P. Sarkisov International Laboratory of
Glass-Based Functional Materials
 

 D. Mendeleyev University of Chemical Technology of Russia
 English   

Spheroidized glass microparticles for nuclear medicine

The term "microsphere" is used to describe spherical particles with diameters in the range 1 μm - 2000 μm. Glass microspheres are free flowing powders consisting of spherical glass particles in the indicated range of size. The possibility to obtain glass with spherical shape and narrow size distribution in the micrometer domain is the basis of one of the most important applications of glass technology in the field of medicine, making glass a controllable medical micro-device compatible with the human organism. Glass microspheres are in fact used for the transportation of radioactive sources to the internal organs in cancer radiotherapy, acting as micro-sized internal radiotherapeutic device in form of glass microspheres (20-40 μm in size) with embedded suitable neutron-activated radioisotopes [1-3]. Microspheres may be implanted as a liquid suspension into the tumor through the surrounding blood vessels and, for size constraints, they stop just at the end arterioles and irradiate the tumor for a depth and a period which depend on the radioisotope decay features. This strategy has a particular potential in the treatment of liver cancer. As a matter of fact, standard drug treatment for liver cancer has not yet been established. So, the alternative way of treating cancer by means of local radiotherapy (radionuclide therapy or brachytherapy) is nowadays particular important. It is worth noting that internal radiation therapy can kill cancer cells with a selectivity, with respect to healthy parts of the organism, impracticable with usual external radiotherapy, since the source of radiation is directly delivered to the affected organ. One of the main points enabling the use of glass microsphere in internal radio-therapy is the size of the microsources of radiation, since their section is comparable to the size of blood vessels, which can be used to direct microspheres to the tumor. This fact allows relatively simple and non invasive medical process, minimal damage to healthy tissues, the possibility to deliver the tumor almost any dose of radiation, a short period of stay in hospital, and low probability of complications. For these reasons spheroidized glassy materials for nuclear medicine have been developed in the last 10 years and successfully used in radiation therapy, mainly in western countries.

    
Fig.1. High-temperature furnace for glass melting     Fig. 2. Plasma torch for the process of micro-powder
     spheroidization

     
Fig. 3. YAS glass powders are selected according to particle size (left), under the leadership of senior researcher V.I. Savinkov (center), and transformed into microspheres (right).

YAS microspheres

The production of YAS microspheres involves the preparation of powder samples, from glass obtained by melting at about 1600C in a platinum crucible, starting from of high-purity reagents of silica and yttrium and aluminum hydroxides. Fast cooling rate of the melt (by gas blowing or by using rapidly rotating water-cooled rollers) allows to suppress crystallization keeping high the content of yttrium oxide (up to 23 mol% Y2O3 compared with 17 mol% of commercial YAS microspheres). The resulting glass is crushed by a multistep procedure in order to maximize the particle fraction in the 20-30 microns range. The selected powder fraction is then exposed to spheroidization process in a plasma torch designed at SILG.

Before the introduction of microspheres into the body, they are exposed to radiation in a nuclear reactor so that thermal neutrons convert yttrium nuclei in the YAS glass into the 90Y short-living isotope with a half-decay period of 64.1 hours. This time is sufficient to deliver the drug to the clinic and to perform surgery. 90Y shows additional benefits for therapeutic applications because of its nuclear characteristics, which give rise ?-emission with energy of 2.28 MeV with an average length of 2.8 mm of penetration depth. Importantly, Al2O3 and SiO2 in the glass do not form long-lived isotopes by irradiation and provide high chemical resistance in the internal environment of the body.

   

Fig. 5. Images at different magnifications of YAS microspheres used in toxicological, radiological, and clinical tests with positive results.

As a result of toxicological, radiological, and clinical tests, Y-rich YAS glass microspheres, produced at SILG in conjunction with the firm BEBIG, are now registered with the code DCF 2011/11568 of August 02 2011, as a medical device named "Microsources of radiation based on radionuclide yttrium-90" and, according to order Roszdravnadzor of August 2, 2011 4671-Pr/11, it is permitted the production, sale and use in the territory of the Russian Federation.

The research on YAS microspheres at SILG also concerns the investigation of engineering process for deplete from yttrium the external microsphere shell so as to reduce the risk of releasing radioactive yttrium into the organism during radiotherapy. Experiments along this line regard the study of microsphere surface modifications aimed to selectively deplete from yttrium. Collected data show the real possibility of yttrium depletion by acid etching the glass in a concentrated HCl solution (Figs. 6 and 7).

    
Fig. 6. X-ray fluorescence analysis of samples of YAS glass before (first point) and after treatment in HCl. The curve is the fit according to an exponential lawFig.7. Depth of the structural modification of the glass according to confocal Raman data on samples etched for different duration time

Confocal Raman spectroscopy shows that the depth of the structurally modified layer after 30 days of etching in HCl is 25 microns, easily controllable by changing the treatment duration within a wide range. Electronic microscope images of YAS microspheres before and after etching in hydrochloric acid are shown in Fig. 8.

   

Fig.8. YAS glass microspheres images before (left) and after (right) etching in HCl.

A comparison of the size of the microspheres before and after etching does not show relevant change of size, but a comparison of fluorescence contrasted images evidence a structural modification corresponding to yttrium depletion in a layer about 8 micron in thickness (Fig. 9).

Fig. 9. Fluorescence map. Image of a glass microsphere after 3 days of HCl treatment (centre) and maps of 633 nm-excited non-bridging-oxygen fluorescence at 760 nm (right) and scattered laser light at 633 nm taken as a reference (left).

Prolonged treatment in saline at 37o C and subsequent tests found that the surface-modified glass microspheres, with yttrium depleted layer, do not release isolated Y3+ ions during the treatment in alkaline environment, even for depletion layer thickness of less than 1 micron.

Porous microspheres

The development at SILG of highly porous glass microspheres with controlled pore size distribution is aimed to assess new methods of delivering radioisotopes by adsorption in micro- or nano-pores. The use of this type of materials can give some advantages, such as higher specific radioactivity, reduced density, and the opportunity of choosing the radioactive source. Moreover, using porous materials, microsphere irradiation may be avoided.

The development of highly porous glass microspheres is indeed very interesting also because they can be used in principle both for diagnostic purpose of cancer diseases (using isotope 11B as a label) and for therapy (introducing radioactive boron isotopes). SILG activity on porous glass microspheres is based on the use of borosilicate glass system in the composition range 60SiO2-(25-31)B2O3-(9-15)Na2O (mol%). The selected compositions fall in a range of metastable phase separation between silicate and borate phases, so as to favor the formation of interpenetrating structures by heat treatment with tunable phase inhomogeneity. This peculiar structure can then be used to promote the subsequent formation of a uniform porosity by liquid phase separation and selective etching process. Preliminary tests on the feasibility of porous microsphere from sodium borosilicates have been performed at SILG looking at the efficiency of the etching process, and evaluating the amount of residual boron in the glass after etching. For this purpose, modifications of content of the two main oxides (B2O3 and Na2O) have been measured using a laser elemental analyzers LEA S-500 before and after chemical treatment (Fig. 10).

Experiments of acid leaching indicate that optimized conditions for microsphere etching involve stirring in HCl 1N at about 70oC. These conditions allow us to obtain porous microspheres with open porous structure and average pore size in the range 50-500 nm (Fig.11).

Fig. 11. Images of porous microspheres and their surface structure.

The results of SILG on glass microspheres for nuclear medicine [1-3] were presented at international and national conferences, forums and seminars, receiving several awards: Winner V Project Competition for young scientists in the XVI International specialized exhibition "Chemistry-2011", Grand Prix III International Forum intellectual property; Gold Medal of the XIII International exhibition and Forum "High technologies of XXI century".

   

Fig. 12. Diploma grand prix III International forum on intellectual property. Right - The award academician P.D. Sarkisov, Professor A. Paleari, Professor V.N. Sigaev and graduate student G. Atroschenko.

Results and processes concerning microspheres are protected by patent applications "microbeads of yttrium-aluminosilicate glass for radiotherapy and their method of preparation" by V.N. Sigaev, N.V. Golubev, S.V. Lotarev, V.I. Savinkov, G.N. Atroschenko, P.D. Sarkisov, I.V. Sinyukov, A.V. Levchuk, and "Method of produce microspheres of yttrium-aluminosilicate glass for radiotherapy" by V.N. Sigaev, G.N. Atroschenko, in . I.V. Savinkov, G.Y. Shakhgildyan, I.L. Selivanenko.

Taking into account miniature nature of the technology, the highest requirements for medical products, and low-volume production, the International Laboratory of functional materials based on glass able to perform not only the development of new methods of local radiation therapy, but also to ensure completely Russian Federation in this new class of materials.

Further works are planned on sferoidized materials for nuclear medicine

- Development and production of 90Y2O3-Al2O3-SiO2 glass microbeads for the introduction into medical practice of Russian oncology;
- Development of pilot technology for the production of YAS beads with yttrium depleted external nano- or microlayer;
- Investigation of Lu2O3-Y2O3-Al2O3-SiO2 glass microspheres and development of therapeutic and diagnostic applications of 90Y β-radiation and 177Lu γ-radiation;
- Development of microspheres based on borosilicate glasses with controlled pore structure in the nano and micro scales and methods of producing radioactive sources based on them.
- Development of glassy and glassceramic microspheres for magnetic hyperthermia.

Publications

  1. G.N. Atroshchenko, V.I. Savinkov, A. Paleari, P.D. Sarkisov, V.N. Sigaev, "Glassy microspheres with elevated yttrium oxide content for nuclear medicine", Glass and Ceram. 69, 39-43 (2012).
  2. V.N. Sigaev, G.N. Atroschenko, V.I. Savinkov, P.D. Sarkisov, G. Babajew, K. Lingel, R. Lorenzi, A. Paleari, "Structural rearrangement at the yttrium-depleted surface of HCl-processed yttrium alumino-silicate glass for 90Y-microsphere brachytherapy", Mater. Chem. Phys., 133, 24-28 (2012).
  3. Proceedings of the International Scientific conference "Pharmaceutical and Medical biotechnology".