Arginine Supplementation Targeting Tumor-Killing Immune Cells Reconstructs the Tumor Microenvironment and Enhances the Antitumor Immune Response.

The tumor microenvironment (TME) is characterized by several immunosuppressive factors, of which weak acidity and l-arginine (l-arg) deficiency are two common features. A weak acidic environment threatens the survival of immune cells, and insufficient l-arg will severely restrain the effect of antitumor immune responses, both of which affect the efficiency of cancer treatments (especially immunotherapy). Meanwhile, l-arg is essential for tumor progression. Thus, two strategies, l-arg supplementation and l-arg deprivation, are developed for cancer treatment. However, these strategies have the potential risk of promoting tumor growth and impairing immune responses, which might lead to a paradoxical therapeutic effect. It is optimal to limit the l-arg availability of tumor cells from the microenvironment while supplying l-arg for immune cells. In this study, we designed a multivesicular liposome technology to continuously supply alkaline l-arg, which simultaneously changed the acidity and l-arg deficiency in the TME, and by selectively knocking down the CAT-2 transporter, l-arg starvation of tumors was maintained while tumor-killing immune cells were enriched in the TME. The results showed that our strategy promoted the infiltration and activation of CD8+ T cells in tumor, increased the proportion of M1 macrophages, inhibited melanoma growth, and prolonged survival. In combination with anti-PD-1 antibody, our strategy reversed the low tumor response to immune checkpoint blockade therapy, showing a synergistic antitumor effect. Our work provided a reference for improving the TME combined with regulating nutritional competitiveness to achieve the sensitization of immunotherapy.

Analgesic effect of single-shot ropivacaine at different layers of the surgical site in primary total hip arthroplasty: a randomised, controlled, observer-blinded study.

OBJECTIVES: The aim of this study was to evaluate the efficacy of local infiltration anaesthesia (LIA) during primary total hip arthroplasty (THA) via a posterolateral approach under general anaesthesia and to compare the efficacy of LIA in all layers with LIA in the deep and superficial fascia. PATIENTS AND METHODS: One hundred twenty patients were randomised into three groups: LIA in the deep and superficial fascia (group A), LIA in all layers (group B) and the control (group C). The primary outcomes were the visual analogue scale (VAS) pain scores at rest and on movement within 72 h (h) postoperatively. The secondary outcomes included opioid consumption, patient satisfaction, range of motion (ROM), straight leg raise completion rate, length of hospital stay, opioid-related side effects and wound complications. We followed the patients until 6 months after discharge. RESULTS: At 2 and 6 h, groups A and B had lower resting VAS scores than group C (p < 0.01); at 12 h, group B had a lower resting VAS score than group C (p < 0.05). At 6 and 12 h, the movement VAS scores in groups A and B were lower than those in group C (p < 0.01). Groups A and B had similar VAS scores during the observation period. Groups A and B had higher levels of patient satisfaction than group C (p = 0.03 and p = 0.018, respectively). Opioid consumption was similar in the three groups. There were no significant differences in the other secondary outcomes amongst the three groups. No difference was found in hip rehabilitation or chronic pain during the follow-up period. CONCLUSION: Single-shot LIA with ropivacaine alone reduces the pain score during the first 12 postoperative hours and improves patients' satisfaction with THA. LIA in the deep and superficial fascia and LIA in all layers have similar analgesic effects. LIA in the deep and superficial fascia may be an alternative method to LIA in all layers.

Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death.

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an 'eat me' signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8+ T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.

Laser Immunotherapy in Combination with Perdurable PD-1 Blocking for the Treatment of Metastatic Tumors.

A convenient and feasible therapeutic strategy for malignant and metastatic tumors was constructed here by combining photothermal ablation (PTA)-based laser immunotherapy with perdurable PD-1 blockade immunotherapy. Hollow gold nanoshells (HAuNS, a photothermal agent) and AUNP12 (an anti PD-1 peptide, APP) were co-encapsulated into poly(lactic- co-glycolic) acid (PLGA) nanoparticles. Unlike monoclonal PD-1/PD-L1 antibodies, PD-1 peptide inhibitor shows lower cost and immunotoxicity but needs frequent administration due to its rapid clearance in vivo. Our data here showed that the formed HAuNS- and APP-loaded PLGA nanoparticles (AA@PN) could maintain release periods of up to 40 days for the peptide, and a single intratumoral injection of AA@PN could replace the frequent administration of free APP. After the administration of AA@PN and irradiation with a near-infrared laser at the tumor site, an excellent killing effect on the primary tumor cells was achieved by the PTA. The nanoparticles also played a vaccine-like role under the adjuvant of cytosine-phospho-guanine (CpG) oligodeoxynucleotide and generated a localized antitumor-immune response. Furthermore, sustained APP release with laser-dependent transient triggering could induce the blockage of PD-1/PD-L1 pathway to activate T cells, thus subsequently generating a systemic immune response. Our data demonstrated that the PTA combined with perdurable PD-1 blocking could efficiently eradicate the primary tumors and inhibit the growth of metastatic tumors as well as their formation. The present study provides a promising therapeutic strategy for the treatment of advanced cancer with metastasis and presents a valuable reference for obtaining better outcomes in clinical cancer immunotherapy.

Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy.

An active cell membrane-camouflaged nanoparticle, owning to membrane antigens and membrane structure, can achieve special properties such as specific recognition, long blood circulation, and immune escaping. Herein, we reported a cancer cell membrane-cloaked nanoparticle system as a theranostic nanoplatform. The biomimetic nanoparticles (indocyanine green (ICG)-loaded and cancer cell membrane-coated nanoparticles, ICNPs) exhibit a core-shell nanostructure consisting of an ICG-polymeric core and cancer cell membrane shell. ICNPs demonstrated specific homologous targeting to cancer cells with good monodispersity, preferable photothermal response, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. Benefited from the functionalization of the homologous binding adhesion molecules from cancer cell membranes, ICNPs significantly promoted cell endocytosis and homologous-targeting tumor accumulation in vivo. Moreover, ICNPs were also good at disguising as cells to decrease interception by the liver and kidney. Through near-infrared (NIR)-FL/PA dual-modal imaging, ICNPs could realize real-time monitored in vivo dynamic distribution with high spatial resolution and deep penetration. Under NIR laser irradiation, ICNPs exhibited highly efficient photothermal therapy to eradicate xenografted tumor. The robust ICNPs with homologous properties of cancer cell membranes can serve as a bionic nanoplatform for cancer-targeted imaging and phototherapy.

Lipid-Polymer Nanoparticles for Folate-Receptor Targeting Delivery of Doxorubicin.

A biocompatible PLGA-lipid hybrid nanoparticles (NPs) was developed for targeted delivery of anticancer drugs with doxorubicin (DOX). The hydrodynamic diameter and zeta potential of DOX-loaded PLGA-lipid NPs (DNPs) were affected by the mass ratio of Lipid/PLGA or DSPE-PEG-COOH/Lecithin. At the 1:20 drug/polymer mass ratio, the mean hydrodynamic diameter of DNPs was the lowest (99.2 1.83 nm) and the NPs presented the encapsulation efficiency of DOX with 42.69 1.30%. Due to the folate-receptor mediated endocytosis, the PLGA-lipid NPs with folic acid (FA) targeting ligand showed significant higher uptake by folate-receptor-positive MCF-7 cells as compared to PLGA-lipid NPs without folate. Confocal microscopic observation and flow cytometry analysis also supported the enhanced cellular uptake of the FA-targeted NPs. The results indicated that the FA-targeted DNPs exhibited higher cytotoxicity in MCF-7 cells compared with non-targeted NPs. The lipid-polymer nanoparticles provide a solution of biocompatible nanocarrier for cancer targeting therapy.

Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles.

A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near-infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect.

Robust ICG theranostic nanoparticles for folate targeted cancer imaging and highly effective photothermal therapy.

Folic acid (FA)-targeted indocyanine green (ICG)-loaded nanoparticles (NPs) (FA-INPs) were developed to a near-infrared (NIR) fluorescence theranostic nanoprobe for targeted imaging and photothermal therapy of cancer. The FA-INPs with good monodispersity exhibited excellent size and fluorescence stability, preferable temperature response under laser irradiation, and specific molecular targeting to MCF-7 cells with FA receptor overexpression, compared to free ICG. The FA-INPs enabled NIR fluorescence imaging to in situ monitor the tumor accumulation of the ICG. The cell survival rate assays in vitro and photothermal therapy treatments in vivo indicated that FA-INPs could efficiently targeted and suppressed MCF-7 cells and xenograft tumors. Hence, the FA-INPs are notable theranostic NPs for imaging-guided cancer therapy in clinical application.