Injectable Carbon Dots-Based Hydrogel for Combined Photothermal Therapy and Photodynamic Therapy of Cancer.

Hydrogel has been widely used in modern biotherapeutics due to its excellent biocompatibility, degradability, and high drug loading capacity. Among them, the construction of a phototherapy system including photosensitizer and hydrogel has aroused great interest in tumor therapy. Unfortunately, complex modifications are necessary to integrate different photosensitizers into the hydrogel. In this work, an injectable hydrogel was proposed by the Schiff base reaction between HA-CHO and carbon dots (CDs), which can realize PTT and PTT simultaneously. Notably, the CDs with rich -NH2 can be used not only as a photosensitizer but also as an efficient cross-linking agent for the Schiff base reaction to form a hydrogel network. The CD@Hydrogel with outstanding biosafety showed a high antitumor effect after 660 nm laser irradiation in in vitro and in vivo experiments. In summary, the CD@Hydrogel can not only realize PTT and PDT synergistic treatment under one light source but also act as a cross-linking agent to react with HA-CHO to form hydrogel, which is simple and efficient, providing a new strategy for cancer phototherapy.

Light-triggered multifunctional nanoplatform for efficient cancer photo-immunotherapy.

Cancer immunotherapy is limited by the immune escape of tumor cells and adverse effects. Photo-immunotherapy, the combination of immunotherapy and phototherapy (such as photodynamic therapy (PDT) and photothermal therapy (PTT)), can improve the effectiveness of immunotherapy in cancer treatment. Here, we first explored mesoporous hexagonal core-shell zinc porphyrin-silica nanoparticles (MPSNs), which are composed of a zinc porphyrin core and a mesoporous silica shell, and exhibit high laser-triggered photodynamic and photothermal activity, as well as outstanding drug loading capacity. In other words, MPSNs can be used not only as excellent photosensitizers for photo-immunotherapy, but also as an ideal drug carrier to achieve more efficient synergy. After loading with R837 (imiquimod, a toll-like receptor-7 agonist), MPSNs@R837 will elicit high-efficiency immunogenic cell death via PDT and PTT, and promote dendritic cell maturation after the PH-responsive release of R837, thereby, inducing tumor-specific immune responses. When combined with a programmed death ligand-1 checkpoint blockade, the photo-immunotherapy system markedly restrains primary tumors and metastatic tumors with negligible systemic toxicity. Therefore, the therapeutic strategy of integrating PTT, PDT and checkpoint blockade, shows great potential for suppressing cancer metastasis.

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.

Silver Mesoporous Silica Nanoparticles: Fabrication to Combination Therapies for Cancer and Infection.

The integration of silver nanoparticles (Ag NPs) with mesoporous silica nanoparticles (MSNs) protects the former from aggregation and promotes the controlled release of silver ions, resulting in therapeutic significance on cancer and infection. The unique size, shape, pore structure and silver distribution of silver mesoporous silica nanoparticles (Ag-MSNs) embellish them with the potential to perform combined imaging and therapeutic actions via modulating optical and drug release properties. Here, we comprehensively review the recent progress in the fabrication and application of Ag-MSNs for combination therapies for cancer and infection. We first elaborate on the fabrication of star-shaped structure, core-shell structure, and Janus structure Ag-MSNs. We then highlight Ag-MSNs as a multifunctional nanoplatform to surface-enhanced Raman scattering-based detection, non-photo-based cancer theranostics and photo-based cancer theranostics. In addition, we detail Ag-MSNs for combined antibacterial therapy via drug delivery and phototherapy. Overall, we summarize the challenges and future perspectives of Ag-MSNs that make them promising for diagnosis and therapy of cancer and infection.

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.

High photoluminescence nitrogen, phosphorus co-doped carbon nanodots for assessment of microbial viability.

Assessment of microbial viability plays a key role in human health protection. Optical imaging based on fluorescent dyes is a simple and convenient way to assess microbial viability. However, it is still a challenge to obtain stable, nontoxic and low-cost dyes. Herein, we prepared a nitrogen and phosphorus co-doped carbon nanodots (N, P-CDs) via a one-step solvothermal method. The prepared CDs possess plenty of functional groups and exhibit high stability, good biocompatibility, excellent photoluminescent and low toxicity. Especially, the properties of high quantum yield (89.9%) and highly negative surface charge (-41.9 mV) make the prepared N, P-CDs ideal materials for microbial differentiation. Compared with commercial dyes, our CDs are more stable, cost less, which can rapidly distinguish dead microorganisms from living ones with higher specificity.

Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence.

Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-deliveries doxorubicin (DOX) and BER to achieve a synergic effect in HCC treatment. The underlying fact of chemotherapy that promotes HCC repopulation was firstly examined and corroborated by clinical samples and murine repopulation model. Then, hyaluronic acid (HA)-conjugated Janus nanocarrier (HA-MSN@DB) was developed to load DOX and BER simultaneously. The HCC targeting efficiency, pH-controlled drug-release and anti-cancer property of HA-MSN@DB were assessed in CD44-overexpressed HCCs and normal liver cells. Magnet resonance imaging, bio-distribution, biocompatibility, tumor and recurrence inhibition studies were performed in H22 tumor-bearing mice. BER significantly reduced doxorubicin (DOX)-triggered HCC repopulation in vitro and in vivo through inhibiting Caspase-3-iPLA2-COX-2 pathway. The delivery of HA-MSN@DB into HCCs through CD44 receptor-mediated targeting effect was demonstrated. The controlled release of DOX and BER in response to acidic tumor microenvironment was validated. Importantly, HA-MSN@DB drastically enhanced the antitumor activity of DOX and suppressed DOX-exacerbated HCC repopulation in vitro and in vivo. Furthermore, HA-MSN@DB exhibited enhanced tumor accumulation and biocompatibility. Our findings revealed the pivotal role of BER in overcoming chemotherapy-exacerbated HCC repopulation through Caspase-3-iPLA2-COX-2 pathway, thereby providing a promising and stable nanocarrier integrating DOX and BER for effective HCC chemotherapy without repopulation. STATEMENT OF SIGNIFICANCE: In this work, we have first demonstrated the fact that berberine (Ber) reduces chemotherapy-exacerbated HCC recurrence and studied its mechanism by the aid of a doxorubicin-induced mice HCC relapse model. We then developed a promising strategy that simultaneously inhibits HCC and its recurrence with an HCC-targeted co-delivery nanocarrier HA-MSN@DB and revealed that such an inhibition was related with the suppression of Caspase-3-iPLA2-COX-2 pathway by berberine.

Janus Gold Triangle-Mesoporous Silica Nanoplatforms for Hypoxia-Activated Radio-Chemo-Photothermal Therapy of Liver Cancer.

Radiation dosage constraints and hypoxia-associated resistance lead to the failure of radiotherapy (RT), especially in hypoxic liver cancer. Therefore, the intricate use of combined strategies for potentiating and complementing RT is especially important. In this work, we fabricated multifunctional Janus-structured gold triangle-mesoporous silica nanoparticles (NPs) as multifunctional platforms to deliver the hypoxia-activated prodrug tirapazamine (TPZ) for extrinsic radiosensitization, local photothermal therapy, and hypoxia-specific chemotherapy. The subsequent conjugation of folic acid-linked poly(ethylene glycol) provided the Janus nanoplatforms with liver cancer targeting and minimized opsonization properties. In vitro and in vivo experiments revealed the combined radiosensitive and photothermal antitumor effects of the Janus nanoplatforms. Importantly, the TPZ-loaded Janus nanoplatforms exhibited pH-responsive release behavior, which effectively improved the cellular internalization and therapeutic efficiency in hypoxic rather than normoxic liver cancer cells. Hypoxia-specific chemotherapy supplemented the ineffectiveness of radio-photothermal therapy in hypoxic tumor tissues, resulting in remarkable tumor growth inhibition without systematic toxicity. Therefore, our Janus nanoplatforms integrated radio-chemo-photothermal therapy in a hypoxia-activated manner, providing an efficient and safe strategy for treating liver cancer.

Berberine-loaded Janus gold mesoporous silica nanocarriers for chemo/radio/photothermal therapy of liver cancer and radiation-induced injury inhibition.

Background: The combination of chemotherapy with radiotherapy serves as a common therapeutic strategy in clinics. However, it is unsatisfactory due to its poor therapeutic efficiency and severe side-effects originating from chemotherapy-exerted systemic toxicity as well as radiation-induced injury. Purpose: Hence, Berberine (Ber), an isoquinolin alkaloid with low toxicity and protective effects against radiotherapy, was used as a novel chemotherapeutic agent for chemo-radiotherapy of liver cancer. Patients and methods: We preloaded Ber into folic acid targeting Janus gold mesoporous silica nanocarriers (FA-JGMSNs) for overcoming the poor bioavailability of Ber. Furthermore, FA-JGMSNs were not only employed as radiosensitizers for expanding radiotherapeutic effect, but also used as photothermal agents for supplementing chemo-radiotherapeutic effect by local photothermal therapy. Results: In vitro and in vivo experiemtal results demonstrated the highly efficient anti-tumor effect, good biosafety as well as the effective protection of normal tissue of this nanoplatform. Conclusion: Based on its superb performance, we believe our work provided a feasible strategy for triple-therapies of liver cancer.

Shape-controlled magnetic mesoporous silica nanoparticles for magnetically-mediated suicide gene therapy of hepatocellular carcinoma.

Magnetic nanoparticles (NPs) have emerged as a promising tool for suicide gene therapy. However, the separate delivery of the suicide gene and prodrug in current systems limits their clinical translation. Therefore, improving magnetically mediated suicide gene therapy by exploring higher performance magnetic NP-based hybrid nanoplatforms is an important challenge. In the current study, shape-controlled magnetic mesoporous silica nanoparticles (M-MSNs) were prepared, and their performance in magnetic resonance imaging (MRI)-guided, magnetically targeted and hyperthermia-enhanced suicide gene therapy of hepatocellular carcinoma (HCC) was investigated. Compared with sphere-like MSNs, rod-like MSNs exhibited higher loading capacity, faster prodrug release behavior, stronger magnetically enhanced gene delivery and better magnetic hyperthermia properties. Utilizing the improved magnetic properties of the M-MSNs allowed us to demonstrate highly effective dual magnetically enhanced suicide gene therapy in vivo with decreased systematic toxicity and with the ability to monitor therapeutic outcome by MRI. Because of their magnetic targeting abilities, magnetic hyperthermia performance and MRI properties, these M-MSNs might prove to be a potentially superior candidate for suicide gene therapy of HCC.

Cancer cell membrane-modified biodegradable mesoporous silica nanocarriers for berberine therapy of liver cancer.

Berberine (Ber) is regarded as a new, active and natural anti-cancer product; however, its clinical application has been limited due to its low aqueous solubility, poor gastrointestinal absorption, short residence time and poor targeting abilities. Hence, we reported a biomimetic nanoparticle as a drug delivery system to surmount these obstacles. We fabricated disulfide (S-S)-bridged mesoporous organosilica nanoparticles (ss-MONs) for Ber loading, which possessed uniform morphology, controllable mesoporous properties, highly-efficient drug loading capacity and superior biocompatibility. More interestingly, ss-MONs exhibited effective biodegradability under glutathione conditions through the breakage of the disulfide bond in ss-MONs, which promoted the Ber release. After coating human liver cancer HepG2 cell membranes (CM) on the surface of ss-MONs, the obtained CM-ss-MONs-Ber enhanced accumulation in liver cancer tissue through homologous targeting and effectively avoiding rapid blood clearance. Our findings indicate that CM-ss-MONs might be desirable drug carriers to promote the clinical use of Ber against liver cancer.

Janus Silver/Silica Nanoplatforms for Light-Activated Liver Cancer Chemo/Photothermal Therapy.

Stimuli-triggered nanoplatforms have become attractive candidates for combined strategies for advanced liver cancer treatment. In this study, we designed a light-responsive nanoplatform with folic acid-targeting properties to surmount the poor aqueous stability and photostability of indocyanine green (ICG). In this Janus nanostructure, ICG was released on-demand from mesoporous silica compartments in response to near-infrared (NIR) irradiation, exhibiting predominant properties to convert light to heat in the cytoplasm to kill liver cancer cells. Importantly, the silver ions released from the silver compartment that were triggered by light could induce efficient chemotherapy to supplement photothermal therapy. Under NIR irradiation, ICG-loaded Janus nanoplatforms exhibited synergistic therapeutic capabilities both in vitro and in vivo compared with free ICG and ICG-loaded mesoporous silica nanoparticles themselves. Hence, our Janus nanoplatform could integrate ICG-based photothermal therapy and silver ion-based chemotherapy in a cascade manner, which might provide an efficient and safe strategy for combined liver cancer therapy.

Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy.

Biomimetic cell membrane-coated nanoparticles (CM-NPs) with superior biochemical properties have been broadly utilized for various biomedical applications. Currently, researchers primarily focus on using ultrasonic treatment and mechanical extrusion to improve the synthesis of CM-NPs. In this work, we demonstrate that microfluidic electroporation can effectively facilitate the synthesis of CM-NPs. To test it, Fe3O4 magnetic nanoparticles (MNs) and red blood cell membrane-derived vesicles (RBC-vesicles) are infused into a microfluidic device. When the mixture of MNs and RBC-vesicles flow through the electroporation zone, the electric pulses can effectively promote the entry of MNs into RBC-vesicles. After that, the resulting RBC membrane-capped MNs (RBC-MNs) are collected from the chip and injected into experimental animals to test the in vivo performance. Owing to the superior magnetic and photothermal properties of the MN cores and the long blood circulation characteristic of the RBC membrane shells, core-shell RBC-MNs were used for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Due to the completer cell membrane coating, RBC-MNs prepared by microfluidic electroporation strategy exhibit significantly better treatment effect than the one fabricated by conventional extrusion. We believe the combination of microfluidic electroporation and CM-NPs provides an insight into the synthesis of bioinpired nanoparticles to improve cancer diagnosis and therapy.

Berberine-loaded Janus nanocarriers for magnetic field-enhanced therapy against hepatocellular carcinoma.

Berberine, an bioactive isoquinolin alkaloid from traditional Chinese herbs, is considered to be a promising agent based on its remarkable activity against hepatocellular carcinoma. However, the clinical application of this nature compound had been hampered owing to its properties such as poor aqueous solubility, low gastrointestinal absorption, and reduced bioavailability. Therefore, we developed Janus magnetic mesoporous silica nanoparticles (Fe3 O4 -mSiO2 NPs) consisting of a Fe3 O4 head for magnetic targeting and a mesoporous SiO2 body for berberine delivery. A pH-sensitive group was introduced on the surface of mesoporous silica for berberine loading to develop a tumor microenvironment-responsive nanocarrier, which exhibited uniform morphology, good superparamagnetic properties, high drug-loading amounts, superior endocytic ability, and low cytotoxicity. Berberine-loaded Fe3 O4 -mSiO2 NPs exerted extraordinarily high specificity for hepatocellular carcinoma cells, which was due to the pH-responsive berberine release, as well as higher endocytosis capacity in hepatocellular carcinoma cells rather than normal liver cells. More importantly, an external magnetic field could significantly improve antitumor activity of Ber-loaded Fe3 O4 -mSiO2 NPs through enhancing berberine internalization. Taken together, our results suggest that Janus nanocarriers driven by the magnetic field may provide an effective and safe way to facilitate clinical use of berberine against hepatocellular carcinoma.