Optimizing CaCO3 Matrix Might Allow To Raise Their Potential Use In Biomedical Application
Received Date: Jun 26, 2018 / Accepted Date: Jul 16, 2018 / Published Date: Jul 23, 2018
The significant step in CaCO3 fabrication is to obtain homogenous population. There is a wide application in biomedical and industry market, since many reports have been investigated possible control of its diameter and shape during fabrication. Nowadays, CaCO3 template can be synthesised in diameter near or less than 120 nm. Control factors affected CaCO3 nucleation with integration of polymer inside were the main purpose in CaCO3 modification. In spite of great work that was done, designing of CaCO3 matrix as a way to be more attractive for hydrophobic cargo molecules could need a second eye for other investigation. The modification of CaCO3 matrix not only can provide mechanical support of all of CaCO3 architecture, or as a vehicle for hydrophobic molecules but also can be used as a smart vector for integration other drug delivery system such as liposome, micelles or even lipid nanoparticles.
Keywords: CaCO3 fabrication; Homogenous population; Liposome; Micelle; Polymers
1) There is no any sign for histological toxicity after core removal with EDTA and it is safer in handling than other templates .
2) The natural porosity of CaCO3 micro/nanoparticles has provided them with great advantages for layer by layer adsorption . Hence polymers used in polyelectrolyte multilayer assembly, will diffuse through these porous forming interior polyelectrolyte network complexes having the same materials presented in the shell after the core removal [2,7]. These connected networks might provide mechanical and protective support for capsules architecture  allowing for long storage and can cause good stability in blood stream.
3) CaCO3 crystals can be formed with simple mixing of inexpensive and widely accessible salt precursors, CaCl2 and Na2CO3 and the core can be removed by EDTA with no more effect on layer by layer capsules [4,9]. Cargo molecules could be encapsulated inside CaCO3 matrix by either using co-precipitation in its porous (Figure 1A, pre loading method)  or by loading cargo molecule inside Layer by Layer (LbL) capsules after core removal (Figure 1, post loading method) .
The above notable advantages give CaCO3 template much important use in medical applications and also can be considered as a good example to study mechanical and physical properties in carrier fabrication. Although CaCO3 has attracted many attentions and used in wide applications, the matrix of CaCO3 is still under optimization. Previously its aggregated state, polymorphism crystallization and its micrometer diameter were completely solved . The nucleation process of CaCO3 during fabrication becomes a way for improving the final CaCO3 template. Indeed, the quality of the resultant microparticles is introduced to be strongly dependent on the experimental conditions such as the type of the used salts, their concentration, pH, temperature, rate of mixing solutions and the intensity of agitation of the reaction mixture [11-14]. In addition, inclusion of various additives, such as divalent cations, organic solvents and macromolecules (synthetic or natural) added to the reaction mixture, are shown to exert a strong effect on the morphology of the formed CaCO3 microparticles [15-18].
Control of CaCO3 Fabrication
In previous reports, CaCO3 synthesis was controlled by adding organic materials and its derivatives during fabrication. These materials might strongly influence the crystallization of CaCO3 whereas, stabilized amorphous CaCO3 could be formed due to the functional groups of organic material leading to control nucleation, growth, and alignment of the crystals [19,20]. Currently, simple polyelectrolytes have been used to control the crystallization of calcium carbonates during synthesis . The functional group of polyelectrolyte allows to control strongly nucleation and crystals agglomeration. Hence the single particle of CaCO3 is agglomerated by tiny smaller crystals resulting from attachment of Ca2+ and CO3- nuclei. In case of absence of electrostatic balance, these nuclei tend to bind with other in the same solution causing aggregation and growth in diameter. Furthermore, their aggregation is not easily separated by using mechanical separation (example: vortex and shaker or even physical separation like sonication). The active group of both polyelectrolyte cationic and anionic polymers could contribute to keep balance among nuclei. This could be explained from the fact that Ca2+ and CO3- nucleation can accept the active group of polymers to keep them in most case under electrostatic balance. This property allows to reduce growth of crystal, furthermore leading to diameter control (Figure 2) .
Figure 2: Scheme of control of CaCO3 crystallization by integration polymer inside matrix of CaCO3 (reproduced with permission from Ref .
Many polymers have been used to control CaCO3 during fabrication such as poly (sodium 4-styrene-sulfonate) PSS [22,23], Poly (allylamine hydrochloride PAH , Poly acrylic acid (PAA) and Chitosan  (CH), poly (vinyl alcohol) (PVA), polyacrylamide, poly(N-isopropyl acrylamide), poly(N-vinyl pyrrolidone), and poly(ethylene oxide) . From previous studies, it is indicated that any peptides can influence strongly on CaCO3 nucleation, should certainly alter the morphology of CaCO3 .The demission of CaCO3 from diameter and shape is already studied and the both are completely controlled by adding polymers during fabrication. As example, PAA can reduce diameter of CaCO3 to less than 200 nm and PAH can control morphology of CaCO3 toward elongated shape like rods. It could be concluded that CaCO3 mineralization can accept physicochemical properties of used polymers.
Drawback of CaCO3 Controlled by Polymers
As a rule, the spherical CaCO3 microparticles that were obtained by simple mixing of Ca2+ and CO3- can be turned into rhombohedral calcite microcrystal after several weeks of storage in water at room temperature because of re-crystallization . In case of used polymer, there is no shape change during successive six months of storage. Since the negatively charged of PSS are adsorbed on the matrix of carbonate nanoparticles constituting the porous CaCO3 microparticles and prevents the re-crystallizations. High stability of the CaCO3 microparticles in water is very important for the successive LbL assembly. However this storage is linked much with distilled water, milli Q water or buffer pH 7.2. In case CaCO3 kept at solution having ionic salts, acidic solution, or strong minerals, Its morphology can be changed and re-crystallization is expected. Indeed the polymer entrapped CaCO3 matrix could answer the ionic stress allowing to modify CaCO3 configuration. Chitosan, poly acrylic acid , poly allylamine hydrochloride  are known with their answer for ionic stress and they could modulate their chain after they are crystallized inside matrix of CaCO3. It is proven in case of polymer integrated in a matrix of CaCO3 to coat them with layer-by-layer alternate adsorption or to keep them as dried particles at room temperature or to keep them in water. This environment could prevent CaCO3 re-crystallization.
Designing Matrix of CaCO3
Recently the porous channel of CaCO3 was employed completely as a safe vector for protein encapsulation (Figure 3) .
Figure 3: Scanning Electron Microscopy image of CaCO3 showing Pores. (reproduced with permission from Ref ).
The empty pores were formed among tiny crystals of CaCO3 during crystallization resulting in connected network after core removal. These networks could be occupied by cargo molecules. Hence, cargo molecule can be mixed initially with CaCl2 or Na2CO3 according toits charge and its ability to be stable under alkaline pH of Na2CO3. After reaction of the mixture, cargo molecules will be entrapped inside matrix of CaCO3 . In another case, biomolecules can be adsorbed in the pores of the CaCO3 crystals, after their crystallization by physical adsorption [29,14] chemical cross-linking  coprecipitation,  and trapping by coating with polyelectrolyte multilayers. In order to control the porosity of CaCO3 crystal, temperature should be optimized during fabrication . It is found that the CaCO3 crystals with larger pores (prepared at 22 or 45°C) will be even more penetrable for molecules of interest. The designing of CaCO3 porous was initially employed by adding several type of polymers during fabrication such as carboxymethyl cellulose (CMC), a negatively charged polysaccharide, which was simultaneously incorporated providing attractive force for positively charged drugs such as doxorubicin (DOX) [28,14]. Wang et al. (2006) reported that ibuprofen, a lipophilic drug, was loaded into the polystyrene sulfonate (PSS)-doped CaCO3 microparticles. Due to the charge repulsion, the loading amount of ibuprofen was not very large. Moreover, the additive of PSS has some uncertainties for biomedical applications . In addition, porous of CaCO3 were design by Cyclodextrins to be accommodated for hydrophobic materials such as curcumin . Another designing is to generate block co polymer micelles inside CaCO3 matrix during fabrication. Since polystyrene-blockpoly (acrylic acid) (PS-b-PAA) was added drop wise into Na2CO3 aqueous solution under vigorous agitation then CaCl2 was rapidly poured into the mixed solution under vigorous agitation . It is found that CaCO3 cores possess high connected and very stable internal area . Yashchenok and co-workers have introduced liposomes for modification of CaCO3 cores and demonstrated that ultrasound (US) triggered mixing of the liposome encapsulated moleculesand coreembedded molecules may be achieved in confined volumes . The other modification for CaCO3 matrix is to involve air bubbles inside matrix during fabrication by using Plexiglas reactor .
CaCO3 and Biological Toxicity
Calcium carbonate nanoparticles have exhibited successful application as biological subcutaneous delivery [5,34,35]. Many reports confirmed their safe use for raise their therapeutic activity without harming biosystems . Jaji and his co-workers investigated the safety of cockle shells (ANC) as a potential agent for subcutaneous delivery of biology and drug materials. Confirming that there is no mortality, it was recorded at the end of the acute and subchronic toxicity experiments for calcium carbonate injected subcutaneously. With a LD50 of 6450 mg/kg body weight, calcium carbonate merged a wide margin of safety and low acute toxicity . The Single doses of 1770 and 11,800 mg/m2 of calcium carbonate did not form any cytotoxicity while the high dose of 29,500 mg/m2 introduced some toxic signs and lesions. Okogbue et al. (2014) showed that histological results revealed that calcium carbonate had no negative impact on the body tissues of the prawns tested both on the muscle and carapace . Furthermore, the total calcium ions was higher in serum after administration of calcium carbonate powder versus calcium citrate tablets . The multilayered nanocapsules produced by calcium carbonate core removal observed no evidence for any histological toxicity because CaCO3 crystals can be removed completely by using disodium ethylenediaminetetraacetic acid (EDTA) and the ions formed upon dissolution can be diffused out through the capsule wall rapidly . In case shell, the histological toxicity depends on the type of polymer formed layers of capsules. From the above mention, calcium carbonate could be highlighted their potential use in biomedical and industrial applications. Recently, many type of particles have been introduced as great vehicles for drug delivery system such as self assembly polymers [40,41], liposomes [42,43] and micelles [44,45], LbL CaCO3 [10,46], and LbL magnetic nanoparticles .
The potential use of drug delivery system could be raised with smart modification of CaCO3. In this sense, the shell and core become more efficient to encapsulate several drugs with hydrophobic and hydrophilic properties. Several studies have been confirmed that CaCO3 crystallization could be acceptable for development.
- Volodkin DV, Larionova NI, Sukhorukov GB (2004) Protein encapsulation via porous CaCO3 microparticles templating. Biomacromolecules 5: 1962-72.
- Sukhorukov GB, Volodkin DV, Günther AM, Petrov AI, Shenoy DB, et al. (2004) Porous calcium carbonate microparticles as templates for encapsulation of bioactive compounds. J Mater Chem 14: 2073-81.
- Stein EW, Volodkin DV, McShane MJ, Sukhorukov GB (2006) Real-time assessment of spatial and temporal coupled catalysiswithin polyelectrolyte microcapsules containing co-immobilized glucose oxidase and peroxidase. Biomacromolecules 7: 710-9.
- Pechenkin MA, Mohwald H, Volodkin DV (2012) pH- and salt-mediated response of layerby- layer assembled PSS/PAH microcapsules: fusion and polymer exchange. SoftMatter 8: 8659-65.
- Zhang X, Sun M, Zheng A, Cao D, Bi Y, Sun J (2012) Preparation and characterization of insulin-loaded bioadhesive PLGA nanoparticles for oral administration. Eur J Pharm Sci 45: 632-638.
- Volodkin DV, Petrov AI, Prevot M, Sukhorukov GB (2004) Matrix polyelectrolyte microcapsules: newsystem for macromolecule encapsulation. Langmuir 20: 3398-406.
- Volodkin DV, Ball V, Voegel JC, Mohwald H, Dimova R, et al. (2007) Control of the interaction between membrane or vesicles: adhesion, fusion and release of dyes. Colloids Surf A: Physicochem Eng Asp 303: 89-96.
- Volodkin D
- Adv Colloid Interface Sci
- Feoktistova N, Rose J, Prokopović VZ, Vikulina AS, Skirtach A, et al. (2016) Controlling the vaterite caco3 crystal pores. design of tailor-made polymer based microcapsules by hard templating. Langmuir 32: 4229-38.
- Hanafy NA, De Giorgi ML, Nobile C, Rinaldi R, Leporatt S (2015) Control of colloidal caco3 suspension by using biodegradable polymers during fabrication”Beni-Suef University Journal of Basic and Applied Sciences 4: 60-70.
- Kitamura M, Konno H, Yasui A, Masuoka H (2002) Controlling factors and mechanism of reactive crystallization of calcium carbonate polymorphs from calcium hydroxide suspensions. J Cryst Growth 236: 323e32.
- Yu SH, Colfen H, Xu AW, Dong W (2004) Complex spherical BaCO3 superstructures self-assembled by a facile mineralizationprocess under control of simple polyelectrolytes. Cryst Growth Des 4: 33e7.
- Wang C, He C, Tong Z, Liu X, Ren B, et al. (2006) Combination of adsorption by porous CaCO3 microparticles and encapsulation by polyelectrolytemultilayer films for sustained drug delivery. Int J Pharm 308: 106e67.
- Babou-Kammoe R, Hamoudi S, Larachi F, Belkacemi K (2012) Synthesis of CaCO3 nanoparticles by controlled precipitation of saturatedcarbonate and calcium nitrate aqueous solutions. J Chem Eng 90: 26e33.
- Kato T, Susuki T, Amamiya T, Irie T, Komiyama M, et al. (1998) Effects of macromolecules onthe crystallization of CaCO3 the formation of organic/inorganic Composites. Supramol Sci 5: 411.
- Manoli F, Dalas E (2000) Spontaneous precipitation of calcium carbonate in the presence of ethanol, isopropanol anddiethylene glycol. J Cryst Growth 218: 359e64.
- Didymus M, Oliver P, Mann S, De Vries AL, Hauschka PV, et al. (1993) Influence of low-molecularweight and macromolecular organic additives on the morphology of calcium carbonate. J Chem Soc Faraday Trans 89: 2891e900.
- Parakhonskiy BV, Tessarolo F, Haase A, Antolini R (2012) Dependence of submicron vaterite container release properties on pH and ionicstrength of the surrounding solution. Adv Sci Technol 86: 81e5.
- Gower LA, Tirrell DA (1998) Calcium carbonate films and helices grown in solutions of poly (aspartate). J Cryst Growth 191: 153-60.
- Jada A, Verraes A (2003) Preparation and micro electrophoresis characterisation of calcium carbonate particles in the presence of anionic polyelectrolyte. Colloids Surf A: Physicochem Eng Asp 219: 7-15.
- Xu L (2013) Sacrificial PSSedoped CaCO3 template to prepare chitosan capsules and their deformation under bulk pressure. Polym Bull 70: 455-65.
- Tong WJ, Dong WF, Gao CY, Möhwald H (2005) Charge control permeability of polyelectrolyte microscopy. J Phys Chem B 109: 13159-65.
- Jiafu S, Chen Y, Shaohua Z, Xiaoli W, Zhongyi J, et al. (2013) Polydopamine microcapsules with different wall structures prepared by a template-mediated method for enzyme immobilization. ACS Appl Mater Interfaces 5: 9991-7.
- Chen CL, Qi J, Zuckermann RN, De Yoreo JJ (2011) Engineered biomimetic polymers as tunable agents for controlling CaCO3 mineralization. J Am Chem Soc 133: 5214-7.
- Hanafy NAN, Quarta A, Ferraro MM, Dini L, Nobile C, et al. (2018) Polymeric nano-micelles as novel cargo-carriers for LY2157299 liver cancer cells delivery. Int J Mol Sci 19:3.
- Hanafy NAN, De Giorgi ML, Nobile C, Cacione M, Rinaldi R, et al. (2016) CaCO3 rods as chitosan polygalacturonic acid carriers for brompyruvic acid delivery. Science of Advanced Materials (SAM) 8: 514-523.
- Peng C, Zhao Q, Gao C (2010) Sustained delivery of doxorubicin by porous CaCO3 and Chitosan/Alginate multilayers-coated CaCO3 microparticles. Colloids Surf A Physicochem Eng Asp 353: 132-139.
- De Temmerman ML, Demeester J, De Vos F, De Smedt SC (2011) Encapsulation performance of layer-by-layer microcapsules for proteins. Biomacromolecules 12: 1283-1289.
- Kurapati R, Raichur AM (2013) Composite cyclodextrin-calcium carbonate porous microparticles and modified multilayer capsules: novel carriers for encapsulation of hydrophobic drugs. J Mater Chem B 1: 3175-3184.
- Yan XH, Li JB, Mohwald H (2012) Templating assembly of multifunctional hybrid colloidal spheres. Adv Mater 24: 2663−2667.
- Yashchenok AM, Delcea M, Videnova K, Jares-Erijman EA, Jovin TM, et al. (2010) Enzyme reaction in the pores of CaCO3 particles upon ultrasound disruption of attached substrate-filled liposomes. Angew Chem Int Ed 49: 8116-20.
- Altiner M (2018) Influences of CO2 Bubbling Types on Preparation of Calcite Nanoparticles by Carbonation Process. Period. Polytech. Chem Eng 62: 209-214.
- Ueno Y, Futagawa H, Takagi Y, Ueno A, Mizushima Y (2004) Drug-incorporating calcium carbonate nanoparticles for a new delivery system. J Control Release 103: 93-98.
- He XW, Liu T, Chen YX, Cheng DJ, Li XR, et al. (2008) Calcium carbonate nanoparticle delivering vascular endothelial growth factor-C siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo. Cancer Gene Ther 15: 193-202.
- Aguilar F, Dusemund B, Galtier P, Gilbert J, Gott DM, et al. (2011) Scientific opinion on re-evaluation of calcium carbonate (E 170) as a food additive. EFSA 9: 231854.
- Okogbue BC, Ansa EJ, Hart AI (2014) Histological impact of calcium carbonate on the juveniles of the brackish river prawn. Inter J Scie Tech Res 3: 2277-8616.
- Higaki M, Kameyama M, Udagawa M, Ueno Y, Yamaguchi Y, et al. (2006) Transdermal delivery of calcium carbonate-nanoparticles containing insulin. Diabetes Technology Therapeutics 8: 369-374.
- Wang H, Bua P, Capodice J (2014) A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women. Food Nutr Res 22:58.
- Zhao Q1, Li B (2008) pH-controlled drug loading and release from biodegradable microcapsules. Nanomedicine 4: 302-10.
- Khanal S, Adhikari U, Rijal NP, Bhattarai SR, Sankar J, et al. (2016) pH-responsive PLGA nanoparticle for controlled payload delivery of diclofenac sodium. J Funct Biomater 7: 3.
- Jiang X, Lin H, Jiang D, Xu G, Fang X, et al. (2016) Co-delivery of VEGF and bFGF via a PLGA nanoparticle-modified BAM for effective contracture inhibition of regenerated bladder tissue in rabbits. Sci Rep 6: 20784.
- Al-Ahmady Z, Lozano N, Mei KC, Al-Jamal WT, Kostarelos K (2016) Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release. Int J Pharm 514: 133-141.
- Seleci M, Ag Seleci D, Scheper T, Stahl F (2017) Theranostic liposome-nanoparticle hybrids for drug delivery and bioimaging. Int J Mol Sci 18: 1415.
- Zhang R, Leeper CN, Wang X , White TA, Ulery BD (2018) Immunomodulatory vasoactive intestinal peptide amphiphile micelles. Biomater Sci 6: 1717-1722.
- Hanafy NAN, El-Kemary M, Leporatti S (2018) Reduction diameter of CaCO3 crystals by using poly acrylic acid might improve cellular uptake of encapsulated curcumin in breast cancer. J Nanomed.
- Zhang R, Kramer JS, Smith JD, Allen BN, Leeper CN, et al. (2018) Vaccine adjuvant incorporation strategy dictates peptide amphiphile micelle immunostimulatory capacity. AAPS J 20: 73.
Citation: Hanafy NAN, El-Kemary M, Leporatti S (2018) Optimizing CaCO3 Matrix Might Allow To Raise Their Potential Use In Biomedical Application. J Nanosci Curr Res 3: 124. DOI: 10.4172/2572-0813.1000124
Copyright: © 2018 Hanafy NAN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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