Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray

アインシュタインの光電効果をがん細胞の中で再現　放射線治療への新展開. 京都大学プレスリリース. 2021-07-14.Quantum physics helps destroy cancer cells. 京都大学プレスリリース. 2021-07-14.X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO₂ incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles

Synthèse et caractérisation de silices hybrides fonctionnelles pour une délivrance autonome de molécules thérapeutiques

The work developed in this thesis is devoted to the design of functional hybrid silica platforms for controlled delivery of therapeutics (e.g. oncologic drugs, antibiotics, etc.) to improve their performance and limit their side effect. The different types of silylated hybrid materials synthesized and described herein, including (1) pH-sensitive nanoparticles; (2) multi-functional periodic mesoporous organosilicas (PMO) mesostructured via PIC micelles; and (3) sophisticated core-shell and raspberry-type PMO hybrids; demonstrate hierarchical organization over multiple length scales, providing appealing features for drug delivery applications.The manuscript focusses, in particular, on the mechanisms controlling pore nanostructuring, using different type of structuring agents (e.g. CTAB, polyion complex (PIC) micelles, silica seeds or decane droplets) and on the subsequent structure-function relationship. The research project also demonstrated the potential of specific systems for future applications in biomedicine articulated.Le travail développé dans cette thèse est consacré au développement de silices hybrides fonctionnelles pour la délivrance contrôlée de produits thérapeutiques (médicaments oncologiques, antibiotiques, etc.) dans l’optique d'améliorer leurs activités et de réduire leurs effets secondaires. Les différents types de matériaux hybrides silylés synthétisés et présentés ici, tels que: (1) des nanoparticules pH-sensibles; (2) des organosilices mésoporeuses périodiques multifonctionnelles mésostructurées via des des micelles de complexe de polyioniques (PIC); (3) des hybrides sophistiqués de type coeur-coquille et de type framboise; ont généralement démontré une organisation hiérarchique offrant des fonctionnalités attrayantes pour les applications de délivrance de médicaments. Ce manuscrit porte une attention particulière sur le mécanisme de formation de la nanostructuration des pores en utilisant différents types d’agents structurants (des micelles PIC, des cœurs de silice ou des gouttes de décane) et sur l’étude de la relation structure-propriété résultantes des systèmes. Les travaux de recherche, effectués ici, démontrent également le potentiel de ses systèmes en biomédecine dont certains apparaissent très prometteurs

Synthèse et caractérisation de silices hybrides fonctionnelles pour une délivrance autonome de molécules thérapeutiques

The work developed in this thesis is devoted to the design of functional hybrid silica platforms for controlled delivery of therapeutics (e.g. oncologic drugs, antibiotics, etc.) to improve their performance and limit their side effect. The different types of silylated hybrid materials synthesized and described herein, including (1) pH-sensitive nanoparticles; (2) multi-functional periodic mesoporous organosilicas (PMO) mesostructured via PIC micelles; and (3) sophisticated core-shell and raspberry-type PMO hybrids; demonstrate hierarchical organization over multiple length scales, providing appealing features for drug delivery applications.The manuscript focusses, in particular, on the mechanisms controlling pore nanostructuring, using different type of structuring agents (e.g. CTAB, polyion complex (PIC) micelles, silica seeds or decane droplets) and on the subsequent structure-function relationship. The research project also demonstrated the potential of specific systems for future applications in biomedicine articulated.Le travail développé dans cette thèse est consacré au développement de silices hybrides fonctionnelles pour la délivrance contrôlée de produits thérapeutiques (médicaments oncologiques, antibiotiques, etc.) dans l’optique d'améliorer leurs activités et de réduire leurs effets secondaires. Les différents types de matériaux hybrides silylés synthétisés et présentés ici, tels que: (1) des nanoparticules pH-sensibles; (2) des organosilices mésoporeuses périodiques multifonctionnelles mésostructurées via des des micelles de complexe de polyioniques (PIC); (3) des hybrides sophistiqués de type coeur-coquille et de type framboise; ont généralement démontré une organisation hiérarchique offrant des fonctionnalités attrayantes pour les applications de délivrance de médicaments. Ce manuscrit porte une attention particulière sur le mécanisme de formation de la nanostructuration des pores en utilisant différents types d’agents structurants (des micelles PIC, des cœurs de silice ou des gouttes de décane) et sur l’étude de la relation structure-propriété résultantes des systèmes. Les travaux de recherche, effectués ici, démontrent également le potentiel de ses systèmes en biomédecine dont certains apparaissent très prometteurs

Synthesis and characterization of functional hybrid silica materials for autonomous drug delivery applications

Le travail développé dans cette thèse est consacré au développement de silices hybrides fonctionnelles pour la délivrance contrôlée de produits thérapeutiques (médicaments oncologiques, antibiotiques, etc.) dans l’optique d'améliorer leurs activités et de réduire leurs effets secondaires. Les différents types de matériaux hybrides silylés synthétisés et présentés ici, tels que: (1) des nanoparticules pH-sensibles; (2) des organosilices mésoporeuses périodiques multifonctionnelles mésostructurées via des des micelles de complexe de polyioniques (PIC); (3) des hybrides sophistiqués de type coeur-coquille et de type framboise; ont généralement démontré une organisation hiérarchique offrant des fonctionnalités attrayantes pour les applications de délivrance de médicaments. Ce manuscrit porte une attention particulière sur le mécanisme de formation de la nanostructuration des pores en utilisant différents types d’agents structurants (des micelles PIC, des cœurs de silice ou des gouttes de décane) et sur l’étude de la relation structure-propriété résultantes des systèmes. Les travaux de recherche, effectués ici, démontrent également le potentiel de ses systèmes en biomédecine dont certains apparaissent très prometteurs.The work developed in this thesis is devoted to the design of functional hybrid silica platforms for controlled delivery of therapeutics (e.g. oncologic drugs, antibiotics, etc.) to improve their performance and limit their side effect. The different types of silylated hybrid materials synthesized and described herein, including (1) pH-sensitive nanoparticles; (2) multi-functional periodic mesoporous organosilicas (PMO) mesostructured via PIC micelles; and (3) sophisticated core-shell and raspberry-type PMO hybrids; demonstrate hierarchical organization over multiple length scales, providing appealing features for drug delivery applications.The manuscript focusses, in particular, on the mechanisms controlling pore nanostructuring, using different type of structuring agents (e.g. CTAB, polyion complex (PIC) micelles, silica seeds or decane droplets) and on the subsequent structure-function relationship. The research project also demonstrated the potential of specific systems for future applications in biomedicine articulated

Synthesis of lamellar mesostructured phenylene-bridged periodic mesoporous organosilicas (PMO) templated by polyion complex (PIC) micelles

International audiencePeriodic mesoporous organosilicas (PMOs), obtained by the surfactant-mediated hydrolysis-condensation of bridged organosilanes, combine versatile organic functionalities with advantages of a stable inorganic framework. Here, we introduce a novel synthesis of lamellar mesostructured phenylene-bridged PMOs templated by polyion complex (PIC) micelles (PICPMOs). The micelles assemble by electrostatic interactions between oppositely charged polyelectrolytes, with one being part of a double hydrophilic block copolymer (DHBC), and the other being a polybase oligochitosan (OC). The PICPMO material was characterized by a range of techniques, including TEM, IR spectroscopy, SAXS, TGA and elemental analysis, which indicates that the material exhibits long-range ordering with an inter-lamellae distance of around 15nm. Advantages of the synthetic approach developed, together with potential applications of the PICPMOs, are discussed

Large-Pore Periodic Mesoporous Organosilicas as Advanced Bactericide Platforms

International audienceDespite the versatility of periodic mesoporous organosilicas (PMOs), the bactericide capacity of these hybrid platforms has seldom been explored. Herein, we describe the synthesis of large-pore phenylene-bridged PMOs, mesostructured by polyion complex (PIC) micelles (PICPMOs) incorporating an antibiotic, neomycin B. A key feature of this approach is that the bioactive molecules are directly encapsulated within the PICPMOs during their formation. The engineered PICPMOs exhibit a well-ordered hexagonal mesophase with a molecular-scale crystallinity and large mesopores (8 nm), which facilitates pH-triggered delivery of the drug. The results obtained with a pathogenic Escherichia coli strain clearly demonstrate the potential of such PICPMOs for antibacterial applications

Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray

高Z元素にX線を照射すると、局所的なDNA切断を誘発する可能性のあるオージェ電子の放出を含む光電効果を引き起こす。我々はこれまで、ガドリニウムを含有したメソポーラスシリカナノ粒子と放射光単色X線によるがんスフェロイドの殺傷効果について研究を進めてきた。本報ではヨウ素に焦点を当て、ヨウ素を含有した多孔質有機シリカ（IPO）ナノ粒子を合成した。IPOをがんスフェロイドに取り込ませ、スフェロイドに33.2keVの単色X線を照射した。インキュベーション後、TUNEL assay法で評価をしたところ、アポトーシス誘導を伴うがんスフェロイドの破壊が観察された。さらに、γH2AX assay法によって、照射直後にDNAの二重鎖切断が起きていることを確認した。これらの結果は、IPO がX線照射時にまずDNAの二重鎖切断を引き起こし、続いて、がん細胞をアポトーシスに誘導することを示唆している。33.0～33.4keVの単色X線で、エネルギーを0.1keVずつ変化させながら実験を行ったところ、がんの形状破壊、アポトーシス誘導、DNA二重鎖切断の3つのイベントは、すべて33.2keVの単色X線のときに発生していた。これらの結果は、ヨウ素含有ナノ粒子によって媒介されたがんスフェロイド破壊における、K吸収端エネルギーX線の優先的効果を示している

Construction of Boronophenylalanine-Loaded Biodegradable Periodic Mesoporous Organosilica Nanoparticles for BNCT Cancer Therapy

Biodegradable periodic mesoporous organosilica (BPMO) has recently emerged as a promising type of mesoporous silica-based nanoparticle for biomedical applications. Like mesoporous silica nanoparticles (MSN), BPMO possesses a large surface area where various compounds can be attached. In this work, we attached boronophenylalanine (10BPA) to the surface and explored the potential of this nanomaterial for delivering boron-10 for use in boron neutron capture therapy (BNCT). This cancer therapy is based on the principle that the exposure of boron-10 to thermal neutron results in the release of α-particles that kill cancer cells. To attach 10BPA, the surface of BPMO was modified with diol groups which facilitated the efficient binding of 10BPA, yielding 10BPA-loaded BPMO (10BPA-BPMO). Surface modification with phosphonate was also carried out to increase the dispersibility of the nanoparticles. To investigate this nanomaterial’s potential for BNCT, we first used human cancer cells and found that 10BPA-BPMO nanoparticles were efficiently taken up into the cancer cells and were localized in perinuclear regions. We then used a chicken egg tumor model, a versatile and convenient tumor model used to characterize nanomaterials. After observing significant tumor accumulation, 10BPA-BPMO injected chicken eggs were evaluated by irradiating with neutron beams. Dramatic inhibition of the tumor growth was observed. These results suggest the potential of 10BPA-BPMO as a novel boron agent for BNCT

Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to “recognise” a complementary molecule, which serves as a “cap” to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells