A nanodrug provokes antitumor immune responses via synchronous multicellular regulation for enhanced cancer immunotherapy.

Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

Reduction-sensitive polymeric carrier for the targeted delivery of a quinazoline derivative for enhanced generation of reactive oxygen species against cancer.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors and the development of effective therapeutics against HCC is urgently needed. A novel quinazoline derivative 04NB-03 (Qd04) has been proved to be highly effective against HCC without obvious toxic side-effects. However, the poor water solubility and low bioavailability in vivo severely limit its clinical application. In addition, Qd04 kills tumor cells by inducing an accumulation of endogenous reactive oxygen species (ROS), which is highly impeded by the overexpression of glutathione (GSH) in tumor cells. Herein, we designed a disulfide cross-linked polyamino acid micelle to deliver Qd04 for HCC therapy. The disulfide linkage not only endowed a tumor-targeted delivery of Qd04 by responding to tumor cell GSH but also depleted GSH to achieve increased levels of ROS generation, which improved the therapeutic efficiency of Qd04. Both in vitro and in vivo results demonstrated that the synthesized nanodrug exerted good anti-hepatoma effects, which provided a potential application for HCC therapy in clinics.

A nanodrug simultaneously inhibits pancreatic stellate cell activation and regulatory T cell infiltration to promote the immunotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer.

Stable high-oxidation-state complex in situ Mn(V)-Mn(III) transition to achieve highly efficient cervical cancer therapy.

Designing metal complexes to target the vulnerable redox balance in cancer cells is a promising strategy to realize successful cancer therapy. The synthesized stable nitridomanganese(V) complex MnV(N) (salen) not only reacts with GSH to achieve in situ Mn(V)-Mn(III) transformation to down-regulate the antioxidant system, but also catalyzes H2O2 to higher oxidation capacity ROS to up-regulate the intracellular oxidative level, finally resulting in cancer cell death.

Porous chitosan/partially reduced graphene oxide/diatomite composite as an efficient adsorbent for quantitative colorimetric detection of pesticides in a complex matrix.

On-site, instrument free quantitative analysis of pesticides is of significant importance for food safety control. However, it is still a great challenge for pesticide detection in food via the current visual detection methods due to the presence of interferents in a complex matrix. In this study, a complex tea matrix had a strong effect on a gold nanoparticles (Au NPs) based colorimetric sensor for the detection of pesticides. Here, a porous chitosan/partially reduced graphene oxide/diatomite (CS/prGO/DM) composite was successfully synthesized via a facile hydrothermal treatment. It could act as an efficient adsorbent for removing different types of tea interferents. A colorimetric sensing platform for the quantitative detection of pesticides in a complex matrix was successfully established. The color changes of the aggregation of Au NPs induced by pesticides were captured using the camera of a smartphone and the images were processed with average RGB (red, green, and blue) values obtained using self-developed software. The G/R values and A700/525 values obtained from UV-vis spectra could be used for quantitative analysis of pesticides. The limits of detection of phosalone and thiram in tea were 90 nM and 13.8 nM, respectively. It is expected that graphene-based materials are attractive for wide application of on-site colorimetric quantitative detection in a variety of fields like environmental protection, food safety and bioanalysis.