Shanghai Silicate is making progress in nano-catalyzed medical research

[ Instrument R&D of Instrumentation Network ] "Nanocatalytic Medicine" is an academic idea proposed by Shi Jianlin, a member of the Chinese Academy of Sciences and a researcher at the Shanghai Institute of Ceramics, Chinese Academy of Sciences. It aims to respond to the specific internal field microenvironment or exogenous laser, Ultrasonic field, using non-toxic/low-toxic nano-materials to catalyze the in-situ catalytic reaction to efficiently achieve oxidative damage and cell death of tumor cells. The catalytic tumor treatment method does not use highly toxic chemotherapy drugs, and has the characteristics of high efficiency, strong specificity and high safety.

Recently, the team has made progress in the field of oncology treatment in nanocatalytic medicine, and related research results have focused on inhibiting cell autophagy to enhance internal field response catalytic tumor therapy, external field excitation photosynthesis enhanced photodynamic catalytic therapy, and external field ultrasound-induced piezoelectric catalysis tumor treatment.

Fenton-like catalytic reaction in combination with new drugs for tumor therapy

In situ catalytic reactions (especially the Fenton reaction that generates reactive oxygen species hydroxyl radical · OH) caused by the introduction of nano-catalysts into the tumor microenvironment or within cancer cells can cause cancer cells to undergo severe oxidative damage and undergo apoptosis. The nano-catalyzed tumor treatment based on the previous iron-based Fenton catalyst can be further combined with other treatment modes to realize a collaborative treatment mode based on catalytic tumor treatment.

The research team used a class of old drugs originally used for alcoholism, disulfiram, to chelate with copper ions to produce drug toxicity against tumors. Fenton-like catalyst copper ions further catalyze the production of reactive oxygen species in Fenton's reaction tumors , To achieve the goal of collaborative treatment of tumors. Using copper-doped mesoporous silica as a carrier, the low-toxic disulfiram drug and copper ions are transported to the tumor (Figure 1). By specifically responding to the weak acidity of the tumor, the mesoporous silica quickly degrades and simultaneously releases the drugs disulfiram and divalent copper ions in the tumor. Chelation of disulfiram with copper ions in situ in the tumor obviously enhances its toxicity. At the same time, the generated monovalent copper ions catalyze the disproportionation reaction of highly expressed hydrogen peroxide in the tumor, generating a large number of highly cytotoxic hydroxyl radicals, thereby Tumor-specific cooperative treatment to achieve low toxicity and side effects. Further, Prussian blue nanoparticles are used as carriers to realize photothermal assisted chemotherapy-nanocatalysis cooperative tumor therapy.

Inhibiting cellular autophagy and enhancing the response of the internal field to catalytic tumor therapy

The in situ Fenton catalytic reaction of nano-catalysts in the tumor microenvironment produces reactive oxygen species hydroxyl radical · OH to kill tumor cells. However, under the action of oxidative stress, cancer cells can degrade the macromolecules and organelles in the injured cells by activating their own autophagy pathway to achieve effective removal of waste in the body and reduce the toxicity of reactive oxygen species such as ·OH to cancer cells . Therefore, inhibiting the autophagy of cancer cells is an effective means to enhance nano-catalytic therapy, so that cancer cells cannot undergo "self-detoxification" under oxidative stress and eventually undergo apoptosis.

To achieve this idea, the team combined an iron-based MOF nanocatalyst with strong catalytic ability and the autophagy inhibitor chloroquine (Figure 2). MOF (Fe) nanoparticles can exhibit peroxidase-like properties in an acidic environment and can decompose H2O2 into strong oxidizing ·OH. Due to the weak acidity of the tumor microenvironment and the internal environment of cancer cells, this catalytic ability of MOF (Fe) can be well demonstrated, causing oxidative damage to cancer cells. In addition, chloroquine can automatically accumulate in the lysosome of cancer cells and raise the pH in the lysosome, thereby inhibiting the function of proteases in the lysosome and finally blocking the autophagic flow. The combination of the two will make the cancer cells unable to degrade these damaged substances through autophagy while undergoing oxidative damage, resulting in the accumulation of these substances, which will increase the toxicity to cancer cells in the long run, thereby enhancing the nanometer The effect of catalytic therapy. Animal experiment results show that the use of chloroquine significantly enhances the inhibitory effect of MOF (Fe) nanocatalysts on the growth of A375 melanoma and HeLa cervical cancer tumors, achieving the effect of "1 + 1> 2".

External field excited photosynthesis enhanced photodynamic catalytic therapy

Photodynamic therapy (PDT) of tumors is an ancient and effective field-stimulated tumor treatment model. In clinical practice, the principle of mass-developed photosensitizers producing singlet oxygen species is based on the triplet annihilation of molecular oxygen, and the hypoxic nature of tumors has been an important factor limiting photodynamic therapy based on type II photosensitizers. In recent years, there have been many reports on tumor oxygenation to improve the therapeutic effect of tumor PDT. However, the use of physical oxygen and chemical oxygen production to enhance PDT has insufficient efficiency and biological safety problems. The development of a new type of tumor oxygenation Ways to enhance the photodynamic therapy of tumors help to solve the bottleneck of clinical tumor photodynamic applications.

Inspired by the ancient photosynthesis of cyanobacteria, the team constructed a photosensitizer hybrid of chlorin (ce6) and cyanobacteria (Sclerococcus elongatus) for photosynthesis under light excitation to enhance tumor PDT treatment (image 3). Based on the similarity between the structure of cyanobacteria chlorophyll and the structure of photosensitizer, this photosensitizing bacterium can realize photosynthesis and photosensitizer activation under the excitation of a single light source (660 nm), so that the chlorinated photosensitizer can quickly interact with the molecule. The triplet annihilation of oxygen generates singlet oxygen species, which can effectively kill tumor cells, and provides a synergistic scheme based on biological oxygen release for overcoming the oxygen dependence of type II photosensitizers.

Studies have shown that light-sensitive cyanobacteria can achieve high-efficiency cytotoxicity at low 660 nm laser power (20 mW cm-2) and low hybrid photosensitizer doses. Compared with the free-state photosensitizer ce6, it plays a half The concentration of photosensitizer required for cell killing efficacy is only 1/18 of the concentration of free photosensitizer. At the level of in vivo animal experiments, the team achieved a volume suppression of up to 79.9% of tumor-transplanted tumors by light-sensitive cyanobacteria in the mode of intratumoral injection, and demonstrated excellent biosecurity in a safety evaluation cycle of up to 1 month . This study explores a class of photosynthetic-photosensitive biohybrid materials with considerable potential, which provides a new solution to the clinical bottleneck problem based on photodynamics.

External field ultrasound-induced piezoelectric catalytic tumor therapy

Cancer is still a public health problem worldwide, and chemotherapy is still an indispensable means for the treatment of cancer. However, traditional chemotherapy belongs to systemic medicine, which not only has low efficacy, strong toxic and side effects, but also easily develops drug resistance.

Recently, the team proposed a new "piezoelectric catalysis" new tumor treatment model, using piezoelectric catalysts as nano-functional drugs, using the microscopic pressure effect of high-penetration external ultrasound, generated by piezoelectric catalytic reactions Reactive oxygen species kill tumor cells while avoiding toxic and side effects on normal tissues.

In this study, ultrasound was selected as the source of excitation in the external field. Ultrasound, as a non-invasive, highly penetrable external source, is often used in the diagnosis and treatment of diseases in the clinic, and the acoustic fluorescence during the transmission process is often used to excite the sensitizer for sonodynamic tumor treatment (Figure 4). In fact, ultrasound, as a mechanical wave, is accompanied by periodic stress during its propagation, up to 108 Pa. The team first synthesized cubic-phase barium titanate nanoparticles with a particle size of about 110 nm, and after calcination at 800°C, they transformed into noncentrosymmetric piezoelectric tetragonal barium titanate nanoparticles. The nanoparticles can effectively degrade methylene blue under the action of ultrasound. Using electron spin resonance technology, the study determined that superoxide anions and hydroxyl radicals were generated in the process. According to the analysis of the energy band structure, the synthesized tetragonal barium titanate nanoparticles did not satisfy the conditions for generating superoxide anions and hydroxyl radicals. Through simulation calculations, under the action of ultrasonic micro-pressure, the piezoelectric potential of the 110 nm tetragonal barium titanate nanocrystal model can reach a maximum of 0.45 V, and increases with the increase of the model particle size. This piezoelectric potential is sufficient to tilt the energy band, so that it tilts to a direction that kinetics satisfies the conditions for simultaneously generating superoxide anions and hydroxyl radicals. In addition, the central symmetry of cubic phase barium titanate nanoparticles was also controlled, and it was found that the nanoparticles could not degrade methylene blue under ultrasonic treatment, and no free radicals were detected in the process, indicating that due to non-central symmetry Piezoelectricity is the key in this research.

The team applied the process of generating free radicals in a piezoelectric catalytic reaction excited by ultrasound to tumor treatment. In order to increase the concentration of nano-functional drugs, the study used temperature-sensitive hydrogels and tetragonal barium titanate nanoparticles to compound, phase change occurred at body temperature, and fixed tetragonal barium titanate nanoparticles in the tumor area. At the same time avoid the impact on normal organizations. At the cell level, cell death was clearly observed after sonication, and reactive oxygen species were detected at the cell level. At the animal level, through the intratumoral injection of a composite of tetragonal barium titanate nanoparticles and a temperature-sensitive hydrogel, after ultrasound treatment, a significant tumor clearance effect can be observed, and the normal organs of mice and blood The indicators have no effect, indicating that they have good in vivo biological safety and the life cycle is extended to more than 40 days.

The relevant results were published in "Advanced Materials" and "Journal of the American Chemical Society". The first authors were Wu Wenzhu, Yang Bowen, Huo Minfeng and Zhu Piao, graduate students of Shanghai Silicate. Relevant work was supported and supported by the National Natural Science Foundation of China, the National Young Research and Development Program "Young Scientist" project, the Shanghai Natural Science Foundation, and the Shanghai Outstanding Academic Leader Program.