Featured paper: Best nanoheaters for cancer treatment.

[Paper: Mean-field and linear regime approach to magnetic hyperthermia of core-shell nanoparticles: can tiny nanostructures fight cancer? Marcus S. Carrião, Andris F. Bakuzis. Nanoscale, 2016,8, 8363-8377. DOI: 10.1039/C5NR09093H]

The authors of the paper published in Nanoscale: Professor Andris Bakuzis (left) and doctoral student Marcus Carrião dos Santos (right).

Hyperthermia, for cancer treatment, is induced by increasing the temperature to activate tumor cell death. This high temperature can be created by introducing nanoparticles into the tumor that function as heaters, and after their function is completed they are eliminated by the body. Magnetic nanoparticles may be used in these treatments because they have the ability to generate heat when subjected to alternating magnetic fields of specific intensity and frequency.

A work on nanomedicine (nanotechnology used in medicine) fully conducted at the Brazilian Federal University of Goiás (UFG) suggests a new strategy using hyperthermia for cancer treatment: using smaller magnetic nanoparticles than those normally used and composed of more than one material, which could provide several advantages to the patient. To reach this conclusion, the researchers developed an innovative theoretical method that paves the way for manufacturing magnetic nanoparticles optimized for hyperthermia. The study was reported in a paper published in the prestigious Nanoscale journal, signed by the doctoral student Marcus Carrião dos Santos and his supervisor Andris Figueiroa Bakuzis, professor at the Physics Institute of UFG.

Hyperthermia cancer treatment generally uses nanoparticles that are relatively large (20 nm size range) and homogeneous (from a single material), which are considered as the most effective to generate heat according to theoretical studies based on traditional methods. However, these “large” nanoparticles accumulate quickly in the liver and it may take several months or years for these particles to leave the body of the patient being treated. On the other hand, nanoparticles smaller than 10 nm are rapidly eliminated in the urine, reducing the possibilities of intoxication and thereby increasing the selection of materials that can be used to manufacture them.

The relationship between particle size and excretion route (liver or kidney) was a conclusion reached by Bakuzis and colleagues from evidence reported in the scientific literature and pre-clinical studies (in vivo) carried out within a multidisciplinary research network, coordinated by Bakuzis, and aimed at solving problems associated with the use of magnetic nanoparticles for cancer treatment.

In addition, smaller nanoparticles have better distribution and penetration in tumors, among other advantages in the context of cancer treatment.

Aware of these characteristics, Bakuzis and dos Santos investigated the possibility of manufacturing nanoparticles of less than 10 nm that could efficiently generate heat. An important insight came from an article published in 2011 in the Nature Nanotechnology journal (Nat. Nanotech. 6, 418 (2011)). Professor Bakuzis says that “in this article, the researchers concluded experimentally that certain heterogeneous (from different materials) core-shell structures of spinel ferrites warmed more efficiently than homogeneous particles”.

The scheme, provided by the authors, sums up the hyperthermia process of magnetic nanoparticles and compares the conventional nanoparticles with the proposal of the UFG researchers, showing the key advantages for its application in the treatment of cancer using hyperthermia.

The pair of scientists then decided to theoretically investigate whether nanoparticles less than 10 nm formed by one material core and a shell of another material could efficiently generate heat and how to optimize them for this function. However, the conventional methods available for this modeling were not adequate. In fact, they considered the nanoparticle as a homogeneous entity, ignoring the fact that the surface atoms and the core atoms respond differently to the application of a magnetic field. This oversight became more significant in the study of particularly heterogeneous particles such as those they intended to study, the reason why the researchers from Goiás decided to develop a more suitable model for the study object.  Bakuzis explains that “in the paper we presented the first analytical hyperthermia model of core-shell nanoparticles within the linear response and mean-field theory, and from these calculations we pointed out important materials properties to achieve efficient heat generation.”

The results obtained by the physicists and published in the paper may have a significant impact in a health issue that concerns humanity, cancer cure. “Our studies indicate that it is possible to develop small particles for cancer treatment that can be quickly eliminated from the body via the kidneys. In particular, by combining different materials in the nanostructure”, summarizes Bakuzis.

To work with impact on this interface theme, Bakuzis is always in contact with a pool of knowledge of various areas. In addition to leading the multidisciplinary nanomedicine network that includes researchers with backgrounds in tumor biology, genetics, physiology, pharmacy, veterinary medicine, biophysics, physics, medical physics and chemistry, the professor and his group actively participate in scientific events that bring together many different professionals, including doctors with various specializations already using hyperthermia in humans for cancer treatment. “These scientific contacts are fundamental in interface areas such as the one our group works with,” concludes Bakuzis.

The research that led to the paper in the Nanoscale journal received funding from the Brazilian National Scientific and Technological Development Council (CNPq) and from the Research Foundation of the State of Goiás (FAPEG) and was carried out as part of the doctoral work of Marcus Carrião dos Santos.

Interviews with plenary lecturers of the XIII SBPMat Meeting: Luís Carlos (Universidade de Aveiro, Portugal).

Prof. Luís Carlos.

“Luminescence applied to nanomedicine” is the subject of one of the plenary lectures that the Materials research community is going to enjoy in our XIII SBPMat Meeting (João Pessoa, Brazil, September 28th to October the 2nd). The speaker will be the Portuguese physicist Luís António Ferreira Martins Dias Carlos, full professor at the University of Aveiro (Portugal), who got his Ph.D. in physics from the University of Évora (Portugal) in 1995 working on photoluminescence of polymer electrolytes incorporating lanthanide salts.

At the University of Aveiro, Luís Carlos created in 2000 a research group in functional organic-inorganic hybrids. The group has established an international network devoted to these luminescent hybrid materials with more than 30 research groups in Europe, China, Japan, Singapore, Brazil and Australia. Also at Aveiro, Luís Carlos has been, since 2009, the vice-director of the Centre for Research in Ceramics and Composite Materials (CICECO), one of the largest European institutes in the Materials and Nano fields.

He is member of the Lisbon Academy of Sciences (Physics section) since 2011. He was visiting professor of São Paulo State University (UNESP), Brazil, in 1999, 2012 and 2013, and of University of Montpellier 2, France, in 2008. He awarded a ‘Pesquisador Visitante Especial’ grant by the CNPq, Science Without Borders Program, Brazil in 2013.

He has co-authored more than 345 papers in international journals, 8 invited reviews, 5 book chapters, and 2 international patents. He has more than 8.050 citations, having h-index of 47. He has given 40 plenary and invited lectures at conferences. He is associate editor of the Journal of Luminescence.

Read our interview with the plenary speaker.

SBPMat newsletter: – Are there nanomedical applications to luminescent materials already on the market/spread in society? Please, give some high-impact examples. 

Luís Carlos: – Undoubtedly yes, there are luminescent materials with important applications in nanomedicine already on the market. I can highlight two examples:

1. Organic complexes based on lanthanide ions (as, for example, cryptates and β-diketonates) are sold as contrast agents for magnetic resonance imaging  (essentially using Gd³+) and luminescent markers (using Eu3+, Sm3+ and Tb3+) for fluoroimmunoassays. The fluoroimmunoassay is an immunological method for clinical diagnosis that is particularly relevant in prenatal and neonatal screening tests, as well as to detect proteins, viruses, antibodies, tumor biomarkers and medicine residues. In this respect, it is worth mentioning the work conducted by several researchers from the INCT INAMI (Brazilian National Institute of Science and Technology on Nanotechnology for Integrated Markers), implementing a prototype in the hospital environment in order to develop methods to diagnose the American cutaneous leishmaniasis, prostate cancer (PSA) and low density lipoprotein (LDL) by fluoroimmunoassay, using recombinant antigens marked with lanthanide ions complexes (for example, Eu3+, Tb3+ and Nd3+). The international market for contrast agents and luminescent markers based on lanthanide ions is valued in many hundreds of millions of US dollars.

2. Luminescent nanoparticles (“quantum dots”, QDs, and nanocrystals incorporating lanthanide ions) have played a major role in the last years thanks to very important applications for diagnosis by optical imaging and therapy techniques. Recent estimates value the international market for luminescent nanoparticles in the medical field in over 20 million US dollars. A notable example in the treatment of tumors is the local hyperthermia. Local hyperthermia, also referred as local thermotherapy, is a type of treatment in which biological tissues (typically cancer cells)  are exposed to temperatures above 45° C, irreversibly damaging them and causing their death (the collateral damage to the healthy tissues surrounding the tumor is usually minimal). Numerous clinical trials with hyperthermia are being currently performed around the world so we can better comprehend and improve the technique. For example, the use of luminescent or magneto-luminescent particles (with magnetic ions such as Iron or Cobalt), vectored to bind to specific points in the cancer cells, enabling the local heating by the absorption of electromagnetic radiation and magnetic induction, respectively, is a new type of local hyperthermia. Precise temperature control in the irradiated area, limiting the effects of high temperature on the rest of the body, still is one of the key challenges for the popularization of the technique.

SBPMat newsletter: –  Could you briefly describe the main challenges in the field of luminescence applied to nanomedicine?

Luís Carlos: – I can point out two examples: improving the imaging techniques for diagnosis and developing luminescent micro/nanothermometers which allow mapping the intracellular temperatures with a resolution of the order of tenths of a degree.

In regard to imaging applications in nanomedicine, emitting centers in the near-infrared region (for example, lanthanide ions such as Nd3+ and Yb3+, QDs and organic dyes) have great advantages over those in the visible region.  For instance, biological tissues present less autofluorescence in the near-infrared window, which enables a better signal-to-noise discrimination and improves the sensibility to detection. Also, in comparison to the ones in the visible region, near-infrared photons interact less with biological tissues, which reduces the risk of disturbance or damage in the observed biological system. Thus, there is no doubt that the synthesis of new luminescent nanoparticles, emitting efficiently in near-infrared (in some cases producing persistent luminescence, i.e., light emissions that last for minutes, hours or even days, after the excitation is over), will lead us to a revolution in fluorescence microscopy, with the development of in vitro and in vivo imaging techniques in near-infrared (whose radiation penetrates deeper into the biological tissue, when compared to visible light).

The development of luminescent micro/nanothermometers to map the intracellular temperature, particularly in cancer cells, will surely improve our current perception on their pathology and physiology, optimizing early diagnosis and therapeutic processes (as seen above in the case of local hyperthermia).  These non-invasive thermometers are a critical tool for better understanding a set of cellular processes followed by alterations in temperature, such as cell division, gene expression, or changes in the metabolic activity. Finally, the development of luminescent nanothermometers in the near-infrared region,  which are capable of sensing heat and penetrate deeper into the biological tissue, will pave the way for in vivo thermal sensing and imaging (in small animals, in a first stage).

SBPMat newsletter: – Under your viewpoint, which are the main contributions you made to the field of Materials Science and Engineering during your scientific career? Could you please include a selection of 3 or 4 of the most important publications among your work in your answer?

Luís Carlos: – Normally, our latest works tend to seem to be the most important… Regardless, I understand that my main contributions to Materials Science and Engineering are related to the development of i) luminescent organic-inorganic hybrid materials, ii) ratiometric nanothermometers based on the characteristic emission of lanthanide ion pairs (Eu3+/Tb3+ and Er3+/Yb3+) and iii) nanoplatforms combining nanoheaters (metal particles of Gold or Silver) and nanothermometers which allow to increase the local temperature by laser irradiation while simultaneously mapping such temperature increase with precision. The following four papers illustrate these contributions:

Full Colour Phosphors From Eu(III)-Based Organosilicates. L. D. Carlos, Y. Messaddeq, H. F. Brito, R. A. Sá Ferreira, V. de Zea Bermudez, S. J. L. Ribeiro, Adv. Mater. 12, 594–598 (2000)

Nanoscopic Photoluminescence Memory as a Fingerprint of Complexity in Self-Assembled Alkylene/Siloxane Hybrids. L. D. Carlos, V. de Zea Bermudez, V. S. Amaral, S. C. Nunes, N. J. O. Silva, R. A. Sá Ferreira, J. Rocha, C. V. Santilli, D. Ostrovskii, Adv. Mater. 19 341–348 (2007)

A Luminescent Molecular Thermometer for Long-Term Absolute Temperature Measurements at the Nanoscale. C. D. S. Brites, P. P. Lima, N. J. O. Silva, A. Millán, V. S. Amaral, F. Palacio, L. D. Carlos, Adv. Mater. 22, 4499–4504 (2010)

All-In-One Optical Heater-Thermometer Nanoplatform Operative From 300 to 2000 K Based on Er3+ Emission and Blackbody Radiation. M. L. Debasu, D. Ananias, I. Pastoriza-Santos, L. M. Liz-Marzan, J. Rocha, L. D. Carlos, Adv. Mater. 25, 4868–4874 (2013)