Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy.

The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NOPS@BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BP-induced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NOPS@BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.

Multi-functional polymeric micelles for chemotherapy-based combined cancer therapy.

Currently, the therapeutic performance of traditional mono-chemotherapy on cancers remains unsatisfactory because of the tumor heterogeneity and multidrug resistance. In light of intricate tumor structures and distinct tumor microenvironments (TMEs), combinational therapeutic strategies with multiple anticancer drugs from different mechanisms can synergistically optimize the outcomes and concomitantly minimize the adverse effects during the therapy process. Extensive research on polymeric micelles (PMs) for biomedical applications has revealed the growing importance of nanomedicines for cancer therapy in the recent decade. Starting from traditional simple delivery systems, PMs have been extended to multi-faceted therapeutic strategies. Here we review and summarize the most recent advances in combinational therapy based on multifunctional PMs including a combination of multiple anticancer drugs, chemo-gene therapy, chemo-phototherapy and chemo-immunotherapy. The design approaches, action mechanisms and therapeutic applications of these nanodrugs are summarized. In addition, we highlight the opportunities and potential challenges associated with this promising field, which will provide new guidelines for advanced combinational cancer chemotherapy.

Inherently nitric oxide containing polymersomes remotely regulated by NIR for improving multi-modal therapy on drug resistant cancer.

The therapeutic potential of nitric oxide (NO) has been highly attractive to tumor treatment, especially for surmounting the multidrug resistance (MDR) of cancer. However, the NO-involved therapy remains extremely challenging because of the difficulty to simultaneously control the NO release rate and real-time concentration. Herein, we construct NO-containing polymersomes with high amount of NO donors inherently grown on the polymer chains to keep the stability. These polymersomes can be simultaneously loaded with photosensitizer of IR780 iodide on the membrane layer and chemotherapeutic of DOX·HCl in the lumen. NO release can be triggered by the reduction conditions, and further accelerated by remote NIR irradiation due to the increased local temperature. The instantaneous NO release with high concentration significantly inhibits the P-gp expression and sensitize the chemotherapy, thus overcoming the tumor MDR and improving the anti-tumor activity. Meanwhile, DOX·HCl release is highly promoted at the intracellular conditions because of the cleavage of acid-labile cis-aconitic amide at endo/lysosomal pH, and the improved hydrophilicity of the membrane layer after NO release. The in vivo results show that the single intravenous injection of polymersome formulation companying with NIR irradiation exerts multi-modal therapies of chemotherapy, PTT/PDT, and NO-therapy on the MCF-7/R tumor models, showing superior and combinational treatment efficacy with the complete eradication of tumors and few side effects.

Black phosphorus assisted polyionic micelles with efficient PTX loading for remotely controlled release and synergistic treatment of drug-resistant tumors.

Nanomedicines have been widely used in the effective delivery of chemotherapeutic drugs due to their advantages such as increasing the half-life of drugs, selectively targeting tumor tissues, and thus reducing systemic toxicity. However, the low drug entrapment rate and the difficulty of real-controlled release at tumor sites hinder their further clinical translations. Here we have developed biodegradable polyionic micelles (PD-M) to facilitate black phosphorus (BP) encapsulation (PD-M@BP) for improved drug loading. With the introduction of BP, PTX-loaded PD-M@BP (PD-M@BP/PTX) with sizes of 124-162 nm exhibited superior encapsulation efficiency over 94% and excellent colloidal stability. Meanwhile, PD-M well protected BP from fast degradation to show the good photothermal performance under near-infrared (NIR) irradiation, thus achieving the remotely controlled fast PTX release due to micelle core melting and dissociation, accompanied by the synergistic photothermal tumor therapy. The in vivo results demonstrated that the PD-M@BP/PTX nanosystem not only realized significant inhibition of multi-drug resistant (MDR) cervical tumors (HeLa/PTXR tumor) by remote NIR-regulation, but also reduced the potential damage of chemotherapeutic drugs to the whole body, rendering these hybrid nanosystems as great tools to treat MDR tumors synergistically.

FeSe2 nanosheets as a bifunctional platform for synergistic tumor therapy reinforced by NIR-II light.

Multi-functionality has been a constant pursuit in the development of next-generation drug carriers, as it will bring the potential for combination therapy by integrating diverse therapeutic modes. In this work, FeSe2 nanosheets (NSs) have been prepared as a bifunctional platform to investigate their use in synergistic cancer therapy. Bifunctional FeSe2 NSs exhibit exceptional Fenton-like activity that generates cytotoxic hydroxyl radical (˙OH) and strong broad photothermal performance including the second-infrared (NIR-II) spectral range, wherein the ˙OH production can be enhanced by NIR-II light irradiation. Furthermore, doxorubicin (DOX) was conjugated onto NSs via a pH-responsive hydrazone bond to achieve preferential drug release in an acidic microenvironment. Upon intratumoral administration, these bifunctional drug-carrying FeSe2 NSs showed an NIR-II irradiation-reinforced strong tumor suppression effect, and no obvious toxicity to normal tissues was observed. This study provides a new paradigm for the design of advanced drug carriers relying on their inherent physicochemical properties.

Wound Healing Activity of a Skin Substitute from Residues of Culinary-Medicinal Winter Mushroom Flammulina velutipes (Agaricomycetes) Cultivation.

A skin substitute TG05 obtained from residues of the culinary-medicinal mushroom Flammulina velutipes cultivation process was developed in this study for the first time. Pre-column derivatization high-performance liquid chromatography fingerprints analysis revealed that TG05 was composed of water-insoluble fibers containing xylose (57%), glucose (19.5%), and arabinose (16.3%) as major monomers. Porous and opaque structure of TG05 was demonstrated by scanning electron microscopy. Animal experiments conducted on mice and rats indicated that TG05 notably accelerated the wound-healing process. In addition, TG05 induced proliferation and migration of human keratinocytes time- and dose-dependently. Taken together, the skin substitute TG05 with new structure promotes wound healing in vitro and in vivo. This study provided a novel method to produce functional biomaterial from abundant and low-cost agricultural residues generated during edible mushroom cultivation.

Immunomodulatory activities of proteins from Astragalus membranaceus waste.

BACKGROUND: Astragalus membranaceus is a traditional Chinese medicine that has a long history of medical applications. It is of interest to investigate the functional components of A. membranaceus waste with regard to its development and utilization and increasing resource utilization. RESULTS: The protein AMWP was isolated from the A. membranaceus waste. This protein was further purified by DEAE-cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography to obtain three fractions, named AMWPDG2, AMWPDG4 and AMWPDG6. Then, their immunomodulatory activities were evaluated by using cell model experiments. The results indicated that the protein fractions could significantly increase the proliferation of splenic lymphocytes, peritoneal macrophages and bone-marrow-derived cells (BMDCs). AMWPDG2 showed the highest immunocompetence. AMWPDG2, AMWPDG4 and AMWPDG6 not only significantly improved the phagocytosis and immunomodulatory factors (interleukin (IL)-6, tumor necrosis factor-α, nitric oxide, hydrogen peroxide) secretion of peritoneal macrophages, but also promoted the expression of inflammatory cytokines (IL-6, IL-12 p40, IL-1ß, IL-1α) and chemokines (CXCL1, CCL3) in BMDCs. CONCLUSION: Taken together, these results indicated that three protein fractions from the A. membranaceus waste might be a potential natural immunomodulator. Moreover, it also provided the theoretical basis for further researching the mechanism of AMWPDG2, AMWPDG4 and AMWPDG6 on improving the immune response. © 2019 Society of Chemical Industry.

[Preparation of curcumin-EC sustained-release composite particles by supercritical CO2 anti-solvent technology].

Curcumin-ethyl-cellulose (EC) sustained-release composite particles were prepared by using supercritical CO2 anti-solvent technology. With drug loading and yield of inclusion complex as evaluation indexes, on the basis of single factor tests, orthogonal experimental design was used to optimize the preparation process of curcumin-EC sustained-release composite particles. The experiments such as drug loading, yield, particle size distribution, electron microscope analysis (SEM) , infrared spectrum (IR), differential scanning calorimetry (DSC) and in vitro dissolution were used to analyze the optimal process combination. The orthogonal experimental optimization process conditions were set as follows: crystallization temperature 45 degrees C, crystallization pressure 10 MPa, curcumin concentration 8 g x L(-1), solvent flow rate 0.9 mL x min(-1), and CO2 velocity 4 L x min(-1). Under the optimal conditions, the average drug loading and yield of curcumin-EC sustained-release composite particles were 33.01% and 83.97%, and the average particle size of the particles was 20.632 µm. IR and DSC analysis showed that curcumin might complex with EC. The experiments of in vitro dissolution showed that curcumin-EC composite particles had good sustained-release effect. Curcumin-EC sustained-release composite particles can be prepared by supercritical CO2 anti-solvent technology.