| Malignant tumor is one of the life-threatening diseases and remained as a major health burden throughout the world.Chemotherapy is an important therapeutic modality for cancers therapy,while the clinical drawbacks of chemotherapeutics,including high toxicity,undesirable side effects and drug resistance,have limited the application in cancer therapies.The combination of biotechnology and nanotechnology has led to the development of cancer nanotechnology that displays application potential in targeted therapy,molecular diagnosis and molecular imaging.Nanodrug delivery systems are expected to depress the toxic side effects and simultaneously enhance the therapeutic efficiency,and thus have drawn more and more attention in the past years.Till now,various biocompatible nanosystems with different structure and compositionshave been designed and prepared to carry anticancer drugs.Among these nanomaterials,mesoporous silica nanoparticles(MSNs)have been well-demonstrated as excellent carriers for anticancer drug delivery.The main results are as follows:1.Herein we describe a cancer-targeted MSNs for delivery of ruthenium or gold(?)porphyrin complex to enhance their anticancer efficacy and selectivity between cancer and normal cells.Specifically,the in vitro anticancer activity and the action mechanisms of RGD peptide-functionalized MSNs carrying metal complexes have been elucidated in detail.RGD peptide surface decoration significantly enhanced the cellular uptake of the nanoparticles through receptor-mediated endocytosis,and increased the selectivity between cancer and normal cells.Induction of apoptosis in cancer cells by MSNs nanosystem was evidenced by accumulation of sub-G1 cell population,DNA fragmentation and caspase activation.The internalized nanoparticles released free Ru POP into the cytoplasm,where they modulated the phosphorylation of p53,AKT and MAPKs pathways to promote cell apoptosis.Taken together,this study may provide an effective strategy for the design and development of cancer-targeted agents.2.As angiogenesis and tumor growth can be mutually enhanced,a dual therapeutic strategy for antiangiogenesis and anticancer is practical and urgently needed.Herein we rationally designed functionalized MSNs to realize the dual therapy of tumor growth and angiogenesis based on the biochemical similarity of cell membranes.This nanosystem demonstrated high selectivity in vitro and in vivo against cancer cells with high integrin expression levels,and could simultaneously inhibit cancer cell growth and disrupt tumor neovasculature,thus achieving satisfactory anticancer efficacy in vivo.Moreover,the nanosystem also effectively reduced the toxic side effects of loaded drugs to normal tissues and prolongs the blood circulation in vivo.Therefore,this study provides an approach for rational design of the next-generation nanodrug delivery system to achieve dual therapy of tumor growth and angiogenesis.3.Radioresistance and limitation of irradiative dosage usually lead to failure in depletion of hypoxic tumors.Herein we developed multifunctional MSNs as a carrier of a novel anticancer selenoamino acid(selenocystine,Se C),to achieve synergistic chemo-/radiotherapy.This multifunctional nanosystem effectively sensitized cancer cells to X-ray radiotherapy.Conjugation of TAT cell penetrating peptide and transferrin to the surface of MSNs significantly enhanced its internalization in cancer cells through receptor-mediated endocytosis.This nanosystem significantly enhanced X-ray-induced growth inhibition in cervical cancer cells by induction of apoptosis,mainly through death receptor-mediated extrinsic apoptotic pathway.Upon radiation,Se C@MSNs-Tf/TAT promoted intracellular ROS overproduction,which induced apoptotic cell death by affecting p53,AKT and MAPKs pathways.Furthermore,Se C@MSNs-Tf/TAT also significantly inhibited He La tumor growth in nude mice model through suppression of cell proliferation and induction of apoptosis.In vivo toxicity of the Se C@MSNs-Tf/TAT indicated that these nanoparticles did not show any obvious damage to these major organs under the experimental conditions,including heart,liver,spleen,lung and kidney.This study demonstrates an effective and safe strategy for cancer-targeted chemo-/radiotherapy.4.Blood-brain barrier(BBB)is the main bottleneck to prevent some macromolecular substance entering the cerebral circulation,resulting the failure of chemotherapy in the treatment of glioma.Cancer nanotechnology displays potent applications in glioma therapy owing to their penetration across BBB and accumulation into the tumor core.In this study,we have tailored the particle size of MSNs through controlling the hydrolysis rate and polycondensation degree of reactants,and optimized the nanosystem that could effectively penetrate BBB and targeted the tumor tissue to achieve enhanced anti-glioma efficacy.Therefore,the c RGD-functionalized nanosystem(DOX@MSNs)selectively recognized and bound to the U87 cells with higher expression level of ???3 integrin,sequentially enhance the cellular uptake and inhibition to giloma cells,especially the particle size at 40 nm.Interestingly,DOX@MSNs at about 40 nm exhibited stronger permeability across the BBB,and could disrupt the VM-capability of glioma cells by regulating the expression of E-cadherin,FAK and MMP-2,thus achieving satisfactory anti-glioblastoma efficacy and avoiding the unwanted toxic side effects to normal brain tissue.Taken together,these results suggest that,tailoring the particle size of MSNs nanosystem could be an effective strategy to antagonize glioblastoma and overcome BBB.Taken together,we have described the design and synthesis of cancer-targeted MSNs nanosystem to reduce the toxicity of the metal-based chemotherapeutics,simultaneously enhance their anticancer activity and selectivity between cancer and normal cells.This multifunctional nanosystem is expected to realize the dual therapy of tumor growth and angiogenesis,especially as radiosensitizer in radiotherapy.We anticipate that,this study may provide an effective strategy for the design and development of cancer-targeted agents that can achieve enhanced anticancer efficacy and reduced toxicity. |
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