WO2011128855A1 - Silica-based nir nano-emitters for applications in vivo and process for production thereof - Google Patents

Silica-based nir nano-emitters for applications in vivo and process for production thereof Download PDF

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Publication number
WO2011128855A1
WO2011128855A1 PCT/IB2011/051594 IB2011051594W WO2011128855A1 WO 2011128855 A1 WO2011128855 A1 WO 2011128855A1 IB 2011051594 W IB2011051594 W IB 2011051594W WO 2011128855 A1 WO2011128855 A1 WO 2011128855A1
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Prior art keywords
nanometric
silica
temperature
emitters
process according
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PCT/IB2011/051594
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English (en)
French (fr)
Inventor
Simonpietro Agnello
Roberto Boscaino
Marco Cannas
Franco Maria Gelardi
Maurizio Leone
Valeria Militello
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Universita' Degli Studi Di Palermo
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Publication of WO2011128855A1 publication Critical patent/WO2011128855A1/en

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    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00Silicon; Compounds thereof
    • C01B33/113Silicon oxides; Hydrates thereof
    • C01B33/12Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • C01B33/18Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00Nanotechnology for materials or surface science, e.g. nanocomposites
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00Silicon; Compounds thereof
    • C01B33/113Silicon oxides; Hydrates thereof
    • C01B33/12Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00Crystal-structural characteristics
    • C01P2002/80Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/82Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00Particle morphology
    • C01P2004/60Particles characterised by their size
    • C01P2004/64Nanometer sized, i.e. from 1-100 nanometer

Definitions

  • the present invention relates to the production of paramagnetic and phosphorescent nanoprobes based on silica (SiO 2 ), with emission in the near infrared (NIR) under excitation in the visible and in the NIR.
  • silica SiO 2
  • NIR near infrared
  • nanometric probes of the type: organic (fluorescent proteins, organometallic dyes), inorganic (compounds of Cd, Pb, Zn, Co) or hybrid organic/inorganic (obtained using for example the core/shell technique for coating organic fluorescent systems with SiO 2 or with polymers).
  • the commercially available nanometric probes mainly cover a spectral range between 300 and 900 nm, which are wavelengths strongly absorbed by tissues and having an average lifetime of a few microseconds (ps) at most. Accordingly, these probes do not permit working in the near infrared, the spectral range in which the biological tissues are particularly transparent, and moreover cannot be used for applications in vivo that have slow dynamics, such as, for example, diffusion through cellular membranes, free and mediated transport in fluids and tissues.
  • nanometric probes in the case when they also display paramagnetic characteristics, is that they can be used as nano-carriers.
  • the latter controlled with suitable magnetic fields, can be guided and diffused in fluids or tissues.
  • the optical and magnetic probes known in the literature are mainly produced by combining materials with different properties; for example, in core/shell systems the core is magnetic and the shell has optical properties, while in other probes the two properties may not even be present simultaneously.
  • silica nanoparticles doped with dyes for example 4,5-benzo-1 '-ethyl- a.S.a' ⁇ '-t t amethyl-l -(4-sulphobutyl)indodicarbocyanin-5*-acetic acid N- succinimidyl ester
  • silica nanoparticles, in which the silica constitutes a capsule within which the chromophore is enclosed for example fluorescein or rhodamine
  • patent documents WO2009090267A2, CN101387639A, CN101283276A and CN1456678A Although the emission may fall within the spectral range of the NIR, in these patents reference is made to specific dyes constituted of molecular complexes that typically have a very short decay time, of the order of nanoseconds, or microseconds.
  • the main aim of the present invention is to produce, starting from non-porous Si0 2 nanoparticles, paramagnetic and phosphorescent nanoprobes with emission in the near infrared, excitation in the visible and in the NIR, quantum efficiency of about 0.1 and characterized by a lifetime of the order of one second. This result is obtained by loading silica nanoparticles of high purity with 0 2 , using a specific diffusion method.
  • the present invention proposes to achieve the aims discussed above by means of a process of synthesis of silica-based nanometric emitters, capable of emitting in the near infrared under excitation both in the visible and in the near infrared.
  • the process comprises the following stages, in accordance with claim 1 : a) providing nanometric silica particles,
  • nanometric silica particles whereby a diffusion of the molecular oxygen is produced into said nanometric silica particles, and the nanometric silica particles enriched with said molecular oxygen, diffused therein, define said nanometric emitters, with the molecular oxygen acting as fluorophore.
  • silica-based nanometric emitters are obtained that have a lifetime of the order of one second.
  • the average diameter of said nanometric emitters is in the range between 7 and 40 nm.
  • the invention consists of producing fluorescent and magnetic probes starting from nanometric silica particles enriched with 0 2 by thermal treatments in a controlled environment, i.e. in a controlled atmosphere enriched with 0 2 .
  • the invention utilizes the magnetic properties and properties of emission in the near infrared of the interstitial O2.
  • the proposed method of loading consists of inserting the silica material in a solid-gas reactor or other suitable system in which it is possible to control the temperature, pressure and composition of the gas atmosphere, expose it to a predetermined initial O2 pressure at ambient temperature, and then heat it while it is exposed to the O2 atmosphere for the specified treatment time. During the process, temperature and pressure are stabilized for a predetermined time interval, respectively by means of a thermostat and a manostat, by connection to high-pressure cylinders.
  • the proposed method of loading consists of inserting the silica material in a solid-gas reactor or other suitable system already suitably preheated and pressurized, by the input of molecular oxygen, and maintaining the temperature and pressure for a predetermined time interval.
  • the particles obtained with this treatment are characterized by emission in the near infrared or by increase in emission efficiency of at least an order of magnitude with respect to the native particles.
  • These particles mainly cover a spectral range between 1260 and 1280 nm; therefore, in contrast to the nanometric probes of the prior art, they make it possible to work in the near infrared, that is the spectral range in which biological tissues are particularly transparent, and moreover can be used for applications in vivo that have slow dynamics.
  • the probes obtained by the process of the invention prove to be completely biocompatible and functionalizable.
  • the particles are of silica, a natural substance contained in many commonly used substances, while the paramagnetic and optically active component is the molecular oxygen which, in contrast to most of the chromophores used in existing technology, is non-toxic.
  • the proposed invention using particles only of pure Si0 2 directly (without further “additives” apart from O2), as well as making the probes produced completely biocompatible, makes them stable so that during their use, the fluorophore (O2) does not undergo changes due to the surroundings.
  • the probes obtained according to the invention can be produced with dimensions preferably from 7 nm to 40 nm, in monodisperse form, or with larger dimensions, in the form of aggregates, using only one material and with the same optical properties of the fluorophore independently of the dimensions of the probe, in contrast to the probes used until now that have dimensions determined by the fluorophore used (about 1 nm for organic dyes, and up to tens of nanometres for quantum dots and core/shell systems).
  • the probes of the invention in contrast to other types that require the application of specific and complex methods of synthesis, have the notable advantage of simplicity of synthesis, based purely on exposure of the particles of Si02 to controlled atmosphere of 0 2 .
  • An important aspect of the invention is that the excitation and emission of these particles occur in the NIR, a region of the spectrum in which the majority of biological tissues is transparent. Moreover, the bands associated with 0 2 are very narrow and make it possible to identify the emitter unambiguously.
  • These probes also have an emission lifetime that is very long compared with the known probes, permitting these particles to be used for studying the dynamics of biological systems, such as molecular diffusion in tissues. In particular, for this use it is thought to be possible to allocate high concentrations of fluorophore within one and the same particle, increasing the intensity and the temporal persistence of emission.
  • the silica nanoparticles loading with oxygen molecules object of the present invention, have the advantage that they can be used in medical-pharmaceutical applications of drug labelling and drug delivery.
  • Another important aspect of the invention is represented by the magnetic character of O 2 that allows to use the loaded particles also as nano-carriers for medical therapies, allowing their diffusion in fluids or tissues by means of a suitable control with magnetic fields. Accordingly, in a single system there would be simultaneous presence of properties of NIR emission and magnetic properties, so that the particles produced can be used simultaneously both for applications as fluorescent probes, and as magnetic carriers.
  • the loaded particles offer considerable potential as optical probes in bio-imaging.
  • they lend themselves to studies of confocal microscopy in the NIR, in view of the properties of absorption and emission in this spectral range.
  • the particles are suitable for investigating biological processes on a time scale of one second, as they have a sufficiently long emission time.
  • the combination of the two properties mentioned above and the possibility of functionalizing the particles make the proposed system a unique probe in the panorama of confocal microscopy.
  • Fig. 1 is a schematic diagram of the process for loading O2 in nanometric silica particles by means of the process of the invention
  • Fig. 2 shows the increase in luminescence centred on 1272 nm, with excitation at 1064 nm, of nanometric silica particles of 14 nm and of 40 nm respectively, enriched with O 2 by the process of the invention
  • Fig. 3 shows temperature and pressure as a function of time in a first preferred embodiment of the process used for loading the Si0 2 nanoparticles with O2;
  • Fig. 4 shows temperature and pressure as a function of time in a second preferred embodiment of the process used for loading the SiOa nanoparticles with O2.
  • Figures 1-4 show the results and the methods of synthesis for obtaining fluorescent and magnetic probes starting from non-porous nanometric silica particles, enriched with 0 2 by means of suitable thermal treatments in a controlled atmosphere, i.e. enriched with a predetermined concentration of O2 so that the latter is absorbed by the silica nanoparticles by means of a suitable diffusion process.
  • Said predetermined concentration of molecular oxygen is between 10% and 100%, preferably between 50% and 100%, more preferably between 90 and 100%.
  • the loading of 0 2 molecules in the silica nanoparticles can be obtained by means of thermal treatments having a duration higher than or equal to 1 minute, with temperatures higher than or equal to the ambient temperature and pressures higher than or equal to 1 bar.
  • the loading of O 2 molecules in the silica nanoparticles can be achieved with thermal treatments of a variable duration from 1 to 100 hours, with temperatures in the range 100 ⁇ 500°C and pressures in the range 20 ⁇ 140 bar.
  • An effective loading of 0 2 molecules was obtained with thermal treatments of a variable duration from 2 to 70 hours, starting from a low temperature, preferably from ambient temperature, until to reach a higher temperature, in the range 00 ⁇ 500°C, which is maintained for a predetermined number of hours, comprised between 0,25 and 40 hours, at a pressure in the range 20 ⁇ 140 bar.
  • a further effective loading of 0 2 molecules is obtained starting from a low temperature, preferably from the ambient temperature, up to reach a higher temperature, preferably comprised in the range 150 ⁇ 450°C, that is maintained for a predetermined number of hours, preferably comprised in the range between 0,5 and 30 hours, at a pressure preferably comprised in the range 30+ 30 bar.
  • the effective loading of O 2 molecules is obtained starting from a low temperature, preferably from the ambient temperature, up to reach a higher temperature, comprised in the range 200 ⁇ 400 o C, that is maintained for a predetermined number of hours, comprised in the range between 1 and 20 hours, at a pressure comprised in the range 45+120 bar.
  • the process of the invention comprises the steps of:
  • heating means for increasing the temperature of the system and of the nanoparticies contained therein up to a predetermined temperature, preferably in the range between 200 and 400°C (limit value included), while they are exposed to the O2 atmosphere; this takes place in a predetermined time interval preferably in the range between 1 and 3 hours, with a heating rate varying between 0.03 and 0.04°C/s.
  • the O2 pressure increases up to a predetermined value in the range between 45 and 120 bar, established according to a transformation at constant volume based on the initial temperature and pressure;
  • the total time for execution of the steps c) and d) is preferably between 2 and 23 hours.
  • the powders of silica nanoparticles can be inserted directly into an available volume of the system, such as a solid-gas reactor, already heated and at high pressure.
  • the particles obtained with this treatment are characterized by emission in the near infrared or by increase in emission efficiency in the near infrared of at least one order of magnitude with respect to the native particles.
  • These nanometric particles can be used as paramagnetic and phosphorescent nanoprobes, with emission in the NIR in the range 1260-1280 nm, for example at about 1270 nm, characterized by a lifetime of the order of one second, at least greater than 500 ms, excitable in the visible region in the range 760-770 nm, for example at about 765 nm, and in the NIR at about 1064 nm.
  • the molecular oxygen used for loading the silica nanoparticles can be of the normal type ( 1 ⁇ ⁇ 2) or isotopic ( 18 C>2); the latter is able to induce an increase in lifetime of NIR emission and of its quantum efficiency.
  • a first process for preparing silica-based nanoprobes enriched with molecular oxygen, carried out on hydrophilic nanoparticles starting from an average diameter of 7 nm, comprises the following steps:
  • the heating is carried out by means of a suitable heating apparatus or simply heater, constituted, for example, of electrical resistances and temperature control based on a thermal probe and a PID controller.
  • the O2 pressure increases to 50 bar, established according to a transformation at constant volume based on the initial temperature and pressure;
  • a second process for preparing silica-based nanoprobes enriched with molecular oxygen, carried out on hydrophilic nanoparticles starting from an average diameter of 7 nm, comprises the same steps as in Example 1, but using the temperature ramp shown in Fig. 4.
  • step b) the initial O2 pressure is about 55 bar and the concentration of O2 is equal to 99%.
  • step c) the temperature reached is 390°C and the maximum 0 2 pressure reached is 100 bar; these conditions are reached in about 3 hours.
  • step d) the system is maintained for 21 hours at a temperature of 390°C and a pressure of 100 bar and then, in step e), it is left to cool down to ambient temperature.
  • the process of the invention can also be carried out on silica nanoparticles that are not hydrophilic.
  • Fig. 2 shows the increase, due to the treatment process according to the invention, in luminescence centred on 1272 nm, with excitation at 1064 nm. It can be seen that the emission increases by almost a factor of 10. This effect is independent of particle size, and the efficiency of loading with O2 is comparable for the treatments outlined above.
  • Fig. 2a relates to the emission from Si0 2 particles enriched with (1 ⁇ 4 having an average diameter of 14 nm
  • Fig. 2b relates to emission from Si0 2 particles enriched with 0 2 having an average diameter of 40 nm.
  • curves 1 show the emission from silica particles that have not undergone the process of the invention
  • curves 2 show the emission from silica particles that underwent thermal treatment for about 3 hours (see Fig. 3 and EXAMPLE 1 ) that envisages raising the temperature to 200°C (in about 1.5 hours) and holding at this temperature and at a pressure of 50 bar (for about 1.5 hours)
  • curves 3 show the emission from silica particles that underwent thermal treatment for about 24 hours (see Fig. 4 and EXAMPLE 2) that envisages raising the temperature to 390°C (in about 3 hours) and holding at this temperature and at a pressure of 100 bar (for about 21 hours).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
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  • Condensed Matter Physics & Semiconductors (AREA)
  • Composite Materials (AREA)
  • General Physics & Mathematics (AREA)
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  • Crystallography & Structural Chemistry (AREA)
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  • Silicates, Zeolites, And Molecular Sieves (AREA)
  • Silicon Compounds (AREA)
  • Luminescent Compositions (AREA)
PCT/IB2011/051594 2010-04-13 2011-04-13 Silica-based nir nano-emitters for applications in vivo and process for production thereof WO2011128855A1 (en)

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ITRM2010A000174 2010-04-13
ITRM2010A000174A IT1399551B1 (it) 2010-04-13 2010-04-13 Nano-emettitori nir a base di silice per applicazioni in-vivo e relativo processo di produzione.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same

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CN101283276A (zh) 2005-09-08 2008-10-08 比特里斯株式会社 具有荧光性的磁性纳米颗粒及其制备方法和应用
CN101387639A (zh) 2002-11-26 2009-03-18 康乃尔研究基金会有限公司 基于二氧化硅的荧光纳米颗粒
WO2009090267A2 (en) 2008-01-17 2009-07-23 Dublin City University Dye-doped nanoparticles, a method of manufacture of the same, and a method of determining a percentage weight of a dye which yields a required relative fluorescent intensity from a dye-doped nanoparticle

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CN1456678A (zh) 2002-05-09 2003-11-19 中南大学 一种生物标志物——荧光硅纳米颗粒的制备方法
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WO2009090267A2 (en) 2008-01-17 2009-07-23 Dublin City University Dye-doped nanoparticles, a method of manufacture of the same, and a method of determining a percentage weight of a dye which yields a required relative fluorescent intensity from a dye-doped nanoparticle

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same

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