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Beyond mesoporous silica nanoparticles (MSNs), mesoporous organosilica nanoparticles (MONs) have been becoming an even more attractive alternative to the traditional organic or inorganic nanomaterials in biomedical applications, especially for drug delivery, due to its high surface area, stable physicochemical properties, low toxicity, high biocompatibility, and particularly the devisable features decided by the incorporated organic fragments. However, it is still challenging to fabricate uniform ultrasmall MONs with tunable composition, morphology and fine biodegradability. Herein, we report, on the large-scale fabrication of monodispersed and molecularly organic-inorganic hybrid MONs with framework-incorporated physiologically active thioether bonds, controllable nanostructure, composition and morphology, which provides the material foundation for exploring the versatile biomedical applications of organosilica nanosystems. The hybrid MONs of less than 50 nm in particle size exhibit the unique reduction-responsive biodegradation behavior, and the biodegradation rate is significantly higher than that of traditional mesoporous silica nanoparticles with pure inorganic Si O Si framework. The reductive microenvironment-triggered biodegradation of MONs induces the concurrent reduction-responsive anticancer drug releasing from MONs, enabling tumor-specific drug delivery. Importantly, these biocompatible and biodegradable MONs exhibit significantly improved drug-delivery efficiency and enhanced tumor-suppressing effect for combating cancer. Based on the facile and large-scale fabrication of MONs with controllable key structure/composition/morphology parameters, unique tumor microenvironment-responsive biodegradation behavior and high performance for drug delivery, the MONs therefore show more promising potentials for clinical translation as compared to traditional MSNs. [ABSTRACT FROM AUTHOR]

Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such ‘priming’ treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticles (MNPs) have been extensively studied for their potential applications to cancer diagnosis and treatment. However, various obstacles limit the use of nanoparticles for delivery in the tumor microenvironment. As a viable solution to such obstacles, advances in nanoparticle surface engineering augmented by a profound understanding of cancer physiology present new opportunities for MNP-based imaging and therapeutic agents. Stimuli-responsive ligands, rationally designed to interact with various physicochemical aspects, can improve the performance of MNPs in cancer-targeted imaging and therapy. In this review, we highlight recent progress in the design of MNP-based stimuli-responsive nanomaterials and their applications to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in tumor-targeting and penetrating drug delivery systems in urgent need. Here, glucose oxidase (GOX) and hypoxia-activated prodrug tirapazamine (TPZ) are loaded into photothermal conversion agent polydopamine (PDA) as the glucose/oxygen-exhausting nanoreactor named PGT. We further construct a tumor cell membrane-coated nanovesicle for the targeted delivery of PGT. This biomimetic nanovesicle exhibits significantly improved tumor-targeting and tumor-penetrating abilities. After internalization by the tumor cells, the loaded drug is quickly released in response to near-infrared (NIR) laser. The PGT nanoreactor can exhaust glucose and oxygen, and further enhance hypoxia within tumor, which efficiently inhibits hypoxic tumor by combining starvation therapy and hypoxia-activated chemotherapy. Mechanically, it is revealed that the nanoreactor significantly increases hypoxia level and downregulates the expression of hypoxia-inhibitory factor-1α (HIF-1α), thereby promoting T cell activation and macrophage polarization to remodel tumor immunosuppressive microenvironment. Therefore, this tumor microenvironment-regulable nanoreactor with sustainable and cascade targeted starvation-chemotherapy provides a novel insight into the treatment of hypoxic tumor. [ABSTRACT FROM AUTHOR]

To efficiently deliver anti-cancer drug to tumor site and reduce its toxic side effects on normal tissues, a polyethylene glycol (PEG) shielding and tumor microenvironment triggering cascade pH-responsive hollow mesoporous silica nanoparticles (HMSNs) drug delivery system was fabricated. 3-(3, 4-dihydroxyphenyl) propionic acid (DHPA) functionalized beta-cyclodextrin (β-CD) was grafted onto the surfaces of HMSNs via boronic acid-catechol ester bonds. Then, PEG conjugated adamantane (Ada) was anchored on HMSNs-β-CD nanocarrier via host-gust interaction. Various techniques proved the successful fabrication of the system. The in vitro tests confirmed that the system was biocompatible. After the system permeating into tumor via enhanced permeability and retention (EPR) effect, the benzoic-imine bonds between the PEG and Ada were cleaved under weak acid condition in tumor microenvironment (pH 6.8), while the dissociated PEG protective layer facilitating cellular uptake of HMSNs system. Subsequently, the boronic acid-catechol ester bonds linkers further hydrolyzed under even low endosomal pH (4.5–6.5) condition for intracellular drug delivery, leading to efficient cell apoptosis. The in vivo results demonstrated that drug loaded HMSNs significantly inhibited tumor growth while only with minimal toxic side effects. The strategy provides new insight into the development of new generation of drug delivery carriers triggering by tumor microenvironment. [ABSTRACT FROM AUTHOR]

Abstract: A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery. [Copyright &y& Elsevier]