1. Introduction: A Field of Tension in a World of Change
1.2 Research gap and research questions
O benzonidazol nanopartículado apresenta efeito tripanocida sobre as três formas de Trypanosoma cruzi, sendo esse efeito mais potente e mais rápido do que o observado para benzonidazol em sua forma livre, os dois tratamentos promovem alterações celulares indicativas de necrose envolvendo dano mitocondrial, demonstrando assim que a entrega de fármacos por meio de nanosistemas é uma ferramenta eficaz para potencializar o efeito terapêutico de fármacos pouco seletivos. Os dados do presente trabalho poderão ser úteis para o desenvolvimento de novos sistemas nanoparticulados e para a investigação dos efeitos in vivo dessa nanopartícula, quanto a eficácia terapêutica e toxicidade.
REFERÊNCIAS
ABE, F. et al. Trypanocidal Constituents in Plants 1 . Evaluation of Some Mexican Plants for Their Trypanocidal Activity and Active Constituents in Guaco , Roots of Aristolochia
taliscana. Biol . Pharm. Bull, v. 25, n. 9, p. 1188–1191, 2002a.
ABE, F. et al. Ursolic Acid as a Trypanocidal Constituent in Rosemary. Biol. Pharm. Bull., v. 25, n.11, p1485-1487, 2002b.
ADADE, C. M.; CHAGAS, G. S. F.; SOUTO-PADRÓN, T. Apis mellifera venom induces different cell death pathways in Trypanosoma cruzi. Parasitology, v. 139, n. 11, p. 1444–61, 2012.
AFONSO, A M.; EBELL, M. H.; TARLETON, R. L. A systematic review of high quality diagnostic tests for Chagas disease. PLoS neglected tropical diseases, v. 6, n. 11, p. e1881, 2012.
ÁLVAREZ-BARRIENTOS, A. et al. Applications of Flow Cytometry to Clinical Microbiology. Clinical Microbiology Reviews, v. 13, n. 2, p. 167–195, 2000. ALVES, C. R. et al. Trypanosoma cruzi : Attachment to perimicrovillar membrane
glycoproteins of Rhodnius prolixus. Experimental Parasitology, v. 116, p. 44–52, 2007. BAHARARA, J. et al. Anti-Angiogenesis Effect of Biogenic Silver Nanoparticles
Synthesized Using Saliva Officinalis on Chick Chorioalantoic Membrane (CAM). Molecules, v. 19, n. 9, p. 13498–13508, 2014.
BARACCA, A. et al. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F0 during ATP synthesis. Biochimica et Biophysica Acta
(BBA) - Bioenergetics, v. 1606, n. 1-3, p. 137–146, 2003.
BARTH, W. Nanotecnologia “Há muito espaço lá embaixo”. Rev Trim, v. 36, n. 153, p. 669–695, 2006.
BD PHARMINGENTM. Technical Data Sheet- PE Annexin V Apoptosis Detection Kit I. Disponível em: <http://www.bdbiosciences.com/ds/pm/tds/559763.pdf >. Acesso em: 5 nov. 2015.
BEARD, C. B. et al. Chagas Disease in a Domestic Transmission Cycle in Southern-USA.
Emerging Infectious Disease, v. 9, n. 1, p. 103–105, 2003.
BECERRA, M. C. et al. In vitro activity of N-benzenesulfonylbenzotriazole on Trypanosoma cruzi epimastigote and trypomastigote forms. Experimental parasitology, v. 131, n. 1, p. 57– 62, 2012a.
BEHESHTI, N. et al. Efficacy of biogenic selenium nanoparticles against Leishmania major: in vitro and in vivo studies. Journal of trace elements in medicine and biology : organ of
the Society for Minerals and Trace Elements (GMS), v. 27, n. 3, p. 203–7, 2013.
BENINCASA, M. et al. Antifungal Activity of Amphotericin B Conjugated to Carbon Nanotubes. ACS Nano, v. 5, n. 1, p. 199–208, 2011.
BEZERRA, E. M. et al. Optical Absorption of the Antitrypanocidal Drug Benznidazole in Water.Molecules, p. 4145–4156, 2014.
BIRADAR, S. et al. Optimization of process parameters of polymer solution mediated growth of calcium carbonate nanoparticles. Iop Publishing Nanotechnology, v. 23, 2012.
BISOGNI, E. et al. Ensinos e aprendizagem de conceitos matemáticos relacionados à nanociência por meio da modelagem matemática. Acta Scientiae, v. 14, n. 2, p. 200–214, 2012.
BONNEY, K. M.; ENGMAN, D. M. Chagas heart disease pathogenesis: One mechanism or many. NIH Public Access. v. 8, n. 6, p. 510–518, 2010.
BORGES, A. R. et al. Trypanocidal and cytotoxic activities of essential oils from medicinal plants of Northeast of Brazil. Experimental Parasitology, v. 132, n. 2, p. 123–128, 2012. BORGHETTI, F.; GUAZZELLI, M. J. Manual de Bolso das Tecnologias em Nanoescala … e a Teoria do “ Little BANG ”Intercâmbio, Informações, Estudos e Pesquisas. ETC group, [s.l: s.n.], 2005.
BRANQUINHO, R. T. et al. Sesquiterpene lactone in nanostructured parenteral dosage form is efficacious in experimental Chagas disease. Antimicrobial agents and chemotherapy, v. 58, n. 4, p. 2067–75, 2014.
BRASIL, Ministério da Saúde, Secretaria de vigilância em Saúde. Doença de Chagas. Caderno 10. 2012. Disponível em:
http://portal.saude.gov.br/portal/arquivos/pdf/gve_7ed_web_atual_doenca_de_chagas.pdf. Acesso em: 29 nov. 2015.
BRAUKAISER. Microscope use in brewing. BRAUKAISER. Disponível em:
<http://braukaiser.com/download/Neubauer_hemocytometer.pdf>. Acesso em: 16 out. 2015. BRAZÃO, V. et al. Immunomodulatory properties and anti-apoptotic effects of zinc and melatonin in an experimental model of chronic Chagas disease. Immunobiology, v. 220, n. 5, p. 626–633, 2015.
BRENER, Z.; ANDRADE, Z. A.; BARRAL-NETTO, M. Trypanosoma cruzi e Doença de Chagas. [s.l: s.n.], 2000.
BURDA, C. et al. hemistry and properties of nanocrystals of different shapes. Chemical
review, v. 105, n. 4, p. 1025–1102, 2005.
CAMARGO, E. . Growth and Differentiation in Trypanosoma Cruzi. I. Origin of Metacyclic Trypanosomes in LiquidMedia. Rev do inst de medicina tropical de são paulo, v. 6, p. 93– 100, 1964.
CANÇADO, J. R. Criteria of Chagas disease cure. Memorias do Instituto Oswaldo Cruz, v. 1, p. 331–335, 1999.
CANÇADO, J. R. Long term evaluation of etiological treatment of Chagas disease with Benznidazole. Memorias do Instituto Oswaldo Cruz, v. 44, p. 29–37, 2002.
CAO, G. Nanostructures and Nanomaterials: Synthesis, Properties and Applications.
Imperial College Press, 2004.
CARNEIRO, Z. A et al. In vitro and in vivo trypanocidal activity of H2bdtc-loaded solid lipid nanoparticles. PLoS neglected tropical diseases, v. 8, n. 5, p. e2847, 2014.
CASTRO, D. P. et al. Trypanosoma cruzi : Ultrastructural studies of adhesion , lysis and biofilm formation by Serratia marcescens. Experimental Parasitology v. 117, p. 201–207, 2007.
CECILIO, A. B. et al. Molecular characterization of Lys49 and Asp49 phospholipases A2 from snake venom and their antiviral activities against Dengue virus. Toxins, v. 5, p. 1780– 1798, 2013.
CHAGAS, C. Nova tripanozomiaze humana. Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruz n. gen, n. ap, ajente etiolojico de nova entidade morbida do homem.
Memorias do Instituto Oswaldo Cruz, p. 1–170, 1909.
CHEANG, T. et al. Calcium carbonate/CaIP6 nanocomposite particles as gene delivery vehicles for human vascular smooth muscle cells. Journal of Materials chemistry, v. 20, p. 8050–8055, 2010.
CHEN, S. . et al. Co-delivery of genes and drugs with nanostrustured calcium carbonate for cancer therapy. Jornal The Royal Society of Chemistry, v. 2, 2012.
COURA, J. R. Chagas disease : what is known and what is needed – A background article.
Memorias do Instituto Oswaldo Cruz, v. 102, n. 1, p. 113–122, 2007.
COURA, J. R.; BORGES-PEREIRA, J. Chagas disease: 100 years after its discovery. A systemic review. Acta tropica, v. 115, n. 1-2, p. 5–13, 2010.
COURA, J. R.; BORGES-PEREIRA, J. Review Article / Artigo de Revisão Chagas disease . What is known and what should be improved : a systemic review Doença de Chagas . O que é conhecido e o que deve ser melhorado : uma visão sistêmica. Revista da Sociedade
Brasileira de Medicina Tropical, v. 45, n. 3, p. 286–296, 2012.
DA SILVA, C. F. et al. In vitro and in vivo activity of the chloroaryl-substituted imidazole viniconazole against Trypanosoma cruzi. Parasitology, v. 141, n. 03, p. 367–373, 2014. DA SILVA, R. et al. Trypanocidal structure-activity relationship for cis- and trans- methylpluviatolide. Phytochemistry, v. 69, n. 9, p. 1890–1894, 2008.
DE ANDRADE, A. R. Aplicação da citometria de fluxo para otimização do método de
determinação da potência da alfaepoetina humana recombinante em bio-manguinhos / fiocruz. 2011. 80f. Dissertação (Mestrado profissional em Tecnologia de Imunobiológicos) –
Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro. 2011. DE SOUZA, E. M. et al. Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. Experimental
parasitology, v. 127, n. 2, p. 429–35, 2011.
DELAVARI, M. . et al. In Vitro Study on Cytotoxic Effects of ZnO Nanoparticles on Promastigote and Amastigote Forms of Leishmania major (MRHO/IR/75/ER). Iran J.
Parasitol, v. 9, n. 1, p. 6–13, 2014.
DIAZ, J. H.; HISTORY, T.; BURDEN, D. Recognizing and Reducing the Risks of Chagas Disease (American Trypanosomiasis) in Travelers. J. Travel. MED v. 15, n. 3, p. 184–195, 2008.
DRUGS FOR NEGLECTED DISEASES INITIATIVE. DNDi, 2015. Disponível em:
http://www.dndi.org/diseases-projects/diseases/chagas.html Acesso em : 09 de nov. de 2015. FUJIWARA, M. . et al. Calcium carbonate microcapsules encapsulating biomacromolecules.
GASCON, J.; BERN, C.; PINAZO, M.-J. Chagas disease in Spain, the United States and other non-endemic countries. Acta tropica, v. 115, n. 1-2, p. 22–7, 2010.
HALAMODA-KENZAOUI, B. et al. Dispersion Behaviour of Silica Nanoparticles in Biological Media and Its Influence on Cellular Uptake. Plos One, v. 10, n. 10, p. e0141593, 2015.
HASSLOCHER-MORENO, A. M. et al. Safety of benznidazole use in the treatment of chronic Chagas ’ disease. Antimicrob Chemother, v.67, p. 1261–1266, 2012.
HERNÁNDEZ-CHINEA, C. et al. In vitro activity of synthetic tetrahydroindeno[2,1- c]quinolines on Leishmania mexicana. Parasitology International, v. 64, n. 6, p. 479–483, 2015.
HIGAKI, M. D. M. . et al. Transdermal Delivery of CaCO 3 -Nanoparticles Containing Insulin. Diabetes Technology & Therapeutics, v. 8, n. 3, p. 369–374, 2006.
HIGINO, T.M.M. Novas perspectivas de fármacos com propriedade tripanocida: estudos biológicos de compostos heterocíclicos. 2012.84p. Dissertação (Mestrado Acadêmico em Saúde Pública) – Centro de Pesquisa Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, 2012. Disponível em: http://www.cpqam.fiocruz.br/bibpdf/2012higino-tmm.pdf Acesso em: 16 out.2013.
INOVECARE. INOVECARE. Disponível em: <http://www.inovecare.com/pesquisa.html>. Acesso em: 19 out. 2015.
JOUVE, N. et al. The involvement of CD146 and its novel ligand galectin-1 in apoptotic regulation of endothelial cells. J Biol Chem, v. 288, n. 4, p. 2571–2579, 2013.
KESSLER, R. L. et al. Trypanosoma cruzi response to sterol biosynthesis inhibitors:
morphophysiological alterations leading to cell death. PloS one, v. 8, n. 1, p. e55497, 2013. KROUBI, M. et al. Development of a nanoparticulate formulation of diminazene to treat African trypanosomiasis. Nanotechnology, v. 21, n. 50, p. 505102, 2010.
KRYSKO, D. V et al. Apoptosis and necrosis : Detection , discrimination and phagocytosis.
Science Direct, v. 44, p. 205–221, 2008.
KUMAR, G. et al. Flow cytometry evaluation of in vitro cellular necrosis and apoptosis induced by silver nanoparticles. Food and Chemical Toxicology, v. 85, p. 45–51, 2015. LIANG, P. et al. Colloids and Surfaces B : Biointerfaces Facile preparation of heparin / CaCO 3 / CaP hybrid nano-carriers with controllable size for anticancer drug delivery. Colloids and
Surfaces B: Biointerfaces, v. 102, p. 783–788, 2013.
LIMA, F. M. et al. The challenge of Chagas ’ disease : Has the human pathogen ,
Trypanosoma cruzi , learned how to modulate signaling events to subvert host cells ? New
biotechnology, v. 27, n. 6, p. 837–843, 2010.
MACEDO, S. R. A. et al. The pentavalent antimonial therapy against experimental Leishmania amazonensis infection is more effective under the inhibition of the NF-κB pathway. International Immunopharmacology, v. 28, n. 1, p. 554–559, 2015.
MALEKI, S. D. et al. Application of Box-Behnken design to prepare gentamicin-loaded calcium carbonate nanoparticles. Artif Cell Nanimed Biotechnol, v. 12, n. 10, 2015.
MANUJA, A. et al. Quinapyramine sulfate-loaded sodium alginate nanoparticles show enhanced trypanocidal activity.Nanomedicine, v. 9, p. 1625–1634, 2013.
MARIN-NETO, J. A. et al. The BENEFIT trial : testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Memorias do Instituto
Oswaldo Cruz, v. 104, n. June, p. 319–324, 2009.
MARTINEZ, D. S. T.; ALVES, O. Interação de nanomateriais com biossistemas e a nanotoxicologia: na direção de uma regulamentação. Cienc Cult, v. 65, n. 3, 2013.
MAYA, J. D. et al. Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comparative Biochemistry and Physiology, v. 146, p. 601–620, 2007.
MEIRA, C.S et al. In vitro and in vivo antiparasitic activity of Physalisangulata L.
concentrated ethanolic extract against Trypanosomacruzi. Phytomedicine, v.22, p969-974,
jul.2015.
MENEZES, R.R.P.P. Estudo dos efeitos do veneno da serpente Bothropoides insularis
sobre células RAW 264.7 in vitro. 2013. 94f. Dissertação (Mestrado em Farmacologia) – Ciências da Saúde, Universidade Federal do Ceará, Fortaleza. 2013.
MONDAL, S. et al. In vitro susceptibilities of wild and drug resistant leishmania donovani amastigote stages to andrographolide nanoparticle: role of vitamin E derivative TPGS for nanoparticle efficacy. PloS one, v. 8, n. 12, p. e81492, 2013.
MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and citotoxicity. J IMMUNOL METHODS, v. 65, p. 55–63, 1983.
MUÑOZ-SARAIVA, S. G. et al. Chronic Chagas ’ heart disease : a disease on its way to becoming a worldwide health problem : epidemiology , etiopathology , treatment , pathogenesis and laboratory medicine. Heart Fail, v. 17, p. 45–64, 2012.
NAYAK, T. R. et al. Thin Films of Functionalized Multiwalled Carbon Nanotubes as Suitable Scaffold Materials for Stem Cells Proliferation and Bone Formation. ACS Nano, v. 4, n. 12, p. 7717–7725, 2010.
NOGUEIRA, A. J. M. et al. Síntese, caracterização e estudo da atividade inibitória de novas dialquilfosforilarilidrazonas sobre o crescimento de tripanossomatídeos. QUIM. NOVA, v. 34, n. 8, p. 1365–1369, 2011.
NOGUEIRA, N. P. et al. Proliferation and Differentiation of Trypanosoma cruzi inside Its Vector Have a New Trigger: Redox Status. Plos One, v. 10, n. 2, p. e0116712, 2015. NOWACK, B.; KRUG, H. F.; HEIGHT, M. 120 Years of Nanosilver History : Implications for Policy Makers. p. 1177–1183, 2011.
OLIVEIRA, M. F. et al. Tratamento etiológico da doença de Chagas no Brasil. Revista de
Patologia Tropical, v. 37, n. 3, p. 209–228, 2008.
OMS, Organização Mundial de saúde. Chagas disease (American trypanosomiasis). Fact Sheet, n.340. 2015. Disponível em:http://who.int/mediacentre/factsheets/fs340/en/. Acesso em: 09 nov. 2015.
PEREIRA, K. S. et al. Chagas’ Disease as a Foodborne Illness. Journal of Food Protection, v. 2, p. 228–446, 2009.
PEREIRA, M. G. et al. Trypanosoma cruzi Epimastigotes Are Able to Manage Internal Cholesterol Levels under Nutritional Lipid Stress Conditions. Plos One, v. 10, n. 6, p. e0128949, 2015.
PEREIRA, T.P. Efeito tripanocida da L-amino ácido oxidase isolada do veneno da bothrops marajoensis. 2015. 82f. Tese (Doutorado em Ciências Farmacêuticas) – Faculdade de Fármacia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, 2015. PÉREZ-AYALA, A. . et al. Chagas disease in Latin American migrants : a Spanish challenge.
Clin Microbiol Infect, v. 17, p. 1108–1113, 2011.
PETHERICK, A. After years of neglect, Brazil takes aim at Chagas disease. Nature
medicine, v. 17, n. 10, p. 1174, out. 2011.
PIACENZA, L. et al. Fighting the oxidative assault : the Trypanosoma cruzi journey to infection a Noel Alvarez , Gonzalo Peluffo and Rafael Radi. Science Direct, v. 12, p. 415– 421, 2009.
QIAN, K. . et al. Preparation and characterization of nano-sized calcium carbonate as controlled release pesticide carrier for validamycin against Rhizoctonia solani. Microchim
Acta, v. 173, p. 51–57, 2011.
RASSI, A.; MARIN-NETO, J. A. Chagas disease. Lancet, v. 375, n. 9723, p. 1388–402, 17 maio 2010.
REN, X. M.; CHEN, C.; NAGATSU, M. Carbon nanotubes as adsorbents in environmental pollution management: a review. Chemical Engineering Journal, v. 170, n. 2, p. 395–410, 2011.
RIBEIRO, C. M. Efeito do Tratamento do Benzonidazol e da Terapia Antioxidante na
Cardiopatia Chagásica Crônica. [s.l.] Universidade de Santa Catarina, 2009.
RIBEIRO, T. G. et al. Novel targeting using nanoparticles: An approach to the development of an effective anti-leishmanial drug-delivery system. International Journal of
Nanomedicine, v. 9, n. 1, p. 877–890, 2014.
ROMERO, E. L.; MORILLA, M. J. Nanotechnological approaches against Chagas disease.
Advanced drug delivery reviews, v. 62, n. 4-5, p. 576–588, 18 mar. 2010.
SÁNCHEZ, G. et al. Cytotoxicity and trypanocidal activity of nifurtimox encapsulated in ethylcyanoacrylate nanoparticles. Biological Research, v. 35, n. 1, p. 39–45, 2002. SANDES, J. M. et al. Trypanosoma cruzi cell death induced by the Morita-Baylis-Hillman adduct 3-hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile). PLoS ONE, v. 9, n. 4, p. 1–9, 2014.
SANTORO, G. F. et al. Trypanosoma cruzi: Activity of essential oils from Achillea millefolium L., Syzygium aromaticum L. and Ocimum basilicum L. on epimastigotes and trypomastigotes. Experimental Parasitology, v. 116, p. 283–290, 2007.
SESTI-COSTA, R. et al. Ruthenium Complex with Benznidazole and Nitric Oxide as a New Candidate for the Treatment of Chagas Disease. PLoS neglected tropical diseases, v. 8, n. 10, 2014.
SHARMA, S. et al. An insight into functionalized calcium based inorganic nanomaterials in biomedicine: Trends and transitions. Colloids and Surfaces B: Biointerfaces, v. 133, p. 120– 139, 2015.
SILVA, C. F. et al. Cellular Effects of Reversed Amidines on Trypanosoma cruzi.
Antimicrobial agents and chemotherapy, v. 51, n. 11, p. 3803–3809, 2007.
SOARES, R. O. A et al. Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-Trypanosoma cruzi. Experimental Parasitology, v. 129, n. 4, p. 381–387, 2011. SOARES-SOBRINHO, J. L. et al. Benznidazole drug delivery by binary and multicomponent inclusion complexes using cyclodextrins and polymers. Carbohydrate Polymers, v. 89, n. 2, p. 323–330, 2012.
SOUZA, W. DE; CARVALHO, T. M. U. DE; BARRIAS, E. S. Review on Trypanosoma cruzi : Host Cell Interaction. v. 2010, 2010.
SUKHORUKOV, G. B. . et al. Porous calcium carbonate microparticles as templates for encapsulation of bioactive compounds. Journal of Materials chemistry, v. 14, p. 2073– 2081, 2004.
UENO, Y. . et al. Drug-incorporating calcium carbonate nanoparticles for a new delivery system. Jornal of controlled release, v. 103, p. 93–98, 2004.
UNCITI-BROCETA, J. D. et al. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. PLOS Pathogens, v. 11, n. 6, p. e1004942, 2015. URBINA, J. A.; DOCAMPO, R. Specific chemotherapy of Chagas disease : controversies and advances. v. 19, n. 11, p. 495–501, 2005.
VAN DE VEN, H. et al. PLGA nanoparticles loaded with the antileishmanial saponin β- aescin: factor influence study and in vitro efficacy evaluation. International journal of
pharmaceutics, v. 420, n. 1, p. 122–32, 2011.
VENDRAMETTO, M. C. et al. Evaluation of antileishmanial activity of eupomatenoid-5, a compound isolated from leaves of Piper regnellii var. pallescens. Parasitology international, v. 59, n. 2, p. 154–8, 2010.
VERMA, N. K. et al. Magnetic core-shell nanoparticles for drug delivery by nebulization. p. 1–12, 2013.
WAYPA, G. B.; SMITH, K. A.; SCHUMACKER, P. T. O2 sensing, mitochondria and ROS signaling: The fog is lifting. p. 1–14, 2016.
WEI, W. et al. Preparation of Hierarchical Hollow CaCO 3 Particles and the Application as. p. 15808–15810, 2010.
WEN, R. et al. Nanotechnology inspired tools for mitochondrial dysfunction related diseases.
Advanced Drug Delivery Reviews, 2016.
WILLKINSON, S. R. et al. Trypanocidal activity of nitroaromatic prodrugs: current
treatments and future perspectives. Curr top med chem, v. 11, n. 16, p. 2072–2084, 2011. XU, B. . et al. Liquid–gas dual phase microfluidic system for biocompatible CaCO3 hollow nanoparticles generation and simultaneous molecule doping. Chem Commun, v. 48, p. 11635–11637, 2012.
ZANETTI, M. Doença de Chagas: sinais e sintomas da fase aguda e crônica. 2012.
Disponível em: http://medifoco.com.br/doenca-de-chagas-sinais-e-sintomas-da-fase-aguda-e- cronica/ Acesso em: 16 nov 2015.
ZHAO, Y. et al. Synthesis of Superparamagnetic CaCO 3 Mesocrystals for Multistage Delivery in Cancer Therapy. Small, v. 6, n. 21, p. 2436–2442, 2010.