Periodic Reporting for period 2 - NORTH (NanOthermomteRs for THeranostics)
Berichtszeitraum: 2022-07-01 bis 2023-12-31
Project NORTH aims at developing new types of multifunctional hybrid nanomaterials, which would combine temperature diagnostics and therapy in just one material. More specifically, in the project we aim at combining thermometry in the physiological range with either drug delivery or photodynamic therapy. For this we use novel types of hybrid materials designed from combining inorganic components with Periodic Mesoporous Organosilica (PMO) particles. The inorganic nanocomponents are grown inside the pores and/or voids of the (hollow) PMO particles and are additionally co-doped with emissive lanthanide ions to generate luminescence properties, and specifically, temperature-dependent luminescence properties.
Nanomaterials which can precisely measure temperature are very important for medical applications, especially in diagnostic purposes, as temperature plays an essential role in biological systems. For example, cancer cells show a higher temperature than healthy cells and by measuring temperature it is possible to determine the existence, and also exact location of cancer cells present in the body. Although temperature detection can be carried out using already commercially available techniques, such as thermocouples or infrared imaging, they have significant disadvantages such as being invasive (thermocouples) or allow measuring temperature only on the surface (infrared imaging). What is more, conventional thermometers have a low spatial resolution insufficient for measurements at the cellular level. Luminescence thermometry, as a technique which has high spatial resolution, is non- or minimally invasive and allows measurements of temperature in real time is an excellent alternative. Making this technique even more appealing for future use in medicine is if we are able to combine nanothermometry as a diagnostic tool with different modes of therapy in such one material. That is what this project aims at. We are exploring the design of hybrid materials, which not only show excellent thermometry behaviour but also exhibit multifunctionality for being combined with modes of therapy (drug release, photodynamic therapy) to deliver systems which would be of added value to cancer treatment.
Nanomaterials which can precisely measure temperature are very important for medical applications, especially in diagnostic purposes, as temperature plays an essential role in biological systems. For example, cancer cells show a higher temperature than healthy cells and by measuring temperature it is possible to determine the existence, and also exact location of cancer cells present in the body. Although temperature detection can be carried out using already commercially available techniques, such as thermocouples or infrared imaging, they have significant disadvantages such as being invasive (thermocouples) or allow measuring temperature only on the surface (infrared imaging). What is more, conventional thermometers have a low spatial resolution insufficient for measurements at the cellular level. Luminescence thermometry, as a technique which has high spatial resolution, is non- or minimally invasive and allows measurements of temperature in real time is an excellent alternative. Making this technique even more appealing for future use in medicine is if we are able to combine nanothermometry as a diagnostic tool with different modes of therapy in such one material. That is what this project aims at. We are exploring the design of hybrid materials, which not only show excellent thermometry behaviour but also exhibit multifunctionality for being combined with modes of therapy (drug release, photodynamic therapy) to deliver systems which would be of added value to cancer treatment.
Project NORTH aims at combining lanthanide doped inorganic materials with organosilica materials to form hybrid nanomaterials simultaneously working as luminescence nanothermometers and drug delivery vehicles or delivery vehicles for photodynamic therapy agents.
The project proposal focused efforts on the LiLuF4 host inorganic material, however due earlier observed ion migration issues in this host material, some of the work was shifted to other inorganic host matrixes (NaYF4, LaF3, NaGdF4 and Na3ZrF7), while at the same time further exploring and learning to hinder emissive ion migration in the LiLuF4 host to be able to employ it in further parts of the project. In project NORTH we have carried out a detailed investigation of the ion migration process in LiLuF4:Er,Yb@LiLuF4 core-shell nanoparticles and looked into find solutions to stop this process based on synthesis modifications as well as building a heterogenous shell forming LiLuF4:Er,Yb@LiYF4 core-shell structures (STEM, EDX maps, XRF, and high temperature thermometry were employed for this investigation). We have also investigated how different synthesis routes affect this ion migration process. The gained knowledge is further allowing us to successfully build heterogenous LiLuF4:Ln@LiYF4 core-shell structures containing various thermometry systems, with significantly hindered ion migration, as well as hybrid LiLuF4:Ln-PMO materials.
In a first attempt to combine thermometry and drug delivery in one system HPMO@NaYF4:Er,Yb and HPMO@NaYF4:Er,Yb,Tm nanorattles (where HPMO = hollow PMO), working both as a thermometer and Doxorubicin (DOX) drug delivery capsule were prepared and reported. The hollow PMOs are first filled with inorganic precursors which upon heat treatment convert to nanoparticles building into the HPMO void, yielding nanorattle type structures. Such materials show very good Yb-Er and Yb-Er-Tm upconversion (UC) thermometry in the physiological range (20-50 C). We have also shown that the nanorattle type structures can be used for pH dependent DOX drug delivery without compromising the thermometry properties. We have compared the release of several types of PMO materials and the final nanorattle type structures, and although the PMOs show very good loading, the release time is much faster from the nanorattle materials. Cytotoxicity of human dermal cells was carried out for these materials to show their lack of toxicity to the human body and potential for application in the biomedical field.
To compare our hybrid PMO-inorganic thermometry-drug release vehicles we have also added to the project an investigation of several purely inorganic vehicles, which we prove also show simultaneous thermometry and drug delivery. For this purpose Y2O3 and Y2O2SO4 hollow spheres doped with Yb-Er ions were developed. In a separate study YOF hollow spheres doped with Yb-Er-Gd ions were also prepared. These materials were tested for their UC Boltzmann thermometry, pH-dependant DOX drug delivery and cytotoxicity to human dermal cells. The results show that the purely inorganic vehicles can work as simultaneous thermometers and drug delivery vehicles without compromising their performance. However, the DOX release is slightly better when working with hybrid materials. Also, hybrid materials of the PMO-inorganic type show more promise for further functionalizations and modifications for example for targeting specific cancer cells.
The project proposal focused efforts on the LiLuF4 host inorganic material, however due earlier observed ion migration issues in this host material, some of the work was shifted to other inorganic host matrixes (NaYF4, LaF3, NaGdF4 and Na3ZrF7), while at the same time further exploring and learning to hinder emissive ion migration in the LiLuF4 host to be able to employ it in further parts of the project. In project NORTH we have carried out a detailed investigation of the ion migration process in LiLuF4:Er,Yb@LiLuF4 core-shell nanoparticles and looked into find solutions to stop this process based on synthesis modifications as well as building a heterogenous shell forming LiLuF4:Er,Yb@LiYF4 core-shell structures (STEM, EDX maps, XRF, and high temperature thermometry were employed for this investigation). We have also investigated how different synthesis routes affect this ion migration process. The gained knowledge is further allowing us to successfully build heterogenous LiLuF4:Ln@LiYF4 core-shell structures containing various thermometry systems, with significantly hindered ion migration, as well as hybrid LiLuF4:Ln-PMO materials.
In a first attempt to combine thermometry and drug delivery in one system HPMO@NaYF4:Er,Yb and HPMO@NaYF4:Er,Yb,Tm nanorattles (where HPMO = hollow PMO), working both as a thermometer and Doxorubicin (DOX) drug delivery capsule were prepared and reported. The hollow PMOs are first filled with inorganic precursors which upon heat treatment convert to nanoparticles building into the HPMO void, yielding nanorattle type structures. Such materials show very good Yb-Er and Yb-Er-Tm upconversion (UC) thermometry in the physiological range (20-50 C). We have also shown that the nanorattle type structures can be used for pH dependent DOX drug delivery without compromising the thermometry properties. We have compared the release of several types of PMO materials and the final nanorattle type structures, and although the PMOs show very good loading, the release time is much faster from the nanorattle materials. Cytotoxicity of human dermal cells was carried out for these materials to show their lack of toxicity to the human body and potential for application in the biomedical field.
To compare our hybrid PMO-inorganic thermometry-drug release vehicles we have also added to the project an investigation of several purely inorganic vehicles, which we prove also show simultaneous thermometry and drug delivery. For this purpose Y2O3 and Y2O2SO4 hollow spheres doped with Yb-Er ions were developed. In a separate study YOF hollow spheres doped with Yb-Er-Gd ions were also prepared. These materials were tested for their UC Boltzmann thermometry, pH-dependant DOX drug delivery and cytotoxicity to human dermal cells. The results show that the purely inorganic vehicles can work as simultaneous thermometers and drug delivery vehicles without compromising their performance. However, the DOX release is slightly better when working with hybrid materials. Also, hybrid materials of the PMO-inorganic type show more promise for further functionalizations and modifications for example for targeting specific cancer cells.
We have been able to develop first examples of (hybrid) materials suitable for simulations thermometry and drug delivery. Up to date, the drug delivery studied systems have been developed based on pH dependent drug release. To further improve the working of such materials, we aim to now construct materials which would show on-demand drug release using the same or different wavelength of light compared to the excitation wavelength used for the nanothermometers. We will use different types of hybrid materials to achieve this goal. Up to date, we have also made significant progress in the field in understanding ion migration in the LiLuF4 host material and of optimizing ways to hinder this process. In the further work in this project, we not only will make use of the core-shell LiLuF4@LiYF4 type structures with hindered ion migration, but also we want to focus efforts on optimizing ways to successfully and reliably monitor this. Up to date, the best way to do this is high-resolution TEM, however, it is not always possible for researchers to have access to such high-end equipment. We will therefore explore complementary techniques that can be of assistance to the assessment. Throughout the project we will continue to explore the cytotoxicity of all developed materials and most promising materials will be tested in agar phantom tissues as well as in ex-vivo tissue experiments. Our on-going goal is to develop hybrid materials suitable for theranostics with no of very low toxicity.