RESUMEN
Developing a neurovascular bone repair scaffold with an appropriate mechanical strength remains a challenge. Calcium phosphate (CaP) is similar to human bone, but its scaffolds are inherently brittle and inactive, which require recombination with active ions and polymers for bioactivity and suitable strength. This work discussed the synthesis of amorphous magnesium-calcium pyrophosphate (AMCP) and the subsequent development of a humidity-responsive AMCP/cassava starch (CS) scaffold. The scaffold demonstrated enhanced mechanical properties by strengthening the intermolecular hydrogen bonds and ionic bonds between AMCP and CS during the gelatinization and freeze-thawing processes. The release of active ions was rapid initially and stabilized into a long-term stable release after 3 days, which is well-matched with new bone growth. The release of pyrophosphate ions endowed the scaffold with antibacterial properties. At the cellular level, the released active ions simultaneously promoted the proliferation and mineralization of osteoblasts, the proliferation and migration of endothelial cells, and the proliferation of Schwann cells. At the animal level, the scaffold was demonstrated to promote vascular growth and peripheral nerve regeneration in a rat skull defect experiment, ultimately resulting in the significant and rapid repair of bone defects. The construction of the AMCP/CS scaffold offers practical suggestions and references for neurovascular bone repair.
Asunto(s)
Regeneración Ósea , Almidón , Andamios del Tejido , Animales , Regeneración Ósea/efectos de los fármacos , Andamios del Tejido/química , Ratas , Almidón/química , Humedad , Humanos , Proliferación Celular/efectos de los fármacos , Ratas Sprague-Dawley , Difosfatos/química , Difosfatos/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/citología , Pirofosfato de Calcio/química , Pirofosfato de Calcio/farmacología , Células de Schwann/efectos de los fármacos , Células de Schwann/citología , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Cráneo/efectos de los fármacosRESUMEN
Squamous cell carcinoma (SCC) is a common nonmelanoma skin cancer. Radiotherapy plays an integral role in treating SCC due to its characteristics, such as diminished intercellular adhesion, heightened cell migration and invasion capabilities, and immune evasion. These problems lead to inaccurate tumor boundary positioning and radiotherapy tolerance in SCC treatment. Thus, accurate localization and enhanced radiotherapy sensitivity are imperative for effective SCC treatment. To address the existing limitations in SCC therapy, we developed monoglyceride solid lipid nanoparticles (MG SLNs) and enveloped them with the A431 cell membrane (A431 CM) to create A431@MG. The characterization results showed that A431@MG was spherical. Furthermore, A431@MG had specific targeting for A431 cells. In A431 tumor-bearing mice, A431@MG demonstrated prolonged accumulation within tumors, ensuring precise boundary localization of SCC. We further advanced the approach by preparing MG SLNs encapsulating 5-aminolevulinic acid methyl ester (MLA) and desferrioxamine (DFO) with an A431 CM coating to yield A431@MG-MLA/DFO. Several studies have revealed that DFO effectively reduced iron content, impeding protoporphyrin IX (PpIX) biotransformation and promoting PpIX accumulation. Simultaneously, MLA was metabolized into PpIX upon cellular entry. During radiotherapy, the heightened PpIX levels enhanced reactive oxygen species (ROS) generation, inducing DNA and mitochondrial damage and leading to cell apoptosis. In A431 tumor-bearing mice, the A431@MG-MLA/DFO group exhibited notable radiotherapy sensitization, displaying superior tumor growth inhibition. Combining A431@MG-MLA/DFO with radiotherapy significantly improved anticancer efficacy, highlighting its potential to serve as an integrated diagnostic and therapeutic strategy for SCC.
Asunto(s)
Carcinoma de Células Escamosas , Membrana Celular , Nanopartículas , Fármacos Sensibilizantes a Radiaciones , Neoplasias Cutáneas , Animales , Ratones , Nanopartículas/química , Humanos , Línea Celular Tumoral , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Membrana Celular/metabolismo , Ácido Aminolevulínico/química , Ácido Aminolevulínico/farmacología , Ácido Aminolevulínico/administración & dosificación , Lípidos/química , Ensayos Antitumor por Modelo de Xenoinjerto , Deferoxamina/química , Deferoxamina/farmacología , Ratones Desnudos , Femenino , Ratones Endogámicos BALB C , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , LiposomasRESUMEN
Background: Radiation stimulates the secretion of tumor stroma and induces resistance, recurrence, and metastasis of stromal-vascular tumors during radiotherapy. The proliferation and activation of tumor-associated fibroblasts (TAFs) are important reasons for the production of tumor stroma. Telmisartan (Tel) can inhibit the proliferation and activation of TAFs (resting TAFs), which may promote radiosensitization. However, Tel has a poor water solubility. Methods: In this study, self-assembled telmisartan nanoparticles (Tel NPs) were prepared by aqueous solvent diffusion method to solve the insoluble problem of Tel and achieve high drug loading of Tel. Then, erythrocyte membrane (ECM) obtained by hypotonic lysis was coated on the surface of Tel NPs (ECM/Tel) for the achievement of in vivo long circulation and tumor targeting. Immunofluorescence staining, western blot and other biological techniques were used to investigate the effect of ECM/Tel on TAFs activation inhibition (resting effect) and mechanisms involved. The multicellular spheroids (MCSs) model and mouse breast cancer cells (4T1) were constructed to investigate the effect of ECM/Tel on reducing stroma secretion, alleviating hypoxia, and the corresponding promoting radiosensitization effect in vitro. A mouse orthotopic 4T1 breast cancer model was constructed to investigate the radiosensitizing effect of ECM/Tel on inhibiting breast cancer growth and lung metastasis of breast cancer. Results: ECM/Tel showed good physiological stability and tumor-targeting ability. ECM/Tel could rest TAFs and reduce stroma secretion, alleviate hypoxia, and enhance penetration in tumor microenvironment. In addition, ECM/Tel arrested the cell cycle of 4T1 cells to the radiosensitive G2/M phase. In mouse orthotopic 4T1 breast cancer model, ECM/Tel played a superior role in radiosensitization and significantly inhibited lung metastasis of breast cancer. Conclusion: ECM/Tel showed synergistical radiosensitization effect on both the tumor microenvironment and tumor cells, which is a promising radiosensitizer in the radiotherapy of stroma-vascular tumors.