In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy.

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

Chemodynamic/Photothermal Synergistic Cancer Immunotherapy Based on Yeast Microcapsule-Derived Au/Pt Nanoparticles.

In recent years, microbiota-based tumor immunotherapy has become a hotspot in cancer research. However, the use of microorganisms alone to activate the immune response for antitumor therapy was unsatisfactory. In this study, we biosynthesized gold nanoparticles (AuNPs) and platinum nanoparticles (PtNPs) based on yeast microcapsules to activate the immune response for antitumor treatment in synergy with chemodynamic therapy (CDT) and photothermal therapy (PTT). We generated AuNPs and PtNPs on yeast microcapsules (YAP) and fabricated nanoscale particles (Bre-YAP) by ultrasonic fragmentation and differential centrifugation. Bre-YAP retained the glucan component of yeast as an adjuvant; in the meantime, these two kinds of metal nanoparticles contained were excellent CDT and PTT mediators. By inspection, they could reach a high level of distribution in tumors and tumor-draining lymph nodes (TDLNs). Under the laser irradiation of tumors, this immunological nanomaterial significantly remodeled the microenvironments of tumors and TDLNs. The primary tumors were effectively inhibited or even eradicated, and the overall survival of mice was significantly improved as well. Therefore, yeast microcapsule-based Bre-YAP with immune properties could be used as an effective cancer treatment modality.

All-in-one approaches for triple-negative breast cancer therapy: metal-phenolic nanoplatform for MR imaging-guided combinational therapy.

BACKGROUND: Conventional chemotherapy has poor efficacy in triple-negative breast cancer (TNBC) which is highly heterogeneous and aggressive. Imaging-guided therapy is usually combined with diverse treatment modalities, could realize the integration of diagnosis and treatments. Therefore, the primary challenge for combinational therapy is designing proper delivery systems to accomplish multiple synergistic effects. RESULTS: Herein, a facile nanoplatform was manufactured to fulfill the all-in-one approaches for TNBC combinational therapy. Fe3+-based metal-phenolic networks (MPNs) with bovine serum albumin (BSA) modification served as drug delivery carriers to encapsulate bleomycin (BLM), forming BFE@BSA NPs. The self-assembly mechanism, pH-responsive drug release behavior, and other physicochemical properties of this system were characterized. The potential of BFE@BSA NPs as photothermal transduction agents and magnetic resonance imaging (MRI) contrast agents was explored. The synergistic anti-tumor effects consisting of BLM-induced chemotherapy, Fenton reactions-mediated chemodynamic therapy, and photothermal therapy-induced apoptosis were studied both in vitro and in vivo. Once internalized into tumor cells, released BLM could cause DNA damage, while Fenton reactions were initiated to produce highly toxic •OH. Upon laser irradiation, BFE@BSA NPs could convert light into heat to achieve synergistic effects. After intravenous administration, BFE@BSA NPs exhibited great therapeutic effects in 4T1 tumor xenograft model. Moreover, as T1-weighted MRI contrast agents, BFE@BSA NPs could provide diagnosis and treatment monitoring for individualized precise therapy. CONCLUSIONS: A nano-system that integrated imaging and combinational therapy (chemotherapy, chemodynamic therapy and photothermal therapy) were developed to kill the tumor and monitor therapeutic efficacy. This strategy provided an all-in-one theranostic nanoplatform for MRI-guided combinational therapy against TNBC.

Green tea extract-assembled nanoclusters for combinational photothermal and chemotherapy.

"Green chemistry" is a newly developed approach that uses natural products to fabricate drug delivery systems; it has many advantages, such as low cost, simplicity, rapidity and environmental friendliness. In this study, we fabricated doxorubicin-loaded gold nanoclusters via a "green chemistry" method, involving the use of green tea extract to realize combinational photothermal and chemotherapy against melanoma. Green tea extract acted as a reducing agent of chloroauric acid and a stabilizer of the nanoclusters, and it also provided a co-polymerization site for doxorubicin. Gold nanoclusters were formed in the presence of the reductive polyphenols in the green tea extract. The accordingly converted polyphenol oxides could assemble into oligomers to stabilize the formulated nanoclusters while co-polymerizing with doxorubicin through π-π stacking and electrostatic interactions. This drug delivery system showed good stability, pH-sensitive drug release properties and enhanced cellular uptake. In vitro and in vivo experiments both demonstrated that our system with combinational photothermal and chemotherapy could achieve significantly enhanced tumor growth inhibition compared to monotherapy. Overall, this platform may provide a safe and efficient strategy for cancer treatment and new insight into green, natural extracts for nanoparticle fabrication.

Intracellularly Generated Immunological Gold Nanoparticles for Combinatorial Photothermal Therapy and Immunotherapy against Tumor.

Gold nanoparticle (AuNP) has been widely used in cancer photothermal therapy (PTT) for ablating accessible tumor, while it is insufficient for inhibiting tumor metastasis and relapse in current stage. Here, we first developed a novel immunological AuNP through intracellular generation and exocytosis for combinatorial PTT and immunotherapy. Melanoma B16F10 cells were employed to generate AuNPs first and then shed nanoparticle trapped vesicles to extracellular environment with retained tumor antigens (AuNP@B16F10). By further introducing the nanoparticles into dendritic cells (DCs), DC-derived AuNPs (AuNP@DCB16F10) were generated with enhanced biosafety, which can induce hyperthermia and provoke antitumor immune responses. This immunological nanoplatform demonstrated efficient inhibition or even eradication of primary tumor, tumor metastasis, as well as tumor relapse, with significantly improved overall survival of mice. With our design, the intracellularly generated AuNPs with immunological property could act as an effective treatment modality for cancer.

Tumor Lysate-Loaded Lipid Hybrid Nanovaccine Collaborated with an Immune Checkpoint Antagonist for Combination Immunotherapy.

Cancer vaccines have shown great potential for treating different types of cancer. However, the application of vaccination still presents two major challenges. One is efficiency of antigen delivery, and the other is dealing with immune tolerance accompanied with tumor development. Lipid zinc phosphate hybrid nanoparticles (LZnP NPs) with a unique material structure can realize efficient delivery of antigens to dendritic cells (DCs) and also serve as an adjuvant to promote immune responses. Herein, ZnP NPs are introduced to load toll-like receptor 4 agonist (monophosphoryl lipid A) and B16F10 melanoma cell-derived tumor lysate (TLS) for vaccination. To regulate immune tolerance, the immune checkpoint antagonist, d-peptide antagonist (D PPA-1), is involved in treatment. TLS-loaded LZnP nanovaccine can efficiently prime DCs and induce cytotoxic T lymphocytes response. The explored combination treatment further exhibits the anticipated tumor inhibition on therapeutic and prophylactic melanoma models with extended survival time. It demonstrates the possibility to combine TLS-loaded LZnP nanovaccine with D PPA-1 against melanoma and provides support to optimize the combination treatment based on nanovaccine and immune checkpoint therapy.

Biomimetic Nanovesicles for Enhanced Antitumor Activity of Combinational Photothermal and Chemotherapy.

The combination of multiple modalities has shown great potential in cancer treatment with improved therapeutic effects and minimized side effects. Here, we fabricated a type of doxorubicin-encapsulated biomimetic nanovesicle (NV) by a facile method with near-infrared dye insertion in the membrane for combinatorial photothermal and chemotherapy. With innate biomimetic properties, NVs enhanced the uptake by tumor cells while reducing the phagocytosis of macrophages. Upon laser irradiation, NVs can convert the absorbed fluorescent energy into heat for effective tumor killing. Hyperthermia can further induce membrane ablation of NVs to accelerate the release of chemotherapeutic drug for potent cytotoxicity to tumor cells. The NVs improved drug accumulation and showed a more efficient in vivo photothermal effect with a rapid temperature increase in tumors. Moreover, the NV-based combinational photothermal and chemotherapy exhibited significant tumor growth suppression with a high inhibitory rate of 91.6% and negligible systemic toxicity. The results indicate that NVs could be an appealing vehicle for combinational cancer treatment.

Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery.

D-ɑ-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) has been approved by FDA as a safe adjuvant and widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its applications in drug delivery like high biocompatibility, enhancement of drug solubility, improvement of drug permeation and selective antitumor activity. Notably, TPGS can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor. In this review, we aim to discuss the recent advances of TPGS in drug delivery including TPGS based prodrugs, nitric oxide donor and polymers, and unmodified TPGS based formulations. These potential applications are focused on enhancing delivery efficiency as well as the therapeutic effect of agents, especially on overcoming MDR of tumors. It also demonstrates that the clinical translation of TPGS based nanomedicines is still faced with many challenges, which requires more detailed study on TPGS properties and based delivery system in the future.