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International Journal of Medical Nano Research





DOI: 10.23937/2378-3664/1410007



Bnct and Nanoparticles: A Long Way to a Routine Clinical Method

Cesare Achilli1*, Stefania Grandi2,3, Annarita Ciana1 and Giampaolo Minetti1


1Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
2Department of Chemistry, University of Pavia, Pavia, Italy
3Nano Analysis & Materials s.r.l., Vigevano, Italy


*Corresponding author: Cesare Achilli,Department of Biology and Biotechnology, University of Pavia, Pavia, Italy E-mail: cesare.achilli@unipv.it
Int J Med Nano Res, IJMNR-2-007, (Volume 2, Issue 1), Commentary; ISSN: 2378-3664
Received: October 29, 2014 | Accepted: January 21, 2015 | Published: January 22, 2015
Citation: Achilli C, Grandi S, Ciana A, Minetti G (2015) Bnct and Nanoparticles: A Long Way to a Routine Clinical Method. Int J Med Nano Res 2:007. 10.23937/2378-3664/1410007
Copyright: © 2015 Achilli C, 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.



We have recently had the chance to read the editorial “Boron Neutron Capture Therapy of cancer as a part of modern nanomedicine”[1], by Alexander V. Safronov, in which the potential of nanomaterials as boron-carriers for the treatment of many types of tumors by BNCT is discusses. The author argues that “Most of the modern papers on BNCT report ‘potential’ BNCT agents […] and don’t even include cell studies”, and “In some cases the abbreviation BNCT may become a ‘golden ticket’ for authors who just want to public their current study without intent to continue”. We agree with the first assertion, which is unequivocally verifiable by reading the recent literature about BNCT, but not with the second, that is somewhat speculative.

The study for a new drugis complex and may last ten years or more. It includesthe preparation of the molecule in a pure form,the experimentation on cell lines, the animal testing, and the three phases of clinical trials on humans. In the case in which in vitro results already point to a possible cytotoxicity, additional in vivo tests on animals become inopportune on the basis of ethical principles that have been even reinforced by novel laws promulgated in some countries, such as the new European regulation (2010/63/UE), that strongly restrict inessential in vivo experiments. Therefore, ascientific work can be interrupted at an early stage and, unfortunately, the obtained data remain generally unpublished, staying hidden to the rest of the world.

In a field such as nanotechnology, when little differences in size, shape and chemical-physical properties of nanoparticles induce great alterations in the interaction with biological systems, the failures and the frustrating difficulties in the interpretation of the results are widespread.

A dramatic obstacle that is encountered in the application of nanomaterials for biological purposes (especially for BNCT,in which the compound must be administered as a homogeneous suspension by intravenous infusion), is their strong tendency to aggregate/agglomerate, in aqueous solvents,intolarge particlesof micrometric size, by reason of their thermodynamic properties. Thesemicrometric particles, besides having an elevated sedimentation rate, induce several adverse reactionsto blood components (e.g. thrombi, inflammation, and hemolysis) and, most importantly,will never be internalized by target cells. The stability of nanoparticle suspensions is influenced by several parameters, including: the intrinsic properties of the nanomaterial (size, porosity, surface polarity), the characteristics of the medium (viscosity, pH, ionic strength, ionic composi¬tion, presence of molecules and/or macromolecules), and nanoparticle concentration. The addition ofvarious molecules canpartially stabilizesome types of nanoparticles in suspension, butoften these additives are not compatible for medical use, because toxic (e.g. alcohols, surfactants) or anyway contraindicated for intravenous injection [2,3].

Little is yet known about the interactions between nanomaterials and biological systems. The safety issues derived from nanoparticle routes of entry and their potential biodistribution are probablygoverned by size, surface area, shape, agglomeration/aggregation tendency, and binding to biological structures. Many types of nanomaterials display strong toxicity to cells during the in vitroexperiments [4] and, furthermore, induce thrombotic [5], inflammatory [6] and hemolytic [7] effects during experiments with purified human blood cells. For some of these materials, however, functionalization with various organic molecules mayreduce the toxicity and the unwanted biological effects, making it desirable to continue the studies in this direction [8,9]. Nevertheless, so poor is the current knowledge concerning the biodistribution, metabolism, clearance mechanism and the consequences of accumulation in the body of the new classes of nanoparticles, that the precautionary principle should discourage their use with lightness in humans [10]. It should be noted, however, that toxicity and adverse effects toward blood cells are not a phenomenon caused only by nanoparticles, in fact also non-nanostructured soluble molecules may trigger strong unwanted biological consequences [11,12].

On the basis of the above mentioned criticalities aboutnanomedicine, it is evident that the absencein the literature of detailed investigations, for most ofthe materials proposed for BNCT (and for many other biological fields of application),shouldnot be intended as a shortcut adopted byresearchers hasty to publish their results. On the contrary, itis related to intrinsic serious difficultiesthat slow down the development in this promising area of research, and that show how several types of nanomaterials, although theoretically valid for their application in medicine, are de facto incompatible with therapeutic use.


Acknowledgements

This work has been supported by FondazioneCariplo, Italy, grant n. 2011-2099.


References
  1. Safronov AV (2014) Boron neutron capture therapy of cancer as a part of modern nanomedicine. Int J Med Nano Res 1: 001e.

  2. Labille J, Brant J (2010) Stability of nanoparticles in water. Nanomedicine (Lond) 5: 985-998.

  3. Wu L, Zhang J, Watanabe W (2011) Physical and chemical stability of drug nanoparticles. Adv Drug Deliv Rev 63: 456-469.

  4. Yu T, Malugin A, Ghandehari H (2011) Impact of silica nanoparticle design on cellular toxicity and hemolytic activity. ACS Nano 5: 5717-5728.

  5. Guidetti GF Consonni A, Cipolla L, Mustarelli P, Balduini C (2012) Nanoparticles induce platelet activation in vitro through stimulation of canonical signalling pathways. Nanomedicine 8: 1329-1336

  6. Gonçalves DM, Chiasson S, Girard D (2010) Activation of human neutrophils by titanium dioxide (TiO2) nanoparticles. Toxicol In Vitro 24: 1002-1008.

  7. Asharani PV, Sethu S, Vadukumpully S, Zhong S, Lim CT, Hande MP, Valiyaveettil S (2010) Investigations on the structural damage in human erythrocytes exposed to silver, gold, and platinum nanoparticles. Advanced Functional Materials 20: 1233-1242.

  8. Grandi S, Spinella A, Tomasi C, Bruni G, Fagnoni M, et al. (2012) Synthesis and characterisation of functionalized borosilicate nanoparticles for boron neutron capture therapy applications. Journal of Sol-Gel Science and Technology 64: 358-366

  9. Achilli C, Grandi S, Ciana A, Guidetti GF, Malara A, et al. (2014) Biocompatibility of functionalized boron phosphate (BPO4) nanoparticles for boron neutron capture therapy (BNCT) application. Nanomedicine 10: 589-597.

  10. Almeida JP1, Chen AL, Foster A, Drezek R (2011) In vivo biodistribution of nanoparticles. Nanomedicine (Lond) 6: 815-835.

  11. Achilli C, Jadhav SA, Guidetti GF, Ciana A, Abbonante V, et al. (2014) Folic acid-conjugated 4-amino-phenylboronate, a boron-containing compound designed for boron neutron capture therapy, is an unexpected agonist for human neutrophils and platelets. Chem Biol Drug Des 83: 532-540.

  12. Achilli C, Ciana A, Fagnoni M, Balduini C, Minetti G (2013) Susceptibility to hydrolysis of phenylboronicpinacol esters at physiological pH. Central European Journal of Chemistry 11: 137-139.

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