Nanodrug research and development: a bioethical approach

Abstract

Nanotechnology consist of using materials at the nanoscale, in which they acquire specific characteristics. Nanodrug research and development is one of the most promising fields today; however, these particles require particular evaluation. Moreover, studies lack consensus on which specific tests to follow, thus hindering the elaboration of legislation that ensure their safety and efficacy, as well as a more effective registration process. Thus, a bioethical approach to nanotechnology and its use in drug development is necessary to ensure scientific progress without irreversible impacts. Given this scenario, this article proposes a nanoethics discussion regarding nanodrug research and development by means of a qualitative, exploratory and descriptive analysis, based on literature review, documental analysis and quantitative data available.

Bioethics; Nanotechnology; Toxicology; Regulatory frameworks for health

Resumo

Nanotecnologia é a utilização de materiais na escala nanométrica, em que estes adquirem características próprias. A área de pesquisa e desenvolvimento de novos nanomedicamentos é uma das mais promissoras atualmente, todavia essas partículas necessitam de avaliação particular e ainda não há consenso referente às testagens específicas a serem seguidas, o que dificulta a formação de uma legislação que garanta a segurança e eficácia destes medicamentos, além de um processo de registro mais eficaz. Assim, é necessária uma abordagem bioética da nanotecnologia e sua utilização em medicamentos, visando garantir que o progresso científico não acarrete impactos irreversíveis. Diante dessa problemática, busca-se promover uma discussão nanoética referente ao processo de pesquisa e desenvolvimento de nanomedicamentos, por meio de estudo qualitativo, exploratório-descritivo e de caráter analítico, utilizando revisão bibliográfica, análise documental e dados quantitativos disponíveis como técnicas de pesquisa.

Bioética; Nanotecnologia; Toxicologia; Marcos regulatórios em saúde

Resumen

La nanotecnología utiliza materiales nanométricos, en que estos adquieren características propias. El área de investigación y desarrollo de nuevas nanomedicinas es una de las más prometedoras en la actualidad, sin embargo, estas partículas requieren de una evaluación particular y aún no existe consenso en cuanto a las pruebas específicas que seguir, lo que dificulta establecer una legislación que garantice la seguridad y eficacia de estos medicamentos, además de un proceso de registro más efectivo. Por lo tanto, se necesita un enfoque bioético de la nanotecnología y su uso en medicamentos para garantizar que el avance científico no tenga impactos irreversibles. Ante esta problemática, se pretende promover el debate sobre la nanoética en el proceso de investigación y desarrollo de nanomedicinas a partir de un estudio cualitativo, exploratorio-descriptivo y analítico, que utiliza como técnicas de investigación la revisión bibliográfica, el análisis de documentos y los datos cuantitativos disponibles.

Bioética; Nanotecnología; Toxicología; Marcos reguladores en salud

Nanoparticles (NP) are materials located on the nanometric scale that present chemical, physical, biological and/or behavioral properties different from those found in the same materials in macroscales. One of the main fields of application of nanomaterials is the pharmaceutical sector, in which this technology enables new formulations of controlled releases using nanocarriers, generating a new class of drugs, called nanomedicines¹ - ³ .

Pereira and Binsfeld⁴ define nanomedicines as any substance or combination of substances with different physical-chemical properties used for prophylactic, healing, palliative, or diagnostic purposes. Nanomedicines are the finished pharmaceutical form that contains a nanoscale medicine or associated with a nanoadjuvant with specific pharmacological action, aiming to modulate metabolic or physiological functions ⁴ .

The research and development (R&D) process of a new drug must ensure efficacy and safety. Scientific efforts and resources employed should thus meet the methodological rigor and principles involved in clinical research⁵ .

Considering sanitary legislation, clinical trials are divided into four stages. In the first stage, known as research stage, the molecular target of a given pathology is selected and a rational molecular design is drawn based on medicinal chemistry, in which its ligands present greater affinity with the chosen target; in vitro and in vivo pharmacological tests are then conducted, culminating in the discovery of a new prototype compound and its eventual optimization⁶ .

The development stage is next, being divided into an initial phase of pre-clinical trials with the prototype compound, covering toxicological tests, and a late phase, which comprises clinical studies in humans, divided into phase I, phase II, phase III and phase IV⁶ .

The pre-clinical stage aims to evaluate the candidate compound, including the methods and animals used in the study, the laboratory tests employed, and the data obtained regarding pharmacodynamics and pharmacokinetics characteristics, and therapeutic and toxicology margins. Finally, the relevance of these results is discussed, considering the desired therapeutic effects and possible adverse effects, then moving on to the clinical phase⁷ .

To assess toxicity in the pre-clinical phase, the Brazilian Health Regulatory Agency (Anvisa), in its Guide for conducting non-clinical toxicology and pharmacological safety studies necessary for drug development, lists the trials to which the new compounds must be submitted and, if approved, they can proceed to the other stages of R&D. However, the guide indicates no specific test for nanotechnology-based drugs. Anvisa also recommends the replacement of in vivo by in vitro tests, as long as validated and accepted internationally⁸ , ⁹ .

Finally, in the regulatory stage the new compound is registered by the regulatory body of each country, such as Anvisa, the Food and Drug Administration (FDA), or the European Medicines Agency (EMA). After registration, the prototype, now already a drug, enters its commercialization stage, with concomitant pharmacovigilance assessment (post-market surveillance) of the new medicine, in which the adverse effects (AE) from the use of this drug should be reported⁶ .

Nanomedicines aim to generate great benefits such as decreasing AE and the dose used, improving adherence to treatment¹⁰ , ¹¹ , as well as the modified drug release⁴ , ⁹ . Some characteristics make nanomaterials very attractive to R&D, though concern and mistrust may be raised, as their unknown intrinsic characteristics can irreversibly damage health and the environment¹² , ¹³ .

Several studies indicate that NP may present health risks due to potential cytotoxic, genotoxic and teratogenic activity, which occur due to its metabolization in the body and permeation in cells, as well as its ability to interact with the organism’s biomolecules, causing several types of reactions, depending on where it occurs. Moreover, these particles can produce reactive oxygen species and neurotoxicity, by crossing the blood-brain barrier, in addition to modulating the metabolism and modifying cell functions and structures¹³ - ¹⁶ .

Despite the great concern with the control of NP use and the various questions about its toxicity and peculiarities, the production and standardization of toxicological tests is insufficient to evaluate the possible consequences that NP may cause in human beings and the environment¹⁷ .

Nanotoxicology is thus an answer to fill this gap, aiming to implement specific studies on the interaction between nanostructures and biological systems and to obtain a better toxicity assessment in preclinical studies in the development of new nanomedicines, ensuring greater patient safety⁹ , ¹⁸ .

Nanotoxicology

The impact of NP on humans depends on several factors and their properties—size, mass, chemical composition and surface, for example—and on how these NP aggregate. The way these particles penetrate the body (via the skin, inhalation, or orally) also generates several impacts¹⁸ - ²⁰ .

The lack of standardization of tests to evaluate the safety of nanomedicines is one of the major problems of nanotechnology given their numerous differences when compared with macromolecules, for which several standardized tests already exist⁸ , ²¹ .

Nanotechnology science is still in development, being characterized by more uncertainties than concrete answers²² , ²³ .

Other than the absence of answers about the toxicology of nanomaterials and the fact that they have applications in several areas, developing alternative research methods and tests is necessary to better assess the possible impacts of this technology. Given the numerous applications of nanotechnology, these tests should be able to evaluate the various properties of each NP, the toxicity of the routes of exposure and their elimination pathways. The individual and specific evaluation of each material is essential to determine the risk arising from its use¹⁷ .

Regarding the application of NPs in the pharmaceutical field, the risks presented by nanotechnology should be analyzed with caution and advance to avoid possible problems that may become irreversible for future generations⁹ , ²⁴ .

New nanomedicines

Nanotoxicology applied to the research and development process

In the R&D of new nanomedicines, the interactions between nanostructures and biological systems are evaluated, seeking answers about the toxicity of such compounds in the pre-clinical phase of development, which ensures greater safety in using them in the different clinical phases¹⁸ , ²⁵ .

After entering a biological system, the toxicity of NPs comes, mostly, from changes in physical-chemical properties after coming into contact with biological fluids, possibly causing affecting size, load and chemical surface, since the route of administration is also an important factor in these changes and one of the main problems related to NPs²⁶ , ²⁷ . Moreover, comparisons comparison between NP with similar physical-chemical properties show significant discrepancies¹ , ² .

According to their intrinsic characteristics, NPs have a “synthetic identity” that describes their standard characteristics when manufactured, and acquire a “biological identity” when they enter a living organism. The lack of adequate methods and the complexity of this evaluation make it difficult to predict whether the nanomedicine will overcome the physical and physiological barriers of the organism and achieve its therapeutic target²⁶ .

Studies conducted in the pre-clinical phase of a medicine’s R&D process are necessary to advance the development of the new compound and justify research in humans. Nonetheless, due to the peculiarities presented by NPs, the exact behavior of a nanomedicine in a living system is not yet clearly understood²⁶ , ²⁷ .

Beyond the toxicological context, a bioethical approach is necessary, considering the animal testing policy of Russell and Burch²⁸ , known as the 3Rs—replacement, reduction, and refinement—which seeks the better use of alternative models for testing the necessary effects in R&D. When developing tools for in vitro , in silico and ex vivo tests for NPs, the use of animal models is reduced and the results obtained are refined⁸ , ²⁷ .

Simulations in silico are thus necessary to predict the NP uptake in vitro , deducing its intracellular distribution and in vivo behavior and efficiency when used as nanocarrier. These tests are essential because the ideal nanocarrier is designed from them, contemplating pharmacokinetics and toxicity characteristics and misdistribution within cells and tissues² .

Several methods were developed to evaluate the pharmacokinetic properties of NP. However, the application of these methods is greatly complex²⁶ .

Pharmacokinetics is characterized by the absorption, distribution, metabolism and excretion (ADME) processes in the body. Physical-chemical properties of NP, including particle size, composition, morphology, load, surface and stability can influence pharmacokinetics. The size of the therapeutic agent mainly influences pharmacokinetics, as it determines the amount of molecules and the absorption of the medicine on the surface of the nanoentity. Similarly, the chemical and physical-chemical composition of the particle controls the activity of the chemical substance, which, influences the pharmacokinetics of the medicine¹ .

Several studies aim to evaluate and compare the kinetics and toxicity of NP using in vitro systems of cultivated cells, three-dimensional (3D) organoid cultures that imitate tissue structures or organs of different animal systems in vivo . However, despite presenting several advantages, important results, and a good correlation between 3D in vitro and in vivo models—as well as a considerable reduction in the use of laboratory animals, considering the ethical issues of animal testing—each system presents limitations² , ²⁶ .

The lack of patterns in the nanotechnology area causes problems in toxicity tests, as these include attempts to compare different NP types, different administration protocols— in vivo and in vitro —poor choice or differences in the chosen cell, resulting in differences in growth kinetics or endocytosis and frequent lack of nanomaterial stability tests or poor choice of methods—the two are fundamental aspects for any pharmaceutical product¹ , ² .

Faced with this issue, the European Union made nanotechnology research an essential point for occupational and environment safety and health. By using the little toxicological data available, the entity adopted a preventive approach to nanotechnologies due to possible exposure to them. In the United States, the National Institute for Occupational Safety and Health²⁹ recommended reducing the exposure of workers to NP until conclusive results were obtained¹⁷ .

The Brazilian scenario of toxicological tests of NP is similar to that of other countries: the document that indicates the toxicological evaluations to be made in the pre-clinical phase, provided by Anvisa, does not highlight any specific test for NP. The global lack of tests and specific regulations to evaluate the consequences of NP action for both humans and the environment is problematic because it adds to the issue of bioaccumulation in the disposal of these products, alerting to the need of developing studies that evaluate this impact in the long term¹⁷ .

Despite uncertainties about nanotoxicology, several medicines that use nanotechnology are already available in the Brazilian market. Such medicines were registered by Anvisa as similar medicines, however, according to the Collegiate Board Resolution (RDC) 60/2014³⁰ of Anvisa, this registration would be incorrect because they should be registered as new medicines, since the bioavailability of nanomedicines can be changed when considering the reference medicine.

Pharmacovigilance is also impaired by the lack of information about the presence and/or type of nanotechnology used in the composition of medicines in packages and inserts, , which may hinder the control of possible AE¹¹ , ³⁰ .

Nanoethics

New technologies should be carefully analyzed when they arise, considering the impacts they can have on the quality of human, animal or plant life. This evaluation should be made by observing and studying its relevance, priority, efficacy/effectiveness/efficiency, and scope, always aiming to ensure social justice and respect for human dignity³¹ .

Considering ethics, the didactic distinction proposed by Vázquez³² is essential, for whom morality is a set of norms, whereas ethics is the science that has moral as its very object. In this sense, ethics does not hold normative character, as it can only assume this role in a second moment, and yet, it is limited to the confines of guiding, and not to casuistry.

Nanoethics must be based on the very principles of bioethics and, given the status quaestionis , the role to be played will be a questioning rather than normative one. Although bioethics evaluates and guides nanomedicines, it requires further investigations, demonstrating the applicability of its principles to specific procedures involving NP.

The principle of non-maleficence can and must be applied in the specific case of NPs, without stopping ongoing research efforts, and, at the same time, without endangering life in general and, especially, human life.

Given the great potential for applicability and profit in nanotechnology, the rate at which studies and applications in the area grow is overly high when considering the scientific knowledge available. This leads to a state of uncertainty about the impact in the future and to debates about the responsibility for regulating this technology, its management and the final destination of waste³³ .

The literature is scarce on the classification of NPs, toxicological matters and trials to be followed. Thus, it is essential to develop a management plan for experiments to ensure greater efficacy in toxicity testing of nanoproducts³³ .

Other than aiming to solve this lack of information about nanotechnologies, investment in R&D and public discussions on the subject are essential to create risk management methods for the use of therapeutic agents at nanometric scale³³ . A limit should be drawn, drafting different designs of risk-benefit analyses of the therapeutic agent, following four essential steps to the assessment of the traditional risk of hazardous materials: 1) hazard identification; 2) exposure assessment; 3) toxicity assessment; and 4) risk characterization.

Product development risk, performance risk and regulation should also be assessed¹ .

When using the traditional risk assessment for nanometric therapeutic agents, estimating comprehensive toxicity of data acquisition, unintentional exposures, production of hazardous waste and contamination of water supply is necessary¹ .

The context allows a bioethical analysis of people’s use of nanotechnology, as this reflects impacts on the entire planet, no longer a solely human interest. The quantitative growth in experimentation results in the use of many laboratory animals and aiming beyond human health, that is, to meet the consumerist contribution of nanotechnological markets³³ .

However, market interests should never come before life. The question of the universal dignity of human life thus comes into discussion. Human life is an inalienable and inviolable principle that must be above any other objective, as advocated by the Universal Declaration of Human Rights , in its art. 1: All human beings are born free and equal in dignity and rights. They are endowed with reason and conscience and should act towards one another in a spirit of brotherhood ³⁴ .

The recognition of the universal equality of rights is seemingly simple. However, what is the principle that must guide human actions so that, in every-day life, the universal dignity of all cannot be set aside? Immanuel Kant, one of the greatest philosophers that humanity has known, formalized the following principle, which can serve as a guide: so act that you use humanity, whether in your own person or in the person of any other, always at the same time as an end, never merely as a means . In other words: people have value, and things, a price. This relationship should never be reversed.

Caution is thus required to prevent such scientific uncertainty from causing irreversible damage to humanity in the future, as Hans Jonas has already warned³⁶ . Therefore, the adoption of the precautionary principle becomes inevitable, since it aims to guarantee and/or preserve the basic rights, seeking the preservation of life without interrupting technological development⁹ .

By adopting the precautionary principle, the assessment of the risks contained in the exposure to NPs is more detailed and rigorous, putting into question the entire scenario in which it is inserted. Legislation to regulate activities that use nanotechnology is necessary, minimizing risks to humans and the environment and, at certain times, delaying or prohibiting practices related to it that may cause irreversible damage in the future³⁷ .

However, regulatory bodies around the world, responsible for the registration and monitoring of medicine, face difficulties related to insufficiency or uncertainty of scientific information. When adopting the precautionary principle policy in regulatory decision making in the health field, it is essential to control the use of nanomedicines until specific results are obtained proving their safety and evaluating the possible cost-benefit of their use to protect the patient and the environment. Risk levels must be reduced to acceptable standards, although they cannot be reduced to zero¹¹ .

Final considerations

Nanotechnology is under development and, thus, many uncertainties about the long-term impacts on humans and the environment persist. Regarding the use of nanotechnology in the R&D of new nanomedicines, current scientific information is scarce to ensure its safe use and effectiveness. This lack of evidence hinders the creation of legislation that regulates production, defines the registration and indicates the pre-clinical and clinical evaluation processes to be conducted in the stages of development of a nanomedicine.

Such difficulties regarding the use and safety of NPs exist worldwide, raising great uncertainty about nanotechnology. Science is still unable to provide sufficient answers to ensure the integrity of humans and the environment, corroborating the need for a bioethical approach to the insertion of this technology in the R&D of nanomedicines, aiming to prevent possible irreversible deleterious effects on society.

From this observation, one can argue that we live in a risk society that requires the adoption of the precautionary principle to obtain a more rigorous and detailed analysis of the use of nanotechnology; thus, minimizing the risks linked to its use and aiming to guarantee and/or preserve the basic rights aimed at the preservation of life without interrupting technological development.

Despite being a promising area—especially when considering health and the development of new medicines—nanotechnology demands caution until science can uncover the gaps related to its peculiarities, which, sometimes, cause euphoria, since they present a wide range of use and/or innovation, given its unique characteristics; on the other hand, concern is also felt, as nanomaterials raise more doubts than answers.

Referências

• ¹
  Sayes CM, Aquino GV, Hickey AJ. Nanomaterial drug products: manufacturing and analytical perspectives. AAPS J [Internet]. 2016 [acesso 4 jan 2023];19(1):18-25. DOI: 10.1208/s12248-016-0008-x
• ²
  Henriksen-Lacey M, Carregal-Romero S, Liz-Marzán LM. Current challenges toward in vitro cellular validation of inorganic nanoparticles. Bioconjug Chem [Internet]. 2017 [acesso 4 jan 2023];28(1):212-21. DOI: 10.1021/acs.bioconjchem.6b00514
• ³
  Allarakhia M, Walsh S. Analyzing and organizing nanotechnology development: application of the institutional analysis development framework to nanotechnology consortia. Technovation [Internet]. 2012 [acesso 4 jan 2023];32:216-26. DOI: 10.1016/j.technovation.2011.11.001
• ⁴
  Pereira IO, Binsfeld PC. Nanomedicamentos: o cenário de regulamentação no Brasil [Internet]. Goiânia: UCG; 2013 [acesso 4 jan 2023]. Disponível: https://bit.ly/3Xlp06n
  » https://bit.ly/3Xlp06n
• ⁵
  Ferreira LLG, Andricopulo AD. Medicamentos e tratamentos para a covid-19. Estud Av [Internet]. 2020 [acesso 4 jan 2023];34(100):7-27. DOI: 10.1590/s0103-4014.2020.34100.002
• ⁶
  Rocco PRM, Xisto DG, Silva JD, Diniz MFFM, Almeida RN, Luciano MN et al. LASSBio-596: da descoberta aos ensaios pré-clínicos. Rev Virtual Química [Internet]. 2010 [acesso 4 jan 2023];2(1):10-27. DOI: 10.5935/1984-6835.20100003
  » https://doi.org/10.5935/1984-6835.20100003
• ⁷
  Brasil. Ministério da Saúde. Resolução nº 251, de 7 de agosto de 1997. Aprova normas de pesquisa envolvendo seres humanos para a área temática de pesquisa com novos fármacos, medicamentos, vacinas e testes diagnósticos. Diário Oficial da União [Internet]. Brasília, 1997 [acesso 4 jan 2023]. Disponível: https://bit.ly/3dRmump
  » https://bit.ly/3dRmump
• ⁸
  Agência Nacional de Vigilância Sanitária. Guia para a condução de estudos não clínicos de toxicologia e segurança farmacológica necessário ao desenvolvimento de medicamentos [Internet]. Brasília: Anvisa; 2013 [acesso 6 fev 2023]. p. 1-48. Disponível: https://bit.ly/3Kbuayc
  » https://bit.ly/3Kbuayc
• ⁹
  Dora CL, Primo FT, Araújo GMS. Reflexões bioéticas acerca da inovação em nanomedicamentos. Rev Bioética y Derecho [Internet]. 2019 [acesso 4 jan 2023];(45):197-212. Disponível: https://bit.ly/3GJ9pq8
  » https://bit.ly/3GJ9pq8
• ¹⁰
  Rossi-Bergmann B. A nanotecnologia: da saúde para além do determinismo tecnológico. Ciênc Cult [Internet]. 2008 [acesso 4 jan 2023];60(2):54-7. Disponível: https://bit.ly/3J3FBaF
  » https://bit.ly/3J3FBaF
• ¹¹
  Batista AJS, Pepe VLE. Os desafios da nanotecnologia para a vigilância sanitária de medicamentos. Ciênc Saúde Colet [Internet]. 2014 [acesso 4 jan 2023];19(7):2105-14. DOI: 10.1590/1413-81232014197.02462013
• ¹²
  Paschoalino MP, Marcone GPS, Jardim WF. Os nanomateriais e a questão ambiental. Quím Nova [Internet]. 2010 [acesso 4 jan 2023];33(2):421-30. DOI: 10.1590/S0100-40422010000200033
• ¹³
  Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol [Internet]. 2004 [acesso 4 jan 2023];16(6-7):437-45. DOI: 10.1080/08958370490439597
  » https://doi.org/10.1080/08958370490439597
• ¹⁴
  Perreault F, Melegari SP, Costa CH, Rossetto ALOF, Popovic R, Matias WG. Genotoxic effects of copper oxide nanoparticles in Neuro 2A cell cultures. Sci Total Environ. 2012 [acesso 4 jan 2023];441:117-24. DOI: 10.1016/j.scitotenv.2012.09.065
• ¹⁵
  Xia XR, Monteiro-Riviere NA, Riviere JE. An index for characterization of nanomaterials in biological systems. Nat Nanotechnol [Internet]. 2010 [acesso 4 jan 2023];5(9):671-5. DOI: 10.1038/nnano.2010.164
• ¹⁶
  Guan R, Kang T, Lu F, Zhang Z, Shen H, Liu M. Cytotoxicity, oxidative stress, and genotoxicity in human hepatocyte and embryonic kidney cells exposed to ZnO nanoparticles. Nanoscale Res Lett [Internet]. 2012 [acesso 4 jan 2023];7(1):602. DOI: 10.1186/1556-276X-7-602
• ¹⁷
  Hohendorff R, Coimbra R, Engelmann W. As nanotecnologias, os riscos e as interfaces com o direito à saúde do trabalhador. RIL [Internet]. 2016 [acesso 4 jan 2023];53(209):151-72. Disponível: https://bit.ly/3ktcp2x
  » https://bit.ly/3ktcp2x
• ¹⁸
  Silva LH, Viana AR, Baldissera MD, Nascimento K, Sagrillo MR, Luchese C. Revisão bibliográfica sobre relações entre nanomateriais, toxicidade e avaliação de riscos: a emergência da nanotoxicologia. Discip Sci [Internet]. 2014 [acesso 4 jan 2023];15(1):19-30. Disponível: https://bit.ly/3QMdZsp
  » https://bit.ly/3QMdZsp
• ¹⁹
  Stone V, Donaldson K. Nanotoxicology: signs of stress. Nat Nanotechnol [Internet]. 2006 [acesso 4 jan 2023];1(1):23-4. DOI: 10.1038/nnano.2006.69
  » https://doi.org/10.1038/nnano.2006.69
• ²⁰
  Oberdörster G, Maynard A, Donaldson K, Castranova V, Fitzpatrick J, Ausman K et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol [Internet]. 2005 [acesso 4 jan 2023];2:8. DOI: 10.1186/1743-8977-2-8
  » https://doi.org/10.1186/1743-8977-2-8
• ²¹
  Allon I, Ben-Yehudah A, Dekel R, Solbakk J-H, Weltring K-M, Siegal G. Ethical issues in nanomedicine: Tempest in a teapot? Med Health Care and Philos [Internet]. 2017 [acesso 6 fev 2023];20(1):3-11. DOI: 10.1007/s11019-016-9720-7
• ²²
  Occupational Safety and Health Administration. Risk perception and risk communication with regard to nanomaterials in the workplace [Internet]. Bilbao: European Agency for Safety and Health at Work; 2012 [acesso 4 jan 2023]. Disponível: https://bit.ly/3Wut7vO
  » https://bit.ly/3Wut7vO
• ²³
  Agência Brasileira de Desenvolvimento Industrial. Cartilha sobre nanotecnologia [Internet]. Brasília: ABDI; 2010 [acesso 4 jan 2023]. p. 1-52. Disponível: https://bit.ly/3WkQNTg
  » https://bit.ly/3WkQNTg
• ²⁴
  Lêdo JCS, Hossne WS, Pedroso MZ. Introdução às questões bioéticas suscitadas pela nanotecnologia. Bioethikos [Internet]. 2007 [acesso 4 jan 2023];1(1):61-7. Disponível: https://bit.ly/3iOMaD6
  » https://bit.ly/3iOMaD6
• ²⁵
  Elsaesser A, Howard CV. Toxicology of nanoparticles. Adv Drug Deliv Rev [Internet]. 2012 [acesso 4 jan 2023];64(2):129-37. DOI: 10.1016/j.addr.2011.09.001
• ²⁶
  Sahlgren C, Meinander A, Zhang H, Cheng F, Preis M, Xu C et al. Tailored approaches in drug development and diagnostics: from molecular design to biological model systems. Adv Healthc Mater [Internet]. 2017 [acesso 4 jan 2023];6(21):1-34. DOI: 10.1002/adhm.201700258
  » https://doi.org/10.1002/adhm.201700258
• ²⁷
  Goldim JR. A avaliação ética da investigação científica de novas drogas: a importância da caracterização adequada das fases da pesquisa. Rev HCPA. [Internet]. 2007 [acesso 4 jan 2023];27(1):66-73. Disponível: https://bit.ly/3DlO9WL
  » https://bit.ly/3DlO9WL
• ²⁸
  Russel WMS, Burch RL. The principles of humane experimental technique. London: Universities Federation for Animal Welfare; 1992 [acesso 6 fev 2023]. Disponível: https://bit.ly/3lyMXZU
  » https://bit.ly/3lyMXZU
• ²⁹
  National Institute for Occupational Safety and Health. Safe nanotechnology in the workplace. Saf Heal [Internet]. 2008 [acesso 4 jan 2023]. Disponível: https://bit.ly/3ZJzSMV
  » https://bit.ly/3ZJzSMV
• ³⁰
  Agência Nacional de Vigilância Sanitária. Resolução da Diretoria Colegiada nº 60, de 10 de outubro de 2014. Dispõe sobre os critérios para a concessão renovação do registro de medicamentos com princípios ativos sintéticos e semissintéticos, classificados como novos, genéricos e similares, e dá outras providências. Diário Oficial da União [Internet]. Brasília, 2014 [acesso 4 jan 2023]. Disponível: https://bit.ly/3wdANHX
  » https://bit.ly/3wdANHX
• ³¹
  Tavares ET. Uma abordagem bioética sobre a moralidade das nanotecnologias do Ministério da Ciência, Tecnologia e Inovação e sua governança [tese] [Internet]. Brasília: Universidade de Brasília; 2015 [acesso 4 jan 2023]. Disponível: https://bit.ly/3WmPhzX
  » https://bit.ly/3WmPhzX
• ³²
  Vázquez AS. Ética. Rio de Janeiro: Civilização Brasileira; 2001.
• ³³
  Engelmann W, Pulz RL. As nanotecnologias no panorama regulatório: entre a ausência de regulação estatal específica e a necessidade de harmonização regulatória não estatal. Araucária [Internet]. 2015 [acesso 4 jan 2023];17(33):151-81. Disponível: https://bit.ly/3XjZmz1
  » https://bit.ly/3XjZmz1
• ³⁴
  Organização das Nações Unidas. Declaração Universal dos Direitos Humanos [Internet]. Paris: ONU; 1948 [acesso 4 jan 2023]. Disponível: https://bit.ly/3XreTfW
  » https://bit.ly/3XreTfW
• ³⁵
  Kant I. Fundamentação da metafísica dos costumes. Lisboa: Edições 70; 2007.
• ³⁶
  Jonas H. O princípio da responsabilidade. Rio de Janeiro: PUC-Rio; 2006.
• ³⁷
  Ferreira AP, Sant’Anna LS. A Nanotecnologia e a questão da sua regulação no Brasil: impactos à saúde e ao ambiente. Rev Uniandrade. 2015 [acesso 4 jan 2023];16(3):119-28. Disponível: https://bit.ly/3SFVNkU
  » https://bit.ly/3SFVNkU

Publication Dates

• Publication in this collection
  26 May 2023
• Date of issue
  2023

History

• Received
  9 July 2021
• Reviewed
  19 Aug 2022
• Accepted
  4 Jan 2023