Tumor immune microenvironment-modulated nanostrategy for the treatment of lung cancer metastasis.

ABSTRACT: As one of the most malignant tumors worldwide, lung cancer, fueled by metastasis, has shown rising mortality rates. However, effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step, complicated, and progressive nature. Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment. However, drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response. Consequently, adverse effects occur, such as autoimmunity, from the non-specific immune activation and non-specific inflammation in off-target organs. Nanocarriers that improve drug solubility, permeability, stability, bioavailability, as well as sustained, controlled, and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects. In particular, nanomedicine-based immunotherapy can be utilized to target tumor metastasis, presenting a promising therapeutic strategy for lung cancer. Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment; the breaking away of primary tumors, circulating tumor cell dissemination, and premetastatic niche formation cause distant secondary site colonization. In this review, we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer. We also discuss prospects for the emerging field and the clinical translation potential of these techniques.

Combination of STING agonist and CXCR3 antagonist disrupts immune tolerance to overcome anti-PD-L1 resistance in lung adenocarcinoma under oxidative stress.

We investigated the role of the STING1-CXCR3 axis using database data and verified it in a mouse model bearing Lewis lung carcinoma (LLC) cells exposed to hydrogen peroxide (H2O2). Mice were treated with STING agonist liposomes (STING-Lip), anti-programmed death-ligand 1 (PD-L1), or STING-Lip + anti-PD-L1. The database data revealed that immune response pathways were enriched in patients with lung adenocarcinoma with upregulated STING1 signaling. Upregulated STING1 signaling was associated with a high abundance of immunoregulatory and effector molecules, cytokines, activated CD8+ T cells, and M1 macrophages in patients with lung adenocarcinoma. In this study, H2O2-treated LLC cells promoted an immunosuppressive microenvironment and enhanced tumor growth in mice. STING-Lip inhibited distant, untreated, and H2O2-induced LLC growth by activating systemic immunity. STING-Lip + anti-PD-L1 failed to slow distant and untreated LLC growth, whereas STING-Lip + anti-PD-L1 + CXCR3 antagonist inhibited distant tumor growth in mice. The combination of STING1 activation and CXCR3 inhibition may be a novel immunotherapeutic strategy to overcome immune checkpoint inhibitor resistance in lung adenocarcinoma by activating systemic immunity in the tumor microenvironment under oxidative stress.

Atomically Dispersed High-Density Al-N4 Sites in Porous Carbon for Efficient Photodriven CO2 Cycloaddition.

Highly active catalysts that can directly utilize renewable energy (e.g., solar energy) are desirable for CO2 value-added processes. Herein, aiming at improving the efficiency of photodriven CO2 cycloaddition reactions, a catalyst composed of porous carbon nanosheets enriched with a high loading of atomically dispersed Al atoms (≈14.4 wt%, corresponding to an atomic percent of ≈7.3%) coordinated with N (AlN4 motif, Al-N-C catalyst) via a versatile molecule-confined pyrolysis strategy is reported. The performance of the Al-N-C catalyst for catalytic CO2 cycloaddition under light irradiation (≈95% conversion, reaction rate = 3.52 mmol g-1 h-1 ) is significantly superior to that obtained under a thermal environment (≈57% conversion, reaction rate = 2.11 mmol g-1 h-1 ). Besides the efficient photothermal conversion induced by the carbon matrix, both experimental and theoretical analysis reveal that light irradiation favors the photogenerated electron transfer from the semiconductive Al-N-C catalyst to the epoxide reactant, facilitating the formation of a ring-opened intermediate through the rate-limiting step. This study not only provides an advanced Al-N-C catalyst for photodriven CO2 cycloaddition, but also furnishes new insight for the rational design of superior photocatalysts for diverse heterogeneous catalytic reactions in the future.

Case Report: Partial Response Following Nivolumab Plus Docetaxel in a Patient With EGFR Exon 20 Deletion/Insertion (p.N771delinsGF) Mutant Lung Adenocarcinoma Transdifferentiated From Squamous Cell Carcinoma.

The histological transformation from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) and p. N771delinsGF mutations in EGFR exon 20 (ex20) are exceedingly rare in non-small cell lung carcinoma (NSCLC). EGFR ex20 mutations are insensitive to EGFR tyrosine kinase inhibitors in NSCLC. Here, we present a 76-year-old male smoker harboring LUAD with a novel p. N771delinsGF deletion/insertion mutation in EGFR ex20 transdifferentiating from advanced LUSC after chemoradiotherapy. The patient presented reduced hydrothorax and relieved tightness with the treatment of nivolumab plus docetaxel and carboplatin after the failure of second-line chemotherapy. The case highlights the importance of rebiopsy and molecular retesting after the progression of lung cancer and supports the idea that the combination of immune checkpoint blockade and chemotherapy may be an attractive option for patients with EGFR ex20 mutations associated with LUSC-LUAD transformation.

Incorporating p-Phenylene as an Electron-Donating Group into Graphitic Carbon Nitride for Efficient Charge Separation.

Low charge-separation transport efficiency resulting from structural defects largely limits photocatalytic hydrogen production over polymeric graphitic carbon nitride (PCN) photocatalyst. Herein, an electron-donating group, namely p-phenylene, is incorporated into PCN by a polycondensation reaction between carbon nitride and p-phenylenediamine (or p-benzoquinone) to repair the structural defects. The p-phenylene-modified PCN exhibits an almost fivefold increase in H2 evolution, a threefold increase in photocurrent density, and higher nonradiative rate (0.285 ns-1 ). Spectroscopic studies confirm that p-phenylene tends to bridge the heptazine-based oligomers through a polycondensation reaction. Theoretical calculations reveal that anchoring of the heptazine units by p-phenylene induces localization of h+ and e- on the phenylene and melem moieties, respectively, which effectively separates the charge carriers. This strategy provides an opportunity to overcome structural defects in carbon nitride for efficient photocatalytic solar energy conversion.

Synergistic Effects of Sm and C Co-Doped Mixed Phase Crystalline TiO2 for Visible Light Photocatalytic Activity.

Mixed phase TiO2 nanoparticles with element doping by Sm and C were prepared via a facile sol-gel procedure. The UV-Vis light-diffuse reflectance spectroscopy analysis showed that the absorption region of co-doped TiO2 was shifted to the visible-light region, which was attributed to incorporation of samarium and carbon into the TiO2 lattice during high-temperature reaction. Samarium effectively decreased the anatase-rutile phase transformation. The grain size can be controlled by Sm doping to achieve a large specific surface area useful for the enhancement of photocatalytic activity. The photocatalytic activities under visible light irradiation were evaluated by photocatalytic degradation of methylene blue (MB). The degradation rate of MB over the Sm-C co-doped TiO2 sample was the best. Additionally, first-order apparent rate constants increased by about 4.3 times compared to that of commercial Degusssa P25 under the same experimental conditions. Using different types of scavengers, the results indicated that the electrons, holes, and •OH radicals are the main active species for the MB degradation. The high visible-light photocatalytic activity was attributed to low recombination of the photo-generated electrons and holes which originated from the synergistic effect of the co-doped ions and the heterostructure.

A charge-adaptive nanosystem for prolonged and enhanced in vivo antibiotic delivery.

Herein we report on a charge-adaptive nanosystem for prolonged and enhanced in vivo antibiotic delivery. The nanocarrier achieves acid-dependent charge conversion, thus prolonging the circulation time and enhancing antibiotic accumulation in subcutaneous inflammation models.

Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff's base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff's base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

Targeting of NHERF1 through RNA interference inhibits the proliferation and migration of metastatic prostate cancer cells.

The present study aimed to investigate the effects of Na+/H+ exchanger regulatory factor 1 (NHERF1) gene knockdown, using short-hairpin RNA (shRNA), on the malignant behaviors of prostate cancer cells. A pSuper.puro NHERF1 shRNA vector was transfected into PC-3M prostate cancer cells using Lipofectamine 2000. Stable cell lines were obtained and NHERF1 knockdown was verified through western blot analysis. MTT assays were then used to measure PC-3M cell proliferation; in addition, cell migration was assessed using a wound healing assay. Flow cytometry was employed in order to determine the effects of NHERF1 knockdown on apoptosis. Expression levels of apoptotic pathway proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein were then determined by western blot analysis. The results demonstrated that shRNA knockdown of NHERF1 significantly suppressed the proliferation of PC-3M cells by >50%. In addition, knockdown of NHERF1 significantly inhibited the migration of PC-3M cells. PC-3M cells harboring NHERF1 shRNA exhibited significantly increased apoptosis, with an ~4-fold increase compared with that of the parental PC-3M cells and cells transfected with an empty vector. Furthermore, the results revealed that knockdown of NHERF1 reduced the protein expression of Bcl-2, although the expression of Bax was unaltered. In conclusion, NHERF1 knockdown using shRNA inhibited the proliferation and migration of PC-3M cells and promoted apoptosis, highlighting the role of NHERF1 in prostate cancer progression.

[Application of target peptide in siRNA delivery 
for the research of lung cancer therapy].

Lung cancer is considered a kind of malignant tumors of the world highest incidence. As it is not sensitive to chemotherapy and easy to produce drug resistance, improving effect of anticancer drug becomes a research focus recent years. siRNA, small interfering RNA, can silence complemenary mRNA which is a kind of gene therapy. Target peptides are small molecular peptides which specifically bind to tumor surface materials. When used with siRNA, target peptides can increase accumulation of siRNA in tumor cells and enhance the silencing effect. As result, drug resistance of lung cancer reduced and the effect of therapy can be improved. This method provides new direction and strategy for targeted therapy of lung cancer. This article will make a brief overview of target peptides applying in siRNA dilivery for the research of lung cancer treatment.

Synthesis of carbon black/carbon nitride intercalation compound composite for efficient hydrogen production.

The photoactivity of g-C3N4 is greatly limited by its high recombination rate of photogenerated carriers. Coupling g-C3N4 with other materials has been demonstrated to be an effective way to facilitate the separation and transport of charge carriers. Herein we report a composite of conductive carbon black and carbon nitride intercalation compound synthesized through facile one-step molten salt method. The as-prepared carbon black/carbon nitride intercalation compound composite was characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM), UV-vis absorption spectrum and photoluminescence spectroscopy (PL). The carbon black nanoparticles, homogeneously dispersed on the surface of carbon nitride intercalation compound, efficiently enhanced separation and transport of photogenerated carriers, thus improving the visible-light photocatalytic activity. The composite of 0.5 wt% carbon black and carbon nitride intercalation compound exhibited a H2 production rate of 68.9 µmol h(-1), which is about 3.2 times higher than hydrogen production on pristine carbon nitride intercalation compound.

Ion coordination significantly enhances the photocatalytic activity of graphitic-phase carbon nitride.

Here we report a facile surface modification route, metal ion coordination, to improve the photoactivity of carbon nitride. The metal ions coordinating into the plane of g-C3N4 significantly contribute to a drastic increase of the photocatalytic activity in solar hydrogen production as well as in the photodegradation of organic pollutants.

Towards efficient solar hydrogen production by intercalated carbon nitride photocatalyst.

The development of efficient photocatalytic material for converting solar energy to hydrogen energy as viable alternatives to fossil-fuel technologies is expected to revolutionize energy shortage and environment issues. However, to date, the low quantum yield for solar hydrogen production over photocatalysts has hindered advances in the practical applications of photocatalysis. Here, we show that a carbon nitride intercalation compound (CNIC) synthesized by a simple molten salt route is an efficient polymer photocatalyst with a high quantum yield. We found that coordinating the alkali metals into the C-N plane of carbon nitride will induce the un-uniform spatial charge distribution. The electrons are confined in the intercalated region while the holes are in the far intercalated region, which promoted efficient separation of photogenerated carriers. The donor-type alkali metal ions coordinating into the nitrogen pots of carbon nitrides increase the free carrier concentration and lead to the formation of novel nonradiative paths. This should favor improved transport of the photogenerated electron and hole and decrease the electron-hole recombination rate. As a result, the CNIC exhibits a quantum yield as high as 21.2% under 420 nm light irradiation for solar hydrogen production. Such high quantum yield opens up new opportunities for using cheap semiconducting polymers as energy transducers.

Tricyclometalated iridium complexes as highly stable photosensitizers for light-induced hydrogen evolution.

The development of an efficient and stable artificial photosensitizer for visible-light-driven hydrogen production is highly desirable. Herein, a new series of charge-neutral, heteroleptic tricyclometalated iridium(III) complexes, [Ir(thpy)2(bt)] (1-4; thpy = 2,2'-thienylpyridine, bt = 2-phenylbenzothiazole and its derivatives), were systematically synthesized and their structural, photophysical, and electrochemical properties were established. Three solid-state structures were studied by X-ray crystallographic analysis. This design offers the unique opportunity to drive the metal-to-ligand charge-transfer (MLCT) band to longer wavelengths for these iridium complexes. We describe new molecular platforms that are based on these neutral iridium complexes for the production of hydrogen through visible-light-induced photocatalysis over an extended period of time in the presence of [Co(bpy)3](2+) and triethanolamine (TEOA). The maximum amount of hydrogen was obtained under constant irradiation over 72 h and the system could regenerate its activity upon the addition of cobalt-based catalysts when hydrogen evolution ceased. Our results demonstrated that the dissociation of the [Co(bpy)3](2+) catalyst contributed to the loss of catalytic activity and limited the long-term catalytic performance of the systems. The properties of the neutral complexes are compared in detail to those of two known non-neutral bpy-type complexes, [Ir(thpy)2(dtb-bpy)](+) (5) and [Ir(ppy)2(dtb-bpy)](+) (6; ppy = 2-phenylpyridine, dtb-bpy = 4,4'-di-tert-butyl-2,2'-dipyridyl). This work is expected to contribute toward the development of long-lasting solar hydrogen-production systems.