
$2H
2
O) and 0.1 M sodium
bicarbonate (NaHCO
3
). The rate of growth of the crystals was
controlled by performing the reaction in water and ethylene
glycol in a ratio of 1 : 5 (v/v). The solution was stirred at 700 rpm
for 30 minutes at room temperature. The precipitate was then
sequentially washed with ethanol, methanol and acetone to
remove any water content. The nal product was dried at 60 C
for an hour. The synthesized nanoparticles were characterized
using Transmission Electron Microscope (TEM) for morpho-
logical studies, X-Ray Diraction (XRD) for crystal phase study,
X-Ray Photocorrelation Spectroscopy (XPS) for surface chemical
composition and dynamic light scattering for stability studies.
2.2. Analysis of antacid prole
The antacid activity assay was done by converting both
synthesized and purchased powdered antacids into liquids at
dierent concentrations, 1 ml of which was added to 150 ml of
deionized water at 37 C. The round bottomed ask was rst
swirled thrice to evenly distribute the antacid and then stirred at
60 rpm to mimic the churning process in the stomach.
16
The
solution was titrated with hydrochloric acid having a pH of 1.2
(ref. 17) to an end point of pH 3, according to Fordtran's
model.
16
The pH was constantly measured using a pH meter,
and values were recorded every minute. The antacid property of
a
Department of Energy, Environmental and Chemical Engineering, Washington
University, St. Louis, Missouri, 63130 USA. E-mail: pbiswas@wustl.edu; Tel: +1 314
935 5548
b
Departments of Biomedical Engineering, Washington University School of Medicine,
St. Louis, Missouri, 63110, USA
c
Indian Institute of Technology Gandhinagar, Gujarat, 382355, India
Electronic supplementary information (ESI) available: Experimental plan; DLS
size distribution; extended detail of material characterization tool (XRD);
antacid prole compared with commercial counterpart; eect of stirring rate on
antacid prole. See DOI: 10.1039/c6ra12856d
RR and AS contributed equally.
Cite this: RSC Adv.,2016,6,54331
Received 17th May 2016
Accepted 30th May 2016
DOI: 10.1039/c6ra12856d
www.rsc.org/advances
This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6, 5433154335 | 54331
RSC Advances
PAPER
the vaterite nanoparticles was tested and compared with
commercial chemicals having antacid properties, such as
sodium bicarbonate, commercially available calcium carbonate,
and TUMS© 500 regular strength chewing tablets. A compara-
tive and extensive study on the dose response characteristics
was done for the synthesized vaterite nanoparticles and TUMS
chewing tablets.
3. Results and discussion
During multiple steps of the synthesis procedure, various
amounts of ethylene glycol were added to the solution to
increase viscosity and thereby reduce the molecular diusion,
2
yielding particle sizes was about 100 8.5 nm (Fig. 1). To
achieve this particle size the optimal ratio of ethylene glycol to
water was found to be 1 : 5. In addition to the role that viscosity
plays in nanoparticle size control, solvent washing to remove
water was found to be essential. Water encourages the particles
to agglomerate as well as change the phase from vaterite to
calcite.
The reaction proceeded as follows:
2NaHCO
3
+ CaCl
2
$2H
2
O/CaCO
3
+ 2NaCl + CO
2
+3H
2
O
(1)
The nucleation and growth of the particles were studied by ex
situ TEM (FEI Transmission Electron Microscope, 120 kV/LaB6
lament; 0.2 nm line resolution) to elucidate phase changes
in the solution. The synthesis reaction mixture was sampled
and transferred to TEM grids at dierent time points. Experi-
ments show that vaterite formed through a multi-phase process,
starting with the formation of amorphous calcium carbonate
(Fig. 2AF). Our ndings of the nucleation and growth process
are consistent with the multi-phase model reported earlier.
9,18,19
To conrm the crystal phase of the CaCO
3
nanoparticles,
XRD patterns were obtained by using a Bruker D8 Advance X-ray
Diractometer (Bruker, USA) congured with a 1.5418 ˚
ACuX-
ray tube for analysis of powder samples using a LYNXEYE_XE
detector. The diraction pattern in Fig. 3 shows a clear repre-
sentation of the vaterite phase of CaCO
3
as shown in Fig. 3. Two
small intensity peaks of aragonite were also observed, repre-
sented by the label (A) in the Fig. 3, although these peak
intensities were non-signicant.
Information about the molecular bonding and functionality
of vaterite CaCO
3
were obtained with X-ray photoelectron
spectroscopy (XPS, PHI 5000 VersaProbe II). XPS permitted
directly probing the surface atomic compositions, showing
chemical shis of the C(1s), O(1s), and Ca(2p) peaks. Fig. 4
shows the XPS spectra of the Survey (S) scan, C1s, O1s, and Ca2p
core levels of the CaCO
3
surface.
Fig. 1 TEM image of the synthesized particles when dispersed in
methanol (agglomerates of the vaterite nanoparticle). Inset: scaled up
image of a single vaterite particle (scale bar of 50 nm).
Fig. 2 Ex situ TEM images showing size and growth of vaterite parti-
cles at dierent instants of time (A) between 0 and 1 min, (B) 1 min, (C) 5
min, (D) 10 min, (E) 15 min, (F) 30 min. The images show the rate at
which the size of these particles increases with time during the
synthesis process. The low rate of growth of these particles could be
attributed to the fact that the rate of diusion in a solution of ethylene
glycol would be very less. Also, it is seen that the vaterite particle
formation occurs within 15 minutes of the start of the synthesis.
Fig. 3 XRD characterization of CaCO
3
nanoparticles.
54332 |RSC Adv.,2016,6,5433154335 This journal is © The Royal Society of Chemistry 2016
RSC Advances Paper
The binding energy of a standard C1s peak at 288.3 eV cor-
responded to CO
3
in the CaCO
3
surface, and an adventitious
carbon peak occurred at 285.8 eV. The binding energy of 283.5
eV corresponded to a carbon centre originating from environ-
mental carbon as a result of open environmental exposure. The
high-energy resolution of the Ca(2p) spectra of the CaCO
3
samples indicated two binding energies, one for Ca2p3/2 (345.8
eV) and another for Ca2p1/2 (349.7 eV). The O1s core level for
CO
3
of the CaCO
3
was observed at 530.2 eV.
The antacid activity time denes its eectiveness, and the
greater the activity time, the greater the eectiveness. Fig. 5
shows that the antacid activity time for the vaterite particles is
much longer than for other tested chemical substances. The
enhanced antacid property of vaterite is attributed to its higher
solubility than that of the calcite phase found in commercially
available CaCO
3
and TUMS.
20
The higher solubility of vaterite
results in a greater concentration of carbonate ions in the
solution, which leads to a higher activity. Also, these small
particles dissolve faster into the solution due to their high
surface-to-volume ratio. The fast dissolution rate also increases
the pH quickly and leads to faster relief when ingested. In Fig. 5
the activity times for TUMS are lower, or at best comparable to
that of commercial CaCO
3
. The dierence in activity time of
TUMS compared to commercial CaCO
3
is likely a result of the
TUMS tablets containing additional ingredients
21
while the
measured commercial CaCO
3
was 99% pure. Results indicated
that as mass concentration increases (2 to 100 mg), antacid
activity times was increased (2.8 minutes to 25 minutes).
The experimental nding of antacid activity by vaterite
nanoparticles was further validated by a computational simu-
lation. The reactions that follow the addition of calcium
carbonate to water are as follows
H
2
CO
3
+H
2
O#H
3
O
+
+ HCO
3
(K
a1
)(2)
HCO
3
+H
2
O#H
3
O
+
+CO
32
(K
a2
)(3)
CaCO
3
#Ca
2+
+CO
32
(K
sp
)(4)
In simulation, a given solution containing a xed amount of
antacid is titrated using hydrochloric acid pH 1.2. The pH of
such a solution would have the following electrical neutrality
expression for all the ions present in the solution:
22
[H
+
] + 2[Ca
2+
]¼2[CO
32
] + [HCO
3
] + [OH
] + [Cl
](5)
Here, the carbonate ion concentration can be represented as
CO32¼Ka1Ka2 ½H2CO3
½Hþ2(6)
A similar equation can be derived for the bicarbonate ion
concentration, and the hydroxyl ion concentration can be
written as a function of the hydrogen ion concentration using
K
w
, the dissociation constant of water. In the simulation, as the
hydrochloric acid was injected into the solution externally at
axed owrate (1 ml min
1
) and xed concentration (0.063 M),
the chloride ion concentration was a function of time as
½Cl¼ 0:063 flowrate time
Viþflowrate time (7)
where V
i
is the initial volume of the antacid solution.
The calcium ion concentration was obtained using the
solubility product equation of calcium carbonate; however,
a restriction had to be set on the calcium ion concentration,
which depends on the initial amount of antacid added to the
solution. Thus, the electrical neutrality expression can be
expressed solely in terms of a single variable, the hydrogen ion
concentration. The equation is solved to determine the time
required for the given solution to reach a pH end point of 3, and
the results of the simulation, compared with experimental
results, are as shown in Table 1.
The simulation is able to capture the neutralization times for
small doses of the antacid, and some deviation from the
experimental observation is seen for higher doses. However, the
simulation gives a good approximation for the activity time of
the antacid and can be used to predict the neutralization time
for a given dose.
As we demonstrated previously in the use of nano-CaCO
3
for
tumor therapy, a chemical compound used for biomedical
application needs colloidal stability during storage, transport
Fig. 4 XPS characterization of vaterite phase CaCO
3
nanoparticles.
Survey (S) spectrum along with high resolution C, O, and Ca spectra for
the corresponding range of binding energy.
Fig. 5 Antacid prole of vaterite nanoparticles and its conventional
counterpart. Neutralization times for all the tested substrates at
dierent concentrations of the liquid antacids (left). Dose response
prole of vaterite nanoparticles.
This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6, 5433154335 | 54333
Paper RSC Advances
and delivery of the compound into a patient's body.
23
Colloi-
dally stable particles may have further utility as pH neutral-
izers in other biological conditions.
1,15,24
To determine
vaterite's feasibility for pH neutralization in vivo, we studied
the size and stability of these particles in dierent solvents,
using time-resolved dynamic light scattering (TR-DLS) for 30
minutes. The duration was selected based estimated antacid
activity.
The stability of vaterite nanoparticles in a variety of solvents,
such as water, saline, bovine serum albumin, Dulbecco's
modied Eagle's medium (DMEM), ethanol, methanol and
phosphate buer saline (PBS). Fig. 6 shows the results of
stability tests that imply that albumin has a high anity for
calcium carbonate and hinders particle agglomeration, thus
stabilizing the particles in solution. The PBS solution promotes
precipitation of the particles by increasing their supersatura-
tion,
25
as a result of added divalent ions (Mg
2+
or Ca
2+
). The
particles are also quite stable in DMEM, facilitating their
possible application in cell growth cultures requiring alkaline
environments. Thus the synthesized particles would be useful
for industrial applications in solvents such as ethanol, and
would be good for biomedical antacid applications when dis-
solved in a solution of albumin.
4. Conclusions
In conclusion, this study describes a stable, rapid, and room
temperature synthesis of vaterite phase nano-CaCO
3
. The
diameter of the particles, determined by TEM, was about 100
8.5 nm. Ex situ TEM-based nucleation and particle growth
observations, along with XRD and XPS analysis, shows that
vaterite phase CaCO
3
particles formed within 15 minutes of
reaction, and remains stable up to 30 minutes of the synthesis
reaction. The synthesized particles showed a considerably
higher antacid prole than their bulk counterpart or commer-
cial compounds used for gastric pH neutralization.
This work introduces nano-antacids with well controlled
properties such as size, crystal phase and morphology. The
gastric pH control of antacids are limited by its dissolution rate,
dose concentration, and stability of neutralized pH. Currently,
gastric-acidity patients use either high amount of sodium
bicarbonate or calcium carbonate based compounds. Nano-
scale engineering of calcium carbonate particles result in a high
surface area to volume size ratio, and therefore expand the
horizon of pH reutilization. Fundamental understanding of the
synthesis mechanism allows us to make nanoparticles that
dissolve at desired controlled rates. Dissolution rate of particles
in acidic medium depends on the crystal phase, which is crucial
for rapid pH neutralization and maintaining the buering
capacity for longer durations.
Conict of interest
All authors declare no competing nancial interest.
Acknowledgements
This work was performed in part at the Nano Research Facility
(NRF) of Washington University in St. Louis. This research
facility was a member of the National Nanotechnology Infra-
structure Network (NNIN) supported by the National Science
Foundation under Grant No. ECS-0335765. Partial support by
the Lopata Endowment and CMMN-WUSTL U54CA199092 is
gratefully acknowledged. AS was supported by the NCI Ruth
Kirschstein Fellowship F30 CA189435 and the Medical Scientist
Training Program at Washington University.
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... Calcium carbonate-based material has been extensively studied for its buffering properties, particularly for the treatment of gastro-esophageal reflux disease and peptic ulcers. 41 The calcium carbonate (CaCO 3 ) constituent of EB-TiO 2 (Figure 1(a)) suggests that it can effectively buffer acidic solutions. The buffering activity for the eggshell powder, EB-TiO 2 , and the Colgate brand of toothpaste at pH values of 2, 4 and 5, respectively, were much more effective than the other tested commercial toothpastes ( Figure 5). ...
... The enhanced buffering property of the carbonate-based products is attributed to their higher solubility in acidic solutions. This supports the argument of Raliya et al. 41 that the higher solubility of calcium carbonate-based material results in a greater concentration of ions in solution. Consequently, this leads to a higher buffering activity as the faster dissolution rate increases the pH quickly, thereby expanding the horizon of neutralization. ...
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Background In this study, we determined the acid-neutralizing capacity (ANC) of Mg/Al-Hydrotalcite-like compounds. The MgAl-hydrotalcites were synthesized by the co-precipitation method at room temperature using Mg/Al molar ratios 2:3. The synthesized bioactive nanomaterials were characterized by various physicochemical techniques such as TG/dTG, XRD, FT-IR spectroscopy, BET/BHJ, and SEM/EDX. The antacid activity assay was done by converting both synthesized samples into liquids, 1 g of which was added to 50 ml of deionized water at 37°C under vigorous agitation. The acid-neutralizing capacity (ANC) was evaluated with 0.1N HCl. The pH was constantly measured using a pH meter and values were recorded every minute up to 35 min. In order to improve the neutralizing power of the samples, we performed an exchange of chlorides by carbonates on the MgAl-HT3 synthesized. The exchanged Mg/Al-Hydrotalcite (MgAl- HTE) showed high acid neutralization capacity (up to 13.5 mEq/g). Objective This study aimed to synthesize MgAl-hydrotalcite-like compounds and evaluate their acid-neutralizing capacity. In order to can be good candidates for pharmaceutical applications as antacid drugs. Methods Following methods are used in this study: - Preparation of MgAl-hydrotalcite-like compounds was done by coprecipitation methods. - Characterization of samples was done by physico-chemical techniques such as TG/dTG, XRD, FT-IR spectroscopy, BET/BHJ and SEM/EDX. - Evaluation of acid-neutralizing capacity was done by titration procedure (Dose-titration). Results This protocol describes the preparation of MgAl-hydrotalcite-like compounds using the classical coprecipitation method. The synthesized samples were characterized by various physicochemical techniques such as TG/dTG, XRD, FT-IR spectroscopy, BET/BHJ, and SEM/EDX. The as-synthetized samples were used for the evaluation of their acid-neutralizing capacity (ANC). Further, an exchanged of MgAl-Hydrotalcite with carbonate was done for the purpose to increase the acid-neutralizing capacity. Conclusion In summary, this study describes a simple synthesis of MgAl-Hydrotalcites compounds by a co-precipitation method at constant pH around 10, with a ratio Mg/Al = 3:2 (referred to as MgAl-HT3 and MgAl-HT2). An exchange of the chlorides (not eliminated by washing) by the carbonates was carried out on hydrotalcite with a ratio Mg/Al = 3, and the solid obtained was named MgAl-HT3E. The materials MgAl-HT2, MgAl-HT3, and MgAl-TH3E were used to evaluate antacid activity. To this end, a study was conducted to determine the acid-neutralizing capacity (ANC). As result, the MgAl-HT3E was able to increase acid-neutralizing capacity and maintain an ideal pH. These results could be interesting to prepare novel antacid drugs (due to the low cost of synthesized materials) essentially the hydrotalcite of mg/Al ratio equal to 3 because of its relatively slow kinetics of releasing basic species and therefore of its beneficial action as an antacid.
Article
Calcium carbonate (CaCO3) is an ideal candidate for use in drug delivery system (DDS) for cancer cure due to good biocompatibility, pH-sensitivity and low-toxicity. However, developing a method that is fast and green, and have large-scale production of CaCO3-based DDS remains a challenge. Here, inspired by biomineralization, for the first time, we develop a one-pot, L-lysine (Lys)-mediated biomineralization method using a CO2 bubbling procedure to green, simply and quickly prepare CaCO3-based DDS. The presence of Lys not only improved the yield of CaCO3, but also controled morphology and crystal phase of CaCO3. Meanwhile, two different crystal forms of CaCO3 microspheres were used in the pH-responsive release of cancer drug Sanguinarine (SAN): calcite CaCO3 (CC) and vaterite CaCO3 (VC). The structure of the as-prepared CC and VC was characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Brunauer-Emmett-Teller analysis (BET). The possible formation mechanism was proposed. As a potential DDS, both different DDS showed good drug-loading capacity (CC: 63.5%; VC: 51.9%), good biocompatibility, pH-sensitivity and low-toxicity. Meanwhile, after loading the SAN, it had obvious inhibitory effects to cancer cells. However, they presented significant differences in drug loading rate, loading capacity and pH-sensitivity due to differences in crystal form and morphology. This biomineralization method of green synthesis of CaCO3-based DDS using CO2 provided a possibility for industrial application of DDS, and the comparative study of CaCO3 with different morphologies and crystal forms gave a good idea for the design of DDS.
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Combined application of nanotechnology and waste reutilisation process resulting in effective and cheap nano-photocatalyst have better dye degradation. Calcium oxide nanoparticles (CaO NPs) were synthesized from waste Eggshells (ES) by calcination process and characterized utilizing the analytical techniques such as XRD, SEM, EDAX, XPS and BET analysis. The synthesized CaO NPs were examined for photocatalytic dye degradation of two model dyes such as Methylene blue (MB) and Toluidine blue (TB) in aqueous medium. From the outcomes, it is clear that CaO effectively degraded both the dyes within 15 min (MB in 15 min and TB in 10 min). The studies include optimisation of parameter which found to be 7 pH, 20 ppm dye concentration and 50 mg of catalyst loading were effective operation condition. The kinetics of dye degradation follows pseudo first order, catalyst recycled for 7 cycles and chemical oxygen demand (COD) removal efficiency also analysed for degraded samples.
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Aim: CaCO3 nanoparticles (nano-CaCO3) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO3 to noninvasively monitor pH modulation and subsequent tumor response. Materials & methods: We synthesized ferromagnetic core coated with CaCO3 (magnetite CaCO3). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models. Results: Magnetite CaCO3-MRI imaging showed that nano-CaCO3 rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO3 infusion could inhibit metastasis. Conclusion: Nano-CaCO3 exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.
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In this paper, we present the results on immobilization of Photoditazine, the photosensitizer of the second generation, on vaterite (metastable modification of calcium carbonate) porous particles of two different sizes. The adsorption efficiency is found to be 3.0 and 3.2 wt % Photoditazine on vaterite particles with average diameters of 5 and 0.5 μm, respectively. The curves of Photoditazine desorption from vaterite particles are determined depending on the composition of the dispersion medium (water and bovine serum albumin solution). It is found that vaterite particles in water are subjected to recrystallization in accordance with the dissolution–precipitation mechanism. The presence of albumin molecules at a physiological concentration allows stabilizing metastable vaterite particles of micron and submicron size for at least 17 days.
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The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors. Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) in vivo increases pH asymptotically to 7.4. We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pH over time. The associated induction of tumor growth stasis is putatively interpreted as a pHe increase. This study establishes an approach to prepare nano-CaCO3 over a wide particle size range, a formulation that stabilizes the nanomaterials in aqueous solutions, and a pH-sensitive nano-platform capable of modulating the acidic environment of cancer for potential therapeutic benefits.
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The characteristic shapes, structures and properties of biominerals arise from their interplay with a macromolecular matrix. The developing mineral interacts with acidic macromolecules, which are either dissolved in the crystallization medium or associated with insoluble matrix polymers, that affect growth habits and phase selection or completely inhibit precipitation in solution. Yet little is known about the role of matrix-immobilized acidic macromolecules in directing mineralization. Here, by using in situ liquid-phase electron microscopy to visualize the nucleation and growth of CaCO3 in a matrix of polystyrene sulphonate (PSS), we show that the binding of calcium ions to form Ca-PSS globules is a key step in the formation of metastable amorphous calcium carbonate (ACC), an important precursor phase in many biomineralization systems. Our findings demonstrate that ion binding can play a significant role in directing nucleation, independently of any control over the free-energy barrier to nucleation.
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Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.
Book
Through both explanation and discussion, this title presents a complete review into mesocrystals, and accurately describes this relatively new study of established materials. This book also provides an introduction to other areas of crystallisation including self-assembly, classical crystallisation and colloidal crystals. Key features: Description of crystals as well as their formation processes and ways to modify them. Examines new ways towards the design of new materials and aids comprehension of the building principles of biominerals. Helps to explain many unusual observations made in the study of crystallisation. Written by the professionals in this subject 'Mesocrystals: New Self-Assembled Structures' outlines the future potential of this topic within a variety of disciplines including engineering science, physics and chemistry, making it a versatile and valuable text.
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Laportea aestuans (L.) Chew (Urticaceae) was historically ingested together with chalk by pregnant women in Ghana when suffering from heartburn. The aim of this study was to evaluate the antacid activity of the aerial parts of L. aestuans. Aerial parts of L. aestuans were collected in the Accra region of Ghana. The antacid activity was measured according to Fordtran's titration model. 90mL tap water and test material in a 500mL beaker were warmed to 37°C on a magnetic stirrer and was continuously stirred at approximately 30rpm in order to mimic the movements of the stomach. A titration was carried out with an artificial gastric acid to the end point of pH 3. The acid secretion rate was approximately 3mL and pH was monitored with a pH meter. Concentrations of 666 and 1,332mg dried plant material were tested, both with and without addition of calcium carbonate (CaCO3). Both CaCO3 and L. aestuans had a significant better ability than water to neutralise an artificial stomach acid. 666mg plant material together with CaCO3 compared to CaCO3 alone showed approximately the same neutralisation time. When mixing 1,332mg plant material with CaCO3 the neutralisation time was significantly higher than for CaCO3 alone and exhibited an antacid profile that was able to maintain the neutralising activity one pH-unit higher for an extended period of time. The results indicate that L. aestuans showed an antacid activity when combined with CaCO3. With further investigations of the active compound, mechanism of action and possible toxicity, the plant could form the basis of a novel antacid. Copyright © 2015. Published by Elsevier Ireland Ltd.
Article
The influence of silk fibroin (SF) on calcium carbonate (CaCO3) bio-mineralization has been investigated, however the formation of small, uniform SF-regulated vaterite microspheres has not been reported. In this work, spherical CaCO3 was synthesized via co-precipitation in the presence of SF. SF nanostructures were first tuned by self-assembly at 60oC to provide better control of the nucleation of CaCO3. Subsequently, monodisperse vaterite microspheres about 1.1 μm were generated by controlling aggregation and growth of CaCO3 under appropriate concentrations of SF and Ca ions. In contrast to unstable vaterite, the microspheres generated in the present study have sufficient stability in aqueous solution for at least 8 days without transformation into calcite, due to the electrostatic interactions between the Ca ions and the preassembled SF nanostructures. The microspheres as drug carriers of doxorubicin (DOX) were assessed and found to have good encapsulation efficiency, sustained drug release without burst release and pH-sensitivity. These new SF/CaCO3 hybrids may provide new options for various biomedical applications.
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Mechanisms of nucleation from electrolyte solutions have been debated for more than a century. Recent discoveries of amorphous precursors and evidence for cluster aggregation and liquid-liquid separation contradict common assumptions of classical nucleation theory. Using in situ transmission electron microscopy (TEM) to explore calcium carbonate (CaCO3) nucleation in a cell that enables reagent mixing, we demonstrate that multiple nucleation pathways are simultaneously operative, including formation both directly from solution and indirectly through transformation of amorphous and crystalline precursors. However, an amorphous-to-calcite transformation is not observed. The behavior of amorphous calcium carbonate upon dissolution suggests that it encompasses a spectrum of structures, including liquids and solids. These observations of competing direct and indirect pathways are consistent with classical predictions, whereas the behavior of amorphous particles hints at an underlying commonality among recently proposed precursor-based mechanisms.
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The CaCO3 microparticle growth from supersaturated aqueous solutions in the presence of oleic acid stabilized magnetite nanoparticles as a water-based magnetic fluid and a natural strong–weak polyanion, chondroitin sulfate A, has been investigated. The study follows the microparticle formation characteristics under different relative CaCO3–magnetite–polymer ratios. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to provide high resolution on particle morphology and distribution of magnetite in the composites and flow particle image analysis (FPIA) to evidence their mean size and circularity, whereas X-ray diffraction (XRD) and Raman spectroscopy were used to determine polymorph type and crystallite characteristics. Polymer and magnetite presence in the composite particles was evidenced by energy dispersive X-ray (EDX), TEM, particle charge density, and ζ potential. The magnetic properties of the obtained microparticles were also investigated. The pH stability of the new composites, given by the presence of acid oleic stabilized magnetite nanoparticles and polymer, has been followed by ζ potential variation.
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The rate and extent of acid consumption of an antacid suspension and tablet were evaluated by in vitro and in vivo techniques. Four different test procedures were used to estimate in vitro antacid reactivity. In vivo effects were determined in the fasted and postcibal states in normal human subjects by a radiotelemetry procedure. The duration of elevation of intragastric pH >3 was in agreement with in vitro estimates of total acid consumption of the antacid. There was also good correlation between onset, extent, and duration of in vivo antacid activity and a modified in vitro Beekman antacid test procedure. There was no significant difference in antacid activity of the tablet or suspension in either in vitro or in vivo test procedures. A wide variation in antacid activity was observed between subjects and also in the fasted versus postcibal states. These studies emphasize the requirements for standardization of antacid products by comparative in vitro and in vivo evaluations to facilitate individualized dose titration of the antacid in each patient and correlation of the acid secretion rate in various types of GI disease with the antacid dose.