Light/glutathione-ignited nanobombs integrating azo and tetrasulfide bonds for multimodal therapy of colorectal cancer.

Reactive chemical bonds are associated with the generation of therapeutic radicals and gases under internal-external stimuli, which are highly attractive for cancer treatments. However, designing multifunctional nanostructures that incorporate multiple chemical bonds remains a significant challenge. Herein, novel core-shell nanobombs integrating azo (NN) and tetrasulfide bonds (SSSS) have been constructed with sensitive ignition by both near-infrared (NIR) laser and tumor microenvironments (TME) for treating colorectal tumors. The nanobombs (GNR/AIPH@MON@PVP, GAMP) were prepared by the in-situ growth of tetrasulfide-contained mesoporous organosilica nanoshell (MON) on gold nanorods (GNR) as the photothermal initiator, the load of azo compound (AIPH) as the radical producer and polymer modification. Upon NIR irradiation, the GNR core exhibits stable and high photothermal effects because of the passivation of the MON shell, leading to the thermal ablation of cancer cells. Simultaneously, the local hyperthermia ignites AIPH to release alkyl radicals to cause extensive oxidative stress without oxygen dependence. Moreover, the MON shell can be gradually decomposed in a reduced environment and release therapeutic H2S gas because of the cleavage of SSSS bonds by the glutathione (GSH) overexpressed in TME, causing mitochondrial injury. Owing to multifunctional functions, the GAMP significantly inhibits the growth rate of tumors upon NIR irradiation and achieves the highest efficacy among treatments. Therefore, this study presents activatable nanoagents containing multiple chemical bonds and provides insights into developing comprehensive antitumor strategies.

GSH-Triggered/Photothermal-Enhanced H2S Signaling Molecule Release for Gas Therapy.

Traditional treatment methods for tumors are inefficient and have severe side effects. At present, new therapeutic methods such as phototherapy, chemodynamic therapy, and gasodynamic therapy have been innovatively developed. High concentrations of hydrogen sulfide (H2S) gas exhibit cancer-suppressive effects. Herein, a Prussian blue-loaded tetra-sulfide modified dendritic mesoporous organosilica (PB@DMOS) was rationally constructed with glutathione (GSH)-triggered/photothermal-enhanced H2S signaling molecule release properties for gas therapy. The as-synthesized nanoplatform confined PB nanoparticles in the mesoporous structure of organosilica silica due to electrostatic adsorption. In the case of a GSH overexpressed tumor microenvironment, H2S gas was controllably released. And the temperature increases due to the photothermal effects of PB nanoparticles, further enhancing H2S release. At the same time, PB nanoparticles with excellent hydrogen peroxide catalytic performance also amplified the efficiency of tumor therapy. Thus, a collective nanoplatform with gas therapy/photothermal therapy/catalytic therapy functionalities shows potential promise in terms of efficient tumor therapy.

A Phase-Change Mediated Intelligent Nanoplatform for Chemo/Photothermal/Photodynamic Therapy of Cancer.

Up to now, chemotherapy is still the main strategy for cancer treatment. However, the emergence of chemo-resistance and systemic side effects often seriously affects the treatment and prognosis. Herein, an intelligent nanoplatform based on dendritic mesoporous organosilica nanoparticles (DMON) is constructed. The encapsulated phase-change material, 1-tetradecanol (TD) can serve as a "doorkeeper" and enable the responsive release of drugs based on the temperature changes. Meanwhile, polyethylene glycol (PEG) is used to improve the dispersibility and biocompatibility. Cisplatin is chosen as the model of chemotherapy drug, which is co-loaded with indocyanine green (ICG) in DMON to produce DMON-PEG-cisplatin/ICG-TD (DPCIT). Exciting, the hyperthermia and reactive oxygen species induced by ICG under the NIR-laser irradiation will initiate a phase transition of TD to release cisplatin, thus leading a combined therapy (chemo/photothermal/photodynamic therapy). The results indicated that under laser irradiation, DPCIT can kill cancer cells and inhibit tumor growth efficiently. In addition, the designed nanoplatform reveals minimal systemic toxicity in vivo, in contrast, the distinct liver damage can be observed by the direct treatment of cisplatin. Overall, this research may provide a general approach for the targeted delivery and controlled release of chemotherapy drugs to realize a cooperatively enhanced multimodal tumor therapy.

3D-CEUS tracking of injectable chemo-sonodynamic therapy-enabled mop-up of residual renal cell carcinoma after thermal ablation.

Thermal ablation (TA), as a minimally invasive therapeutic technique, has been extensively used to the treatment of solid tumors, such as renal cell carcinoma (RCC), which, unfortunately, still fails to overcome the high risk of local recurrence and distant metastasis since the incomplete ablation cannot be ignored due to various factors such as the indistinguishable tumor margins and limited ablation zone. Herein, we report the injectable thermosensitive hydrogel by confining curcumin (Cur)-loaded hollow mesoporous organosilica nanoparticles (Cur@HMON@gel) which can locate in tumor site more than half a month and mop up the residual RCC under ultrasound (US) irradiation after transforming from colloidal sol status to elastic gel matrix at physiological temperature. Based on the US-triggered accelerated diffusion of the model chemotherapy drug with multi-pharmacologic functions, the sustained and controlled release of Cur has been demonstrated in vitro. Significantly, US is employed as an external energy to trigger Cur, as a sonosensitizer also, to generate reactive oxygen species (ROS) for sonodynamic tumor therapy (SDT) in parallel. Tracking by the three-dimensional contrast-enhanced ultrasound (3D-CEUS) imaging, the typical decreased blood perfusions have been observed since the residual xenograft tumor after incomplete TA were effectively suppressed during the chemo-sonodynamic therapy process. The high in vivo biocompatibility and biodegradability of the multifunctional nanoplatform confined by thermogel provide the potential of their further clinical translation for the solid tumor eradication under the guidance and monitoring of 3D-CEUS.

A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.

Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed. Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation. Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity. Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMONs) as a versatile platform for multimodal imaging and phototherapeutic-triggered endolysosomal disruption in ovarian cancer.

A major impediment in the development of nanoplatform-based ovarian cancer therapy is endo/lysosome entrapment. To solve this dilemma, a hollow mesoporous organosilica-based nanoplatform (HMON@CuS/Gd2O3) with a mild-temperature photothermal therapeutic effect and multimodal imaging abilities was successfully synthesized. HMON@CuS/Gd2O3 exhibited an appropriate size distribution, L-glutathione (GSH)-responsive degradable properties, and high singlet oxygen generation characteristics. In this study, the nanoplatform specifically entered SKOV-3 cells and was entrapped in endo/lysosomes. With a mild near infrared (NIR) power density (.5 W/cm2), the HMON@CuS/Gd2O3 nanoplatform caused lysosome vacuolation, disrupted the lysosomal membrane integrity, and exerted antitumour effects in ovarian cancer. Additionally, our in vivo experiments indicated that HMON@CuS/Gd2O3 has enhanced T1 MR imaging, fluorescence (FL) imaging (wrapping fluorescent agent), and infrared thermal (IRT) imaging capacities. Using FL/MRI/IRT imaging, HMON@CuS/Gd2O3 selectively caused mild phototherapy in the cancer region, efficiently inhibiting the growth of ovarian cancer without systemic toxicity in vivo. Taken together, the results showed that these well-synthesized nanoplatforms are likely promising anticancer agents to treat ovarian cancer and show great potential for biomedical applications.

Intelligent Pore Switch of Hollow Mesoporous Organosilica Nanoparticles for High Contrast Magnetic Resonance Imaging and Tumor-Specific Chemotherapy.

Hollow mesoporous organosilica nanoparticles (HMONs) are widely considered as a promising drug nanocarrier, but the loaded drugs can easily leak from HMONs, resulting in the considerably decreased drug loading capacity and increased biosafety risk. This study reports the smart use of core/shell Fe3O4/Gd2O3 (FG) hybrid nanoparticles as a gatekeeper to block the pores of HMONs, which can yield an unreported large loading content (up to 20.4%) of DOX. The conjugation of RGD dimer (R2) onto the DOX-loaded HMON with FG capping (D@HMON@FG@R2) allowed for active tumor-targeted delivery. The aggregated FG in D@HMON@FG@R2 could darken the normal tissue surrounding the tumor due to the high r2 value (253.7 mM-1 s-1) and high r2/r1 ratio (19.13), and the intratumorally released FG as a result of reducibility-triggered HMON degradation could brighten the tumor because of the high r1 value (20.1 mM-1 s-1) and low r2/r1 ratio (7.01), which contributed to high contrast magnetic resonance imaging (MRI) for guiding highly efficient tumor-specific DOX release and chemotherapy.

Interface-Engineered Paclitaxel-Based Hollow Mesoporous Organosilica Nanoplatforms for Photothermal-Enhanced Chemotherapy of Tumor.

Having benefited from the combination of different therapeutic modalities, functionalized nanoplatforms with synergistic strategies have aroused great interest in anticancer treatment. Herein, an engineered, a biodegradable hollow mesoporous organosilica nanoparticle (HMON)-based nanoplatform was fabricated for photothermal-enhanced chemotherapy of tumor. For the first time, we demonstrated that HMONs could serve as nanocarriers for co-delivering of both the paclitaxel and photothermal agent new indocyanine green (IR820), denoted as Paclitaxel/IR820@ HMONs-PEG. The as-prepared nanosystem exhibited a high paclitaxel-loading capacity of 28.4%, much higher than most paclitaxel-loaded nanoformulations. Furthermore, incorporating thioether bonds (S-S) into the HMONs' framework endowed them with GSH-responsive biodegradation behavior, leading to the controllable release of drugs under a tumor reducing microenvironment, and hindered the premature release of paclitaxel. Upon being irradiated with an NIR laser, the obtained co-delivery nanosystem exhibited great photothermal properties generated from IR820. The fabricated nanocomposites could significantly suppress tumor growth under NIR laser irradiation, as validated by in vitro and in vivo assessments. Combined with outstanding biocompatibility, the constructed nanosystem holds great potential in combinational antitumor therapy.

Co-delivery of nanoparticle and molecular drug by hollow mesoporous organosilica for tumor-activated and photothermal-augmented chemotherapy of breast cancer.

BACKGROUND: In comparison with traditional therapeutics, it is highly preferable to develop a combinatorial therapeutic modality for nanomedicine and photothermal hyperthermia to achieve safe, efficient, and localized delivery of chemotherapeutic drugs into tumor tissues and exert tumor-activated nanotherapy. Biocompatible organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) have shown high performance in molecular imaging and drug delivery as compared to other inorganic nanosystems. Disulfiram (DSF), an alcohol-abuse drug, can act as a chemotherapeutic agent according to its recently reported effectiveness for cancer chemotherapy, whose activity strongly depends on copper ions. RESULTS: In this work, a therapeutic construction with high biosafety and efficiency was proposed and developed for synergistic tumor-activated and photothermal-augmented chemotherapy in breast tumor eradication both in vitro and in vivo. The proposed strategy is based on the employment of HMONs to integrate ultrasmall photothermal CuS particles onto the surface of the organosilica and the molecular drug DSF inside the mesopores and hollow interior. The ultrasmall CuS acted as both photothermal agent under near-infrared (NIR) irradiation for photonic tumor hyperthermia and Cu2+ self-supplier in an acidic tumor microenvironment to activate the nontoxic DSF drug into a highly toxic diethyldithiocarbamate (DTC)-copper complex for enhanced DSF chemotherapy, which effectively achieved a remarkable synergistic in-situ anticancer outcome with minimal side effects. CONCLUSION: This work provides a representative paradigm on the engineering of combinatorial therapeutic nanomedicine with both exogenous response for photonic tumor ablation and endogenous tumor microenvironment-responsive in-situ toxicity activation of a molecular drug (DSF) for augmented tumor chemotherapy.

Nanosilver-Decorated Biodegradable Mesoporous Organosilica Nanoparticles for GSH-Responsive Gentamicin Release and Synergistic Treatment of Antibiotic-Resistant Bacteria.

PURPOSE: Antibiotic-resistant bacteria are pathogens that have emerged as a serious public health risk. Thus, there is an urgent need to develop a new generation of anti-bacterial materials to kill antibiotic-resistant bacteria. METHODS: Nanosilver-decorated mesoporous organosilica nanoparticles (Ag-MONs) were fabricated for co-delivery of gentamicin (GEN) and nanosilver. After investigating the glutathione (GSH)-responsive matrix degradation and controlled release of both GEN and silver ions, the anti-bacterial activities of Ag-MONs@GEN were systematically determined against several antibiotic-susceptible and antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Furthermore, the cytotoxic profiles of Ag-MONs@GEN were evaluated. RESULTS: The GEN-loaded nanoplatform (Ag-MONs@GEN) showed glutathione-responsive matrix degradation, resulting in the simultaneous controlled release of GEN and silver ions. Ag-MONs@GEN exhibited excellent anti-bacterial activities than Ag-MONs and GEN alone via inducing ROS generation, especially enhancing synergetic effects against four antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Moreover, the IC50 values of Ag-MONs@GEN in L929 and HUVECs cells were 313.6 ± 15.9 and 295.7 ± 12.3 µg/mL, respectively, which were much higher than their corresponding minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. CONCLUSION: Our study advanced the development of Ag-MONs@GEN for the synergistic and safe treatment of antibiotic-resistant bacteria.

Periodic mesoporous organosilica-coated magnetite nanoparticles combined with lipiodol for transcatheter arterial chemoembolization to inhibit the progression of liver cancer.

Transcatheter arterial chemoembolization (TACE) is standard locoregional therapy for hepatocellular carcinoma (HCC) that involves the injection of chemotherapeutic drugs with embolic agents into tumor tissues through intra-arterial transcatheter infusion. TACE technology using lipiodol emulsion has been most widely used in the treatment of human HCC. However, lipiodol emulsions with anticancer drugs do not stably maintain high drug concentrations at tumor sites. Herein, we developed a dual-modality imaging nanoplatform for the TACE treatment of liver cancer by integrating periodic mesoporous organosilica (PMO) with magnetite (Fe3O4) nanoparticles and Cy5.5 molecules (denoted as Fe3O4@PMO-Cy5.5). Fe3O4@PMO-Cy5.5 showed an excellent doxorubicin (Dox)-loading capacity, sensitive drug release behavior under acidic conditions, and good biocompatibility. Moreover, Cy5.5-mediated optical imaging showed that Dox-loaded Fe3O4@PMO-Cy5.5 (Fe3O4@PMO-Cy5.5-Dox) could enter liver cancer cells and effectively inhibit their growth. In addition, Fe3O4@PMO-Cy5.5-Dox was used in combination with transarterial embolization for the treatment of in situ VX2 liver tumors in rabbits. Magnetic resonance imaging (MRI) evaluation showed that Fe3O4@PMO-Cy5.5-Dox perfused through arteries was deposited into liver tumors, and Fe3O4@PMO-Cy5.5-Dox combined with lipiodol to control liver tumors yielded the optimal therapeutic effect. In addition, histological analysis showed that compared with both lipiodol embolization and traditional lipiodol combined with Dox chemoembolization, Fe3O4@PMO-Cy5.5-Dox combined with lipiodol chemoembolization induced more complete tumor tissue necrosis. In summary, these results indicate that the Fe3O4@PMO-Cy5.5-Dox platform has the potential to become an advanced tool for the transarterial treatment of unresectable liver cancer.

Biomimetic Diselenide-Bridged Mesoporous Organosilica Nanoparticles as an X-ray-Responsive Biodegradable Carrier for Chemo-Immunotherapy.

Chemotherapy causes off-target toxicity and is often ineffective against solid tumors. Targeted and on-demand release of chemotherapeutics remains a challenge. Here, cancer-cell-membrane-coated mesoporous organosilica nanoparticles (MONs) containing X-ray- and reactive oxygen species (ROS)-responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX-loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low-dose X-ray radiation, the DOX-loaded MONs exhibit carrier degradation-controlled release via cleavage of diselenide bonds, resulting in DOX-mediated immunogenic cell death at the tumor site. Combination with a PD-L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiation-responsive diselenide-bond-bridged MONs in chemo-immunotherapy.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer.

BACKGROUND: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells' apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells' mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). RESULTS: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. CONCLUSION: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Biodegradable nanotheranostics with hyperthermia-induced bubble ability for ultrasound imaging-guided chemo-photothermal therapy.

BACKGROUND: Theranostics, elaborately integrating both therapeutic and diagnostic functions into a nanoplatform holds great potential for precision cancer medicine. METHODS: Herein, a biodegradable theranostic nanoplatform with hyperthermia-induced bubble ability for highly efficient ultrasound (US) imaging-guided chemo-photothermal therapy of breast tumors was developed. The prepared nanoparticles consisted of polydopamine (PDA)-modified hollow mesoporous organosilica nanoparticles (HMONs) with approximately 75 nm in diameter for doxorubicin (DOX) loading and perfluoropentane (PFP) filling. In addition, the pH-sensitive PDA coating served as both gatekeeper controlling DOX release and photothermal agent for inducing hyperthermia. RESULTS: Such nanoplatform (PDA@HMONs-DOX/PFP, PHDP) provides efficient loading (328 mg/g) and controllable stimuli-responsive release of DOX for chemotherapy. The incorporated disulfide bonds in the framework of HMONs endowed nanoparticles with intrinsic glutathione-responsive biodegradability and improved biocompatibility. Benefiting from the hyperthermia upon an 808-nm laser irradiation of PDA, the liquid-gas phase transition of the loaded PFP was induced, resulting in the generation of the nanobubbles, followed by the coalescence into microbubbles. This conversation could enhance the tumor cell uptake of nanoparticles, as well as intensify the US imaging signals. In addition, a synergistic therapeutic effect of our fabricated nanoplatform on cells/tumor growth effect has been systematically evaluated both in vitro and in vivo. CONCLUSION: Therefore, such "all-in-one" PHDP nanoparticles with satisfactory biocompatibility and biodegradability, hyperthermia-induced bubble ability and simultaneous US imaging performance hold great potential for cancer nanotheranostics.

Acidity/Reducibility Dual-Responsive Hollow Mesoporous Organosilica Nanoplatforms for Tumor-Specific Self-Assembly and Synergistic Therapy.

Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.

Chemodrug-Gated Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Multimodal Imaging-Guided Low-Temperature Photothermal Therapy/Chemotherapy of Cancer.

Noninvasive physical treatment with relatively low intensity stimulation and the development of highly efficient anticancer medical strategy are still desirable for cancer therapy. Herein a versatile, biodegradable, hollow mesoporous organosilica nanocapsule (HMONs) nanoplatform that is capped by the gemcitabine (Gem) molecule through a pH-sensitive acetal covalent bond is designed. The fabricated nanocapsule exhibits desirable small molecule release at the tumor tissues/cell sites and shows a reduced risk for drug accumulation. After loading indocyanine green (ICG), the heat-shock protein 90 (Hsp 90) inhibitor, and 17AAG and modification with polyethylene glycol (NH2-PEG), the resulting ICG-17AAG@HMONs-Gem-PEG exhibited a precisely controlled release of ICG and 17AAG and low-temperature photothermal therapy (PTT) (∼41 °C) with excellent tumor destruction efficacy. In addition, ICG loading conferred the nanoplatform with near-infrared fluorescence imaging (FL) and photoaccoustic (PA) imaging capability. In short, this work not only presents a smart drug self-controlled nanoplatform with pH-responsive payload release and theranostic performance but also provides an outstanding low-temperature PTT strategy, which is highly valid in the inhibition of cancer cells with minimal damage to the organism. Therefore, this research provides a paradigm that has a chemodrug-gated HMONs-based theranostic nanoplatform with intrinsic biodegradability, multimodal imaging capacity, high low-temperature PTT/chemotherapy efficacy, and reduced systemic toxicity.

Fabrication of multifunctional triple-responsive platform based on CuS-capped periodic mesoporous organosilica nanoparticles for chemo-photothermal therapy.

INTRODUCTION: For an ideal drug delivery system, the outstanding drug-loading capacity and specific control of the release of therapeutics at the desired lesions are crucial. In this work, we developed a triple-responsive nanoplatform based on copper sulfide (CuS)-capped yolk-shell-structured periodic mesoporous organosilica nanoparticles (YSPMOs) for synergetic chemo-photothermal therapy. METHODS: Herein, the YSPMOs were employed as a drug carrier, which exhibited a high doxorubicin (DOX) loading capacity of 386 mg/g. In this controlled-release drug delivery system, CuS serves as a gatekeeper to modify YSPMOs with reduction-cleavable disulfide bond (YSPMOs@CuS). CuS could not only avoid premature leakage in the delivery process, but also endowed the excellent photothermal therapy (PTT) ability. RESULTS: Upon entering into cancer cells, the CuS gatekeeper was opened with the breaking of disulfide bonds and the DOX release from YSPMOs(DOX)@CuS in response to the intracellular acidic environment and external laser irradiation. Such a precise control over drug release, combined with the photothermal effect of CuS nanoparticles, is possessed by synergistic chemo-photothermal therapy for cancer treatment. Both in vitro and in vivo experimental data indicated that the synergistic effect of YSPMOs(DOX)@CuS showed efficient antitumor effect. In addition, low systemic toxicity was observed in the pathologic examinations of liver, spleen, lungs, and kidneys. CONCLUSION: This versatile nanoplatform combination of PTT, chemotherapeutics, and gating components shows general potential for designing multifunctional drug delivery systems.

Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Mild Hyperthermia-Induced Bubble-Enhanced Oxygen-Sensitized Radiotherapy.

Alleviation of tumor hypoxia has been the premise for improving the effectiveness of radiotherapy, which hinges upon the advanced delivery and rapid release of oxygen within the tumor region. Herein, we propose a "bubble-enhanced oxygen diffusion" strategy to achieve whole tumor oxygenation for significant radiation enhancement based on the "bystander effect". Toward this end, sub-50 nm CuS-modified and 64Cu-labeled hollow mesoporous organosilica nanoparticles were constructed for tumor-specific delivery of O2-saturated perfluoropentane (PFP). Through the aid of PFP gasification arising from NIR laser-triggered mild hyperthermia, simultaneous PET/PA/US multimodality imaging and rapid oxygen diffusion across the tumor can be achieved for remarkable hypoxic radiosensitization. Furthermore, the multifunctional oxygen-carrying nanotheranostics also allow for other oxygen-dependent treatments, thus greatly advancing the development of bubble-enhanced synergistic therapy platforms.

Synergistic Chemo-Photothermal Therapy of Breast Cancer by Mesenchymal Stem Cell-Encapsulated Yolk-Shell GNR@HPMO-PTX Nanospheres.

Mesenchymal stem cells (MSCs) have attracted increasing attention as vehicles for cancer treatment. Herein, MSC-based synergistic oncotherapy strategy is presented for the first time. To achieve this goal, yolk-shell structured gold nanorod embedded hollow periodic mesoporous organosilica nanospheres (GNR@HPMOs) with high paclitaxel (PTX) loading capability and excellent photothermal transfer ability upon near-infrared (NIR) light irradiation are first prepared. Cytotoxicity and migration assays show that the viability and tumor-homing capability of MSCs are well-retained after internalization of high content of PTX loaded GNR@HPMOs (denoted as GNR@HPMOs-PTX). In vitro experiments show the GNR@HPMOs-PTX loaded MSCs (GNR@HPMOs-PTX@MSCs) possess synergistic chemo-photothermal killing effects for breast cancer cells. Also, photoacoustic imaging shows that the MSCs can improve dispersion and distribution in tumor tissue for GNR@HPMOs-PTX after intratumoral injection. In vivo experiments in breast cancer model of nude mice further demonstrate that the GNR@HPMOs-PTX@MSCs significantly inhibit tumor growth, suggesting their great potential for synergistic therapy of cancer.

A zinc phthalocyanine based periodic mesoporous organosilica exhibiting charge transfer to fullerenes.

Periodic mesoporous organosilica (PMO) materials offer a strategy to position molecular semiconductors within a highly defined, porous network. We developed thin films of a new semiconducting zinc phthalocyanine-bridged PMO exhibiting a face-centered orthorhombic pore structure with an average pore diameter of 11 nm. The exceptional degree of order achieved with this PMO enabled us to create thin films consisting of a single porous domain throughout their entire thickness, thus providing maximal accessibility for subsequent incorporation of a complementary phase. The phthalocyanine building blocks inside the pore walls were found to be well-aggregated, enabling electronic conductivity and extending the light-harvesting capabilities to the near IR region. Ordered 3D heterojunctions capable of promoting photo-induced charge transfer were constructed by impregnation of the PMO with a fullerene derivative. When integrated into a photovoltaic device, the infiltrated PMO is capable of producing a high open-circuit voltage and a considerable photocurrent, which represents a significant step towards potential applications of PMOs in optoelectronics.