NANOMEDICINA: APLICACAÇÕES NO DIAGNÓSTICO E TRATAMENTO DO CÂNCER
Palavras-chave:
Nanotecnologia; câncer; tratamento; diagnóstico.
Resumo
O estudo trata-se de uma revisão integrativa da literatura, com o objetivo de descrever o uso da nanotecnologia para o rastreamento, diagnóstico e tratamento dos vários tipos de neoplasias, considerando que a ferramenta tem mostrado resultados satisfatórios, com melhora do prognóstico dos pacientes. Para a coleta de dados, foram utilizadas as bases de dados SCIELO e PUBMED, nas quais foram encontrados 1.643 artigos. Desses, apenas 44 abordavam, diretamente, aspectos relacionados a nanotecnologia no diagnóstico e tratamento do câncer e estavam de acordo com os critérios de inclusão. Os achados sugeriram a nanotecnologia como ferramenta útil no diagnóstico precoce e tratamento efetivo para os vários tipos de câncer, pois apresenta especificidade para muitos tipos de células alteradas, uma entrega farmacológica direcionada, reduzindo, consequentemente, os efeitos colaterais e a melhoria da eficácia medicamentosa. É sugerida, ainda, a relação dessa tecnologia com menores chances de resistência aos medicamentos quimioterápicos. Considerando os benefícios da nanotecnologia como ferramenta eficiente no diagnóstico e tratamento de várias neoplasias, faz-se necessário ampliar o conhecimento sobre o assunto entre a população e os profissionais da saúde.
Palavras chave: Nanotecnologia; câncer; tratamento; diagnóstico.
Referências
1. Brasil.Organização Mundial Da Saúde/Organizacão Pan-Americana De Saúde OMS/OPAS. Folha informativa-câncer. Brasília, Brasil: 2018.
2. Bittencourt R, scaletzky A, boehl JAR. Perfil epidemiológico do câncer na rede pública em Porto Alegre-RS. Rev bras cancerol, 2004; 50(2): 95-101.
3. Helmy KY, Patel SA, Nahas GR, et al. Cancer immunotherapy: accomplishments to date and future promise. Therapeutic delivery, 2013; 4(10): 1307-1320.
4. Cancino J, marangoni V, Zucolotto V. Nanotecnologia em medicina: aspectos fundamentais e principais preocupações. Química Nova, 2014; 37(3): 521-526.
5. Darwiche K, Zarogoulidis P, Krauss L, et al. “One-stop shop” spectral imaging for rapid on-site diagnosis of lung cancer: a future concept in nano-oncology. International journal of nanomedicine, 2013; v.8, p.4533.
6. Rizvi SB, Rouhi S, Taniguchi S, et al. Near-infrared quantum dots for HER2 localization and imaging of cancer cells. International journal of nanomedicine. 2014; v. 9, p. 1323.
7. Halo TL, McMahon KM, Angeloni NL, et al. NanoFlares for the detection, isolation, and culture of live tumor cells from human blood. Proceedings of the National Academy of Sciences, 2014; 111(48): 17104-17109.
8. You M, Zhu G, Chen T, et al. Programmable and multiparameter DNA-based logic platform for cancer recognition and targeted therapy. Journal of the American Chemical Society, 2015; 137(2): 667-674.
9. Cui D, Zhang C, Liu B, et al. Regression of gastric cancer by systemic injection of RNA nanoparticles carrying both ligand and siRNA. Scientific reports, 2015; v. 5, p. 10726.
10. Sweeney SK, Luo Y, O’Donnell MA, et al. Nanotechnology and cancer: improving real-time monitoring and staging of bladder cancer with multimodal mesoporous silica nanoparticles. Cancer nanotechnology,2016; 7(1) 3.
11. Dobiasch S, Szanyi S, Kjaev A, et al. Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. Journal of nanobiotechnology, 2016;14(1), 81.
12. Khaniabadi PM, Shahbazi-Gahrouei D, Jaafar M S, et al. Magnetic iron oxide nanoparticles as T2 MR imaging contrast agent for detection of breast cancer (MCF-7) cell. Avicenna journal of medical biotechnology, 2017; 9(4) 181.
13. Dapkute D, Steponkiene S, Bulotiene D, et al. Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors. International Journal of Nanomedicine, 2017; v.12, p. 8129.
14. Wu X, Xiao T, Luo Z, et al.A micro-/nano-chip and quantum dots-based 3D cytosensor for quantitative analysis of circulating tumor cells. Journal of nanobiotechnology, 2018; 16(1) 1-9.
15. Garrigue P, Tang J, Ding L, et al. Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors. Proceedings of the National Academy of Sciences, 2018; 115(45): 11454-11459.
16. Affram K, Smith T, Helsper S, et al. Comparative study on contrast enhancement of Magnevist and Magnevist-loaded nanoparticles in pancreatic cancer PDX model monitored by MRI. Cancer Nanotechnology, 2020; 11(1): 1-14.
17. Singh AK, Hahn MA, Gutwein LG, et al. Multi-dye theranostic nanoparticle platform for bioimaging and cancer therapy. International journal of nanomedicine, 2012; v.7, p. 2739.
18. Dadgar N, Esfahani MKM, Torabi S, et al. Effects of nanoliposomal and pegylated nanoliposomal artemisinin in treatment of breast cancer. Indian journal of clinical biochemistry, 2014; 29(4): 501-504.
19. Wei T, Chen C, Liu J, et al. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proceedings of the National Academy of Sciences, 2015; 112(10): 2978-2983.
20. Gurunathan S, Park JH, Han JW, et al. Comparative assessment of the apoptotic potential of silver nanoparticles synthesized by Bacillus tequilensis and Calocybe indica in MDA-MB-231 human breast cancer cells: targeting p53 for anticancer therapy. International journal of nanomedicine, 2015; v10, p. 4203.
21. Fang YQ, Wu JY, Li TC, et al. Nanoparticle mediated chemotherapy of hormone refractory prostate cancer with a novel combi-molecule. American journal of translational research, 2015; 7(8): 1440.
22. Kalanaky S, Hafizi M, Fakharzadeh S, et al. BCc1, the novel antineoplastic nanocomplex, showed potent anticancer effects in vitro and in vivo. Drug design, development and therapy, 2016; v. 10, p. 59.
23. Guo JUN, Wu SH, Ren WG, et al. Anticancer activity of bicalutamide-loaded PLGA nanoparticles in prostate cancers. Experimental and therapeutic medicine, 2015; 10(6): 2305-2310.
24. Shu D, Li H, Shu Y, et al. Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS nano, 2015; 9(10): 9731-9740.
25. Zhang M, Xiao B, Wang H, et al. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Molecular Therapy, 2016; 24(10): 1783-1796.
26. Drewes CC, Fiel LA, Bexiga CG, et al. Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models. International journal of nanomedicine, 2016; v. 11, p. 1261.
27. Li Y, Lin Z, Zhao M, et al. Multifunctional selenium nanoparticles as carriers of HSP70 siRNA to induce apoptosis of HepG2 cells. International journal of nanomedicine, 2016; v. 11, p. 3065.
28. Hassan CE, Webster TJ. The effect of red-allotrope selenium nanoparticles on head and neck squamous cell viability and growth. International journal of nanomedicine, 2016; v. 11, p. 3641.
29. Zhang M, Xiao B, Wang H, et al. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Molecular Therapy, 2016; 24(10): 1783-1796.
30. Yaari Z, Da Silva D, Zinger A, et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nature communications, 2016; 7(1): 1-10.
31. Manivasagan P, Bui NQ, Bharathiraja S, et al. Multifunctional biocompatible chitosan-polypyrrole nanocomposites as novelagents for photoacoustic imaging-guided photothermal ablation of cancer. Scientific reports, 2017; v. 7, p. 43593.
32. Kim YH, Min KH, Wang Z, et al. Development of sialic acid-coated nanoparticles for targeting cancer and efficient evasion of the immune system. Theranostics, 2017; 7(4): 962.
33. Vinhas R; Fernandes AR; Baptista PV. Gold Nanoparticles for BCR-ABL1 gene silencing: Improving tyrosine kinase inhibitor efficacy in chronic myeloid leukemia. Molecular Therapy-Nucleic Acids, 2017; v. 7, p. 408-416.
34. Shen S, Li Y, Xiao Y, et al. Folate-conjugated nanobubbles selectively target and kill cancer cells via ultrasound-triggered intracellular explosion. Biomaterials, 2018; v. 181, p. 293-306.
35. Marino A, Battaglini M, De Pasquale D, et al. Ultrasound-activated piezoelectric nanoparticles inhibit proliferation of breast cancer cells. Scientific reports, 2018; 8(1): 1-13.
36. Kheirkhah P, Denyer S, Bhimani AD, et al. Magnetic drug targeting: a novel treatment for intramedullary spinal cord tumors. Scientific reports, 2018; 8(1): 1-9.
37. Ma J, Kala S, Yung S, et al. Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery. Molecular Therapy 2018; 26(1): 70-83.
38. Guo X, Qu J, Zhu C, Li W, et al. Synchronous delivery of oxygen and photosensitizer for alleviation of hypoxia tumor microenvironment and dramatically enhanced photodynamic therapy. Drug delivery, 2018; 25(1): 585-599.
39. Alyafee YA, Alaamery M, Bawazeer S, et al. Preparation of anastrozole loaded PEG-PLA nanoparticles: evaluation of apoptotic response of breast cancer cell lines. International Journal of Nanomedicine, 2018; v. 13, p. 199.
40. Bai F, Yin Y, Chen T, et al. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer. International journal of nanomedicine 2018; v. 13, p. 1327.
41. Martínez-Torres AC, Zarate-Triviño DG, Lorenzo-Anota HY, et al. Chitosan gold nanoparticles induce cell death in HeLa and MCF-7 cells through reactive oxygen species production. International journal of nanomedicine, 2018; v. 13, p. 3235.
42. Abou-El-Naga AM, Mutawa G, El-Sherbiny IM, et al. Activation of polymeric nanoparticle intracellular targeting overcomes chemodrug resistance in human primary patient breast cancer cells. International journal of nanomedicine, 2018; v. 13, p. 8153.
43. Higuchi T, Kawaguchi K, Miyake K, et al. The combination of gemcitabine and nab-paclitaxel as a novel effective treatment strategy for undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Biomedicine & Pharmacotherapy, 2019; v. 111, p. 835-840.
44. Xu Y, Pang L, Wang H, et al. Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-γ-linolenic acid for colon cancer suppression. Redox biology, 2019; v. 21, p. 101085.
45. Khiavi MA, Safary A, Barar J, et al. PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells. BioImpacts: BI, 2020; 10(1): 27.
46. Ishiguro K, Yan IK, Lewis‐Tuffin L, et al. Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer. Hepatology communications, 2020; 4(2): 298-313.
47. Nalepa P, Gawecki R, Szewczyk G, et al. A [60] fullerene nanoconjugate with gemcitabine: synthesis, biophysical properties and biological evaluation for treating pancreatic cancer. Cancer Nanotechnology, 2020; 11(1): 1-21.
48. Wiranowska M, Singh R, Falahat R, et al. Preferential drug delivery to tumor cells than normal cells using a tunable niosome–chitosan double package nanodelivery system: a novel in vitro model. Cancer Nanotechnology, 2020; v. 11, p. 1-20.
49. González-López MA, Gutiérrez-Cárdenas EM, Sánchez-Cruz C, et al. Reducing the effective dose of cisplatin using gold nanoparticles as carriers. Cancer Nanotechnology, 2020; v. 11, p. 1-15.
50. Khoobchandani M, Katti KK, Karikachery AR, et al. New Approaches in Breast Cancer Therapy Through Green Nanotechnology and Nano-Ayurvedic Medicine–Pre-Clinical and Pilot Human Clinical Investigations. International Journal of Nanomedicine, 2020; v. 15, p. 181.
2. Bittencourt R, scaletzky A, boehl JAR. Perfil epidemiológico do câncer na rede pública em Porto Alegre-RS. Rev bras cancerol, 2004; 50(2): 95-101.
3. Helmy KY, Patel SA, Nahas GR, et al. Cancer immunotherapy: accomplishments to date and future promise. Therapeutic delivery, 2013; 4(10): 1307-1320.
4. Cancino J, marangoni V, Zucolotto V. Nanotecnologia em medicina: aspectos fundamentais e principais preocupações. Química Nova, 2014; 37(3): 521-526.
5. Darwiche K, Zarogoulidis P, Krauss L, et al. “One-stop shop” spectral imaging for rapid on-site diagnosis of lung cancer: a future concept in nano-oncology. International journal of nanomedicine, 2013; v.8, p.4533.
6. Rizvi SB, Rouhi S, Taniguchi S, et al. Near-infrared quantum dots for HER2 localization and imaging of cancer cells. International journal of nanomedicine. 2014; v. 9, p. 1323.
7. Halo TL, McMahon KM, Angeloni NL, et al. NanoFlares for the detection, isolation, and culture of live tumor cells from human blood. Proceedings of the National Academy of Sciences, 2014; 111(48): 17104-17109.
8. You M, Zhu G, Chen T, et al. Programmable and multiparameter DNA-based logic platform for cancer recognition and targeted therapy. Journal of the American Chemical Society, 2015; 137(2): 667-674.
9. Cui D, Zhang C, Liu B, et al. Regression of gastric cancer by systemic injection of RNA nanoparticles carrying both ligand and siRNA. Scientific reports, 2015; v. 5, p. 10726.
10. Sweeney SK, Luo Y, O’Donnell MA, et al. Nanotechnology and cancer: improving real-time monitoring and staging of bladder cancer with multimodal mesoporous silica nanoparticles. Cancer nanotechnology,2016; 7(1) 3.
11. Dobiasch S, Szanyi S, Kjaev A, et al. Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. Journal of nanobiotechnology, 2016;14(1), 81.
12. Khaniabadi PM, Shahbazi-Gahrouei D, Jaafar M S, et al. Magnetic iron oxide nanoparticles as T2 MR imaging contrast agent for detection of breast cancer (MCF-7) cell. Avicenna journal of medical biotechnology, 2017; 9(4) 181.
13. Dapkute D, Steponkiene S, Bulotiene D, et al. Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors. International Journal of Nanomedicine, 2017; v.12, p. 8129.
14. Wu X, Xiao T, Luo Z, et al.A micro-/nano-chip and quantum dots-based 3D cytosensor for quantitative analysis of circulating tumor cells. Journal of nanobiotechnology, 2018; 16(1) 1-9.
15. Garrigue P, Tang J, Ding L, et al. Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors. Proceedings of the National Academy of Sciences, 2018; 115(45): 11454-11459.
16. Affram K, Smith T, Helsper S, et al. Comparative study on contrast enhancement of Magnevist and Magnevist-loaded nanoparticles in pancreatic cancer PDX model monitored by MRI. Cancer Nanotechnology, 2020; 11(1): 1-14.
17. Singh AK, Hahn MA, Gutwein LG, et al. Multi-dye theranostic nanoparticle platform for bioimaging and cancer therapy. International journal of nanomedicine, 2012; v.7, p. 2739.
18. Dadgar N, Esfahani MKM, Torabi S, et al. Effects of nanoliposomal and pegylated nanoliposomal artemisinin in treatment of breast cancer. Indian journal of clinical biochemistry, 2014; 29(4): 501-504.
19. Wei T, Chen C, Liu J, et al. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proceedings of the National Academy of Sciences, 2015; 112(10): 2978-2983.
20. Gurunathan S, Park JH, Han JW, et al. Comparative assessment of the apoptotic potential of silver nanoparticles synthesized by Bacillus tequilensis and Calocybe indica in MDA-MB-231 human breast cancer cells: targeting p53 for anticancer therapy. International journal of nanomedicine, 2015; v10, p. 4203.
21. Fang YQ, Wu JY, Li TC, et al. Nanoparticle mediated chemotherapy of hormone refractory prostate cancer with a novel combi-molecule. American journal of translational research, 2015; 7(8): 1440.
22. Kalanaky S, Hafizi M, Fakharzadeh S, et al. BCc1, the novel antineoplastic nanocomplex, showed potent anticancer effects in vitro and in vivo. Drug design, development and therapy, 2016; v. 10, p. 59.
23. Guo JUN, Wu SH, Ren WG, et al. Anticancer activity of bicalutamide-loaded PLGA nanoparticles in prostate cancers. Experimental and therapeutic medicine, 2015; 10(6): 2305-2310.
24. Shu D, Li H, Shu Y, et al. Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS nano, 2015; 9(10): 9731-9740.
25. Zhang M, Xiao B, Wang H, et al. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Molecular Therapy, 2016; 24(10): 1783-1796.
26. Drewes CC, Fiel LA, Bexiga CG, et al. Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models. International journal of nanomedicine, 2016; v. 11, p. 1261.
27. Li Y, Lin Z, Zhao M, et al. Multifunctional selenium nanoparticles as carriers of HSP70 siRNA to induce apoptosis of HepG2 cells. International journal of nanomedicine, 2016; v. 11, p. 3065.
28. Hassan CE, Webster TJ. The effect of red-allotrope selenium nanoparticles on head and neck squamous cell viability and growth. International journal of nanomedicine, 2016; v. 11, p. 3641.
29. Zhang M, Xiao B, Wang H, et al. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Molecular Therapy, 2016; 24(10): 1783-1796.
30. Yaari Z, Da Silva D, Zinger A, et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nature communications, 2016; 7(1): 1-10.
31. Manivasagan P, Bui NQ, Bharathiraja S, et al. Multifunctional biocompatible chitosan-polypyrrole nanocomposites as novelagents for photoacoustic imaging-guided photothermal ablation of cancer. Scientific reports, 2017; v. 7, p. 43593.
32. Kim YH, Min KH, Wang Z, et al. Development of sialic acid-coated nanoparticles for targeting cancer and efficient evasion of the immune system. Theranostics, 2017; 7(4): 962.
33. Vinhas R; Fernandes AR; Baptista PV. Gold Nanoparticles for BCR-ABL1 gene silencing: Improving tyrosine kinase inhibitor efficacy in chronic myeloid leukemia. Molecular Therapy-Nucleic Acids, 2017; v. 7, p. 408-416.
34. Shen S, Li Y, Xiao Y, et al. Folate-conjugated nanobubbles selectively target and kill cancer cells via ultrasound-triggered intracellular explosion. Biomaterials, 2018; v. 181, p. 293-306.
35. Marino A, Battaglini M, De Pasquale D, et al. Ultrasound-activated piezoelectric nanoparticles inhibit proliferation of breast cancer cells. Scientific reports, 2018; 8(1): 1-13.
36. Kheirkhah P, Denyer S, Bhimani AD, et al. Magnetic drug targeting: a novel treatment for intramedullary spinal cord tumors. Scientific reports, 2018; 8(1): 1-9.
37. Ma J, Kala S, Yung S, et al. Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery. Molecular Therapy 2018; 26(1): 70-83.
38. Guo X, Qu J, Zhu C, Li W, et al. Synchronous delivery of oxygen and photosensitizer for alleviation of hypoxia tumor microenvironment and dramatically enhanced photodynamic therapy. Drug delivery, 2018; 25(1): 585-599.
39. Alyafee YA, Alaamery M, Bawazeer S, et al. Preparation of anastrozole loaded PEG-PLA nanoparticles: evaluation of apoptotic response of breast cancer cell lines. International Journal of Nanomedicine, 2018; v. 13, p. 199.
40. Bai F, Yin Y, Chen T, et al. Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer. International journal of nanomedicine 2018; v. 13, p. 1327.
41. Martínez-Torres AC, Zarate-Triviño DG, Lorenzo-Anota HY, et al. Chitosan gold nanoparticles induce cell death in HeLa and MCF-7 cells through reactive oxygen species production. International journal of nanomedicine, 2018; v. 13, p. 3235.
42. Abou-El-Naga AM, Mutawa G, El-Sherbiny IM, et al. Activation of polymeric nanoparticle intracellular targeting overcomes chemodrug resistance in human primary patient breast cancer cells. International journal of nanomedicine, 2018; v. 13, p. 8153.
43. Higuchi T, Kawaguchi K, Miyake K, et al. The combination of gemcitabine and nab-paclitaxel as a novel effective treatment strategy for undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Biomedicine & Pharmacotherapy, 2019; v. 111, p. 835-840.
44. Xu Y, Pang L, Wang H, et al. Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-γ-linolenic acid for colon cancer suppression. Redox biology, 2019; v. 21, p. 101085.
45. Khiavi MA, Safary A, Barar J, et al. PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells. BioImpacts: BI, 2020; 10(1): 27.
46. Ishiguro K, Yan IK, Lewis‐Tuffin L, et al. Targeting Liver Cancer Stem Cells Using Engineered Biological Nanoparticles for the Treatment of Hepatocellular Cancer. Hepatology communications, 2020; 4(2): 298-313.
47. Nalepa P, Gawecki R, Szewczyk G, et al. A [60] fullerene nanoconjugate with gemcitabine: synthesis, biophysical properties and biological evaluation for treating pancreatic cancer. Cancer Nanotechnology, 2020; 11(1): 1-21.
48. Wiranowska M, Singh R, Falahat R, et al. Preferential drug delivery to tumor cells than normal cells using a tunable niosome–chitosan double package nanodelivery system: a novel in vitro model. Cancer Nanotechnology, 2020; v. 11, p. 1-20.
49. González-López MA, Gutiérrez-Cárdenas EM, Sánchez-Cruz C, et al. Reducing the effective dose of cisplatin using gold nanoparticles as carriers. Cancer Nanotechnology, 2020; v. 11, p. 1-15.
50. Khoobchandani M, Katti KK, Karikachery AR, et al. New Approaches in Breast Cancer Therapy Through Green Nanotechnology and Nano-Ayurvedic Medicine–Pre-Clinical and Pilot Human Clinical Investigations. International Journal of Nanomedicine, 2020; v. 15, p. 181.
Publicado
2021-03-01
Seção
Artigos
Declaro que os conteúdos apresentados nos artigos e demais trabalhos são de minha autoria e tenho total responsabilidade sobre os mesmos, os quais estou cedendo os direitos autorais à Revista Saúde e Meio Ambiente, para fins de divulgação científica em qualquer meio disponível.
