A comprehensive study of the colloidal properties, biocompatibility, and synergistic antioxidant actions of Antarctic krill phospholipids.

Excipient selection is crucial to address the oxidation and solubility challenges of bioactive substances, impacting their safety and efficacy. AKPL, a novel ω-3 polyunsaturated fatty acids (PUFAs) esterified phospholipid derived from Antarctic krill, demonstrates unique antioxidant capabilities and synergistic effects. It exhibits pronounced surface activity and electronegativity at physiological pH, as evidenced by a critical micelle concentration (CMC) of 0.15 g/L and ζ-potential of -49.9 mV. In aqueous environments, AKPL self-assembles into liposomal structures, offering high biocompatibility and promoting cell proliferation. Its polyunsaturated bond-rich structure provides additional oxidation sites, imparting antioxidant properties superior to other phospholipids like DSPC and DOPC. Additionally, AKPL augments the efficacy of lipophilic antioxidants, such as alpha-tocopherol and curcumin, in aqueous media through both intermolecular and intramolecular interactions. In sum, AKPL emerges as an innovative unsaturated phospholipid, offering new strategies for encapsulating and delivering oxygen-sensitive agents.

Self-delivery photothermal-boosted-nanobike multi-overcoming immune escape by photothermal/chemical/immune synergistic therapy against HCC.

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to "cold" tumors' immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC.

A Polymer Nanocomposite with Strong Full-Spectrum Solar Absorption and Infrared Emission for All-Day Thermal Energy Management and Conversion.

Realizing efficient energy utilization from the heat source of the sun and the cold source of outer space is of great significance for addressing the global energy and environmental crisis. Materials with ideal full-spectrum solar absorption and infrared emission are highly desirable for adapting to the continuous weather dynamic throughout the day, nonetheless, their development remains challenging. Here, a polymer nanocomposite with full-spectrum strong solar (280-2500 nm) absorption ranging from 88.8% to 94.8% with an average value of 93.2% and full-spectrum high infrared (8-13 µm) emission ranging from 81.3% to 90.0% with an average value of 84.2%, is reported by melt-processing polypropylene and uniformly dispersed low-loading MXene nanosheets (1.9 vol%). The nanocomposite can achieve daytime photothermal enhancement of ≈50 °C and nighttime radiative cooling of 8 °C. The temperature difference throughout the day ensures all-day uninterrupted thermoelectric generation, yielding a power density output of 1.5 W m-2 (daytime) and 7.9 mW m-2 (nighttime) in real outdoor environment without any additional energy consumption. This work provides an impressive polymer nanocomposite with ideal full-spectrum solar absorption and infrared emission for all-day uninterrupted thermal energy management and conversion.

Distribution characteristics of perioperative deep vein thrombosis (DVT) and risk factors of postoperative DVT exacerbation in patients with thoracolumbar fractures caused by high-energy injuries.

OBJECTIVE: To investigate the distribution characteristics of perioperative deep venous thrombosis (DVT) in patients with thoracolumbar fractures caused by high-energy injuries and analyze the risk factors of postoperative DVT exacerbation. METHODS: From October 2016 to July 2021, a total of 550 patients with thoracolumbar fractures due to high-energy injuries in our hospital were retrospectively analyzed. Both lower limbs were examined by ultrasound before and after operation. Depending on whether the postoperative DVT was exacerbating, the group was divided into a DVT exacerbation group and a non-DVT exacerbation group. Clinical data were used to study the characteristics of perioperative DVT. Logistic regression analysis and receiver operating characteristic (ROC) curve were used to explore the risk factors of postoperative DVT exacerbation. RESULTS: DVT was found in 97 patients before operation, including 78 cases of distal thrombus, 6 cases of proximal thrombus, and 13 cases of mixed thrombus. Postoperative DVT increased to 116, including 87 distal thrombus, 10 proximal thrombus, and 19 mixed thrombus. The intermuscular vein was the most easily involved vein. Compared with lumbar fractures, thoracic fractures were more likely to have postoperative proximal thrombus (P=0.014). There were 48 cases of thrombus exacerbation after operation. Logistic regression analysis revealed that age, lower extremity muscle strength, time from injury to operation, and blood loss were risk factors for postoperative DVT exacerbation. CONCLUSIONS: The intermuscular vein is the most easily involved vein. The anatomical distribution of DVT at different fracture sites is different, and patients with thoracic fractures are more likely to have proximal DVT after operation. Age, lower extremity muscle strength, time from injury to operation, and blood loss were risk factors for postoperative DVT exacerbation.

Nomogram for predicting postoperative deep vein thrombosis in patients with spinal fractures caused by high-energy injuries.

OBJECTIVE: Deep venous thrombosis (DVT) is a common complication in patients with spinal fractures caused by high-energy injuries. Early identification of patients at high risk of postoperative DVT is essential for the prevention of thrombosis. This study aimed to develop and validate a prediction model based on a nomogram to predict DVT in patients with spinal fractures caused by high-energy injuries. METHODS: Clinical data were collected from 936 patients admitted to our hospital between January 2016 and December 2021 with spinal fractures caused by high-energy injuries. Multivariate logistic regression analysis was used to identify the risk factors for postoperative DVT and to develop a nomogram. The predictive performance of the nomogram was evaluated by the receiver operating characteristic (ROC) curve and calibration curve. RESULTS: The incidence of preoperative DVT was 15.38% (144/936). The postoperative incidence of DVT was 20.5% (192/936). The multivariate analysis revealed that age, operation time, blood transfusion, duration of bed rest, American Spinal Injury Association (ASIA) score and D-dimer were risk factors for postoperative DVT. The area under the ROC curve of the nomogram was 0.835 and the calibration curve showed good calibration. CONCLUSIONS: The nomogram showed a good ability to predict postoperative DVT in patients with spinal fractures caused by high-energy injuries, which may benefit pre- and postoperative DVT prophylaxis strategy development.

A Novel Approach for Apple Freshness Prediction Based on Gas Sensor Array and Optimized Neural Network.

Apple is an important cash crop in China, and the prediction of its freshness can effectively reduce its storage risk and avoid economic loss. The change in the concentration of odor information such as ethylene, carbon dioxide, and ethanol emitted during apple storage is an important feature to characterize the freshness of apples. In order to accurately predict the freshness level of apples, an electronic nose system based on a gas sensor array and wireless transmission module is designed, and a neural network prediction model using an improved Sparrow Search Algorithm (SSA) based on chaotic sequence (Tent) to optimize Back Propagation (BP) is proposed. The odor information emitted by apples is studied to complete an apple freshness prediction. Furthermore, by fitting the relationship between the prediction coefficient and the input vector, the accuracy benchmark of the prediction model is set, which further improves the prediction accuracy of apple odor information. Compared with the traditional prediction method, the system has the characteristics of simple operation, low cost, reliable results, mobile portability, and it avoids the damage to apples in the process of freshness prediction to realize non-destructive testing.

Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling.

Targeting tumour immunosuppressive microenvironment is a crucial strategy in immunotherapy. However, the critical role of the tumour lymph node (LN) immune microenvironment (TLIME) in the tumour immune homoeostasis is often ignored. Here, we present a nanoinducer, NIL-IM-Lip, that remodels the suppressed TLIME via simultaneously mobilizing T and NK cells. The temperature-sensitive NIL-IM-Lip is firstly delivered to tumours, then directed to the LNs following pH-sensitive shedding of NGR motif and MMP2-responsive release of IL-15. IR780 and 1-MT induces immunogenic cell death and suppress regulatory T cells simultaneously during photo-thermal stimulation. We demonstrate that combining NIL-IM-Lip with anti-PD-1 significantly enhances the effectiveness of T and NK cells, leading to greatly suppressed tumour growth in both hot and cold tumour models, with complete response in some instances. Our work thus highlights the critical role of TLIME in immunotherapy and provides proof of principle to combine LN targeting with immune checkpoint blockade in cancer immunotherapy.

Patellar development after patella instability and early reduction in growing rabbits.

BACKGROUND: Patella-shaped disorder has been considered as a predisposing factor for patella instability. But the influence of early patella reduction for patellar development remains unclear. This study aimed to evaluate whether early operation in patella instability could improve patella morphology in growing rabbits. METHODS: Fifty rabbits (1-month-old) were included in the study. The control group underwent no surgical procedures. The two experimental groups (reduction group and non-reduced group), underwent medial soft tissue restraint release surgery. The reduction group, rabbits underwent the medial soft tissue sutura surgery in order to stabilize the patella 2 months after release surgery. The non-reduced group, rabbits did not undergo suture surgery. Computed Tomography (CT) scans analysis in two experimental endpoints (2, 5 months after release surgery) were selected to evaluate the transverse diameter, thickness, Wiberg index and Wiberg angle. Gross observation was conducted to assess morphological changes of the patella. RESULTS: CT scans showed significant difference in the mean transverse diameter, Wiberg angle between the two experimental groups and the control group 2 months after release surgery. 5 months after release surgery, the indices of patella were found no statistically difference in the reduction group versus the control group. However, the transverse diameter, Wiberg angle in the non-reduced group were significantly differences than that in the reduction group (P < 0.05). Gross observation showed a flattened articular surface of the patella in the non-reduced group. CONCLUSIONS: The results indicated that patella instability may lead to patella-shaped disorder, showing a flattened morphology. Early patella reduction can improve the patella morphology in growing rabbits.

Dynamic Changes and Relevant Factors of Perioperative Deep Vein Thrombosis in Patients with Thoracolumbar Fractures Caused by High-Energy Injuries.

OBJECTIVE: To investigate the dynamic changes and relevant factors of deep vein thrombosis (DVT) in patients with thoracolumbar fractures caused by high-energy injuries. METHODS: From January 2016 to June 2021, a total of 655 patients with thoracolumbar fractures who underwent surgical treatment in our hospital were retrospectively analyzed. The patients were examined by preoperative and postoperative ultrasonography, and divided into thrombus growth group, thrombus invariant group, and thrombus regression group according to the preoperative and postoperative ultrasonographic results. Medical record data, including demographic data, surgical data, and laboratory results, were collected and the differences in various factors among the groups were compared. RESULTS: DVT was found in 99 patients (15.1%, 99/655) before surgery, including 79 cases of distal thrombus, 7 cases of proximal thrombus, and 13 cases of mixed thrombus. The incidence of postoperative DVT increased to 20.6% (134/655), including 96 cases of distal thrombus, 15 cases of proximal thrombus, and 23 cases of mixed thrombus. Among them, 39.7% had thrombus growth, 49.3% had thrombus basically unchanged and 11.0% had thrombolysis. There were significant differences in age, lower extremity muscle strength, time from trauma to surgery, operation time, blood loss, blood transfusion, and post 3-D-dimer among the three groups. CONCLUSIONS: In patients with thoracolumbar fractures caused by high-energy injuries, the majority of patients with DVT do not change or grow after surgery, and only a few of them have thrombolysis. Younger age, lower extremity motor, and fewer blood transfusion contribute to thrombolysis. Delayed surgical intervention, longer operation time, and higher blood loss can lead to thrombosis growth. Post 3-D-dimer is closely related to the dynamic changes of thrombus.

Multi-therapies Based on PARP Inhibition: Potential Therapeutic Approaches for Cancer Treatment.

The nuclear enzymes called poly(ADP-ribose)polymerases (PARPs) are known to catalyze the process of PARylation, which plays a vital role in various cellular functions. They have become important targets for the discovery of novel antitumor drugs since their inhibition can induce significant lethality in tumor cells. Therefore, researchers all over the world have been focusing on developing novel and potent PARP inhibitors for cancer therapy. Studies have shown that PARP inhibitors and other antitumor agents, such as EZH2 and EGFR inhibitors, play a synergistic role in cancer cells. The combined inhibition of PARP and the targets with synergistic effects may provide a rational strategy to improve the effectiveness of current anticancer regimens. In this Perspective, we sum up the recent advance of PARP-targeted agents, including single-target inhibitors/degraders and dual-target inhibitors/degraders, discuss the fundamental theory of developing these dual-target agents, and give insight into the corresponding structure-activity relationships of these agents.

Two-Wave Variable Nanotheranostic Agents for Dual-Mode Imaging-Guided Photo-Induced Triple-Therapy for Cancer.

Photothermal therapy (PTT) is a promising strategy for cancer treatment, but its clinical application relies heavily on accurate tumor positioning and effective combination. Nanotheranostics has shown superior application in precise tumor positioning and treatment, bringing potential opportunities for developing novel PTT-based therapies. Here, a nanotheranostic agent is proposed to enhance magnetic resonance imaging (MRI)/ near-infrared fluorescence imaging (NIRFI) imaging-guided photo-induced triple-therapy for cancer. Thermosensitive liposomes co-loaded with SPIONs/IR780 and Abemaciclib (SIA-TSLs), peptide ACKFRGD, and click group 2-cyano-6-amino-benzothiazole (CABT) are co-modified on the surface of SIA-TSLs to form SIA-αTSLs. ACKFRGD can be hydrolyzed to expose the 1, 2-thiolamino groups in the presence of cathepsin B in tumors, which click cycloaddition with the cyano group on CABT, resulting in the formation of SIA-αTSLs aggregates. The aggregation of SIA-αTSLs in tumors enhances the MRI/NIRFI imaging capability and enables precise PTT. Photo-induced triple-therapy enhances precision cancer therapy. First, PTT ablates specific tumors and induces ICD via localized photothermal. Second, local tumor heating promotes the rupture of SIA-αTSLs, which release Abemaciclib to block the tumor cell cycle and inhibit Tregs proliferation. Third, injecting GM-CSF into tumor tissue leads to recruitment of dendritic cells and initiation of antitumor immunity. Collectively, these results present a promising nanotheranostic strategy for future cancer therapy.

Artificial Assembled Macrophage Co-Deliver Black Phosphorus Quantum Dot and CDK4/6 Inhibitor for Colorectal Cancer Triple-Therapy.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Amphiphilic small molecular mates match hydrophobic drugs to form nanoassemblies based on drug-mate strategy.

Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-of-concept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation, we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction. Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.

Multipoint Costriking Nanodevice Eliminates Primary Tumor Cells and Associated-Circulating Tumor Cells for Enhancing Metastasis Inhibition and Therapeutic Effect on HCC.

Eliminating primary tumor ("roots") and inhibiting associated-circulating tumor cells (associated-CTCs, "seeds") are vital issues that need to be urgently addressed in cancer therapy. Associated-CTCs, which include single CTCs, CTC clusters, and CTC-neutrophil clusters, are essential executors in metastasis and the cause of metastasis-related death in cancer patients. Herein, a "roots and seeds" multipoint costriking nanodevice (GV-Lipo/sorafenib (SF)/digitoxin (DT)) is developed to eliminate primary tumors and inhibit the spread of associated-CTCs for enhancing metastasis inhibition and the therapeutic effect on hepatocellular carcinoma (HCC). GV-Lipo/SF/DT eliminates primary tumor cells by the action of SF, thus reducing CTC production at the roots and improving the therapeutic effect on HCC. GV-Lipo/SF/DT inhibits associated-CTCs effectively via the enhanced identification and capture effects of glypican-3 and/or vascular cell adhesion molecule 1 (VCAM1) targeting, dissociating CTC clusters using DT, blocking the formation of CTC-neutrophil clusters using anti-VCAM1 monoclonal antibody, and killing CTCs with SF. It is successfully verified that GV-Lipo/SF/DT increases the CTC elimination efficiency in vivo, thus effectively preventing metastasis, and shows enhanced antitumor efficacy in both an H22-bearing tumor model and orthotopic HCC models. Overall, the "roots and seeds" multipoint costriking strategy may open a new cancer treatment model for the clinic.

Depleting Tumor Infiltrating B Cells to Boost Antitumor Immunity with Tumor Immune-Microenvironment Reshaped Hybrid Nanocage.

Tumor infiltrating B cells (TIBs)-dependent immunotherapy has emerged as a promising method for tumor treatment. Depleting TIBs to boost antitumor immunity is a highly desirable yet challenging approach to TIBs-dependent immunotherapy. Herein, a tumor immune-microenvironment reshaped hybrid nanocage CPN-NLI/MLD coloaded with the Bruton's tyrosine kinase inhibitor ibrutinib, and cytotoxic drug docetaxel was developed for stepwise targeting TIBs and tumor cells, respectively. The tumor microenvironment responsive CPN-NLI/MLD promoted charge reversal and size reduction under acidic conditions (pH < 6.5). The accumulation of CPN-NLI/MLD in tumor tissues was achieved through CD13 targeting, and cellular uptake was increased due to the differ-targeting delivery. Targeting of docetaxel to tumor cells was achieved by the interaction of α-MSH modified on inner docetaxel-particle MLD and melanocortin-1 receptor on the surface of tumor cells. Targeting of ibrutinib to TIBs was achieved by the interaction of Neu5Ac modified on inner ibrutinib-particle NLI and CD22 on the surface of TIBs. The boosted antitumor immunity was achieved mainly by the inhibition of Bruton's tyrosine kinase activation mediated by ibrutinib, which reduced the proportion of TIBs, enhanced infiltration of CD8+ and CD4+ T cells, increased the secretion of immunogenic cytokines including IL-2 and IFN-γ, and inhibited the proliferation of regulatory T cells and secretion of immunosuppressive cytokines including IL-10, IL-4, and TGF-ß. Furthermore, CPN-NLI/MLD improved the antitumor efficiency of chemoimmunotherapy by reshaping tumor immune-microenvironment by TIBs depletion. Taken together, CPN-NLI/MLD represents a promising method for effective tumor treatment and combination therapy by TIBs-dependent immunotherapy.

Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies.

Immune checkpoint antibodies have emerged as novel therapeutics, while many patients are refractory. Researchers had identified tumor-associated macrophages (TAMs) is the pivotal factor involved in immune resistance and that manipulation of TAMs functions would improve the immunotherapies effectively. NF-κB pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-κB pathway could achieve both re-polarization M2 TAMs and downregulation the expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1) on TAMs to improve the effect of immunotherapies. Here, IMD-0354, inhibitor of NF-κB pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were co-loaded in matrix metalloproteinase 2 (MMP2) responsive and tumor target nanogels (P/ML-NNG). P/ML-NNG could co-deliver drugs to tumor site, disintegrated by MMP2 and release drugs to different targets. Evaluation of PD-1 expression, inhibition of NF-κB pathway, expression of PD-L1 on M2 TAMs and M2 TAMs re-polarization demonstrated that P/ML-NNG could block the PD-1/PD-L1 and NF-κB pathways simultaneously. Evaluation of CD4 + T cells, CD8 + T cells, Tregs, cytokines and antitumor immunity confirmed that IMD-0354 could improve the immunotherapies effectively. Those results provided forceful references for tumor immunetherapy.

High-Specific Isolation and Instant Observation of Circulating Tumour Cell from HCC Patients via Glypican-3 Immunomagnetic Fluorescent Nanodevice.

PURPOSE: Specific targeting receptors for efficiently capturing and applicable nanodevice for separating and instant observing of circulating tumour cells (CTC) are critical for early diagnosis of cancer. However, the existing CTC detection system based on epithelial cell adhesion molecule (EpCAM) was seriously limited by low expression and poor specificity of targeting receptors, and not instant observation in clinical application. METHODS: Herein, an alternative glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of CTC from hepatocellular carcinoma (HCC) patients' peripheral blood was developed. The high-specific HCC targeting receptor, GPC3, was employed for improving the sensitivity and accuracy in CTC detection. GPC3 monoclonal antibody (mAb) was linked to immunomagnetic mesoporous silica for specific targeting capture and separate CTC, and fluorescent molecule coumarin-6 (C6) was loaded for instant detection of CTC. RESULTS: The cell recovery (%) of C6/MMSN-GPC3 increased in 106 HL-60 cells (from 49.7% to 83.0%) and in whole blood (from 42% to 80.3%) compared with MACS® Beads. In clinical samples, the C6/MMSN-GPC3 could capture more CTC in the 13 cases of HCC patients and the capture efficiency was improved by 83.3%-350%. Meanwhile, the capture process of C6/MMSN-GPC3 was harmless, facilitating for the subsequent culture. Significantly, the C6/MMSN-GPC3 achieved the high-specific isolation and instant observation of CTC from HCC patients' blood samples, and successfully separated CTC from one patient with early stage of HCC (Stage I) and one post-surgery patient, further indicating the potential ability of C6/MMSN-GPC3 for HCC early diagnosis and prognosis evaluation. CONCLUSION: Our study provides a feasible glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of HCC CTC.

Lymph Node Delivery Strategy Enables the Activation of Cytotoxic T Lymphocytes and Natural Killer Cells to Augment Cancer Immunotherapy.

Lymph nodes are the main sites for immune activation and surveillance. Effective delivery of immunomodulators into lymph nodes to trigger antitumor immunity is essential for cancer treatment. Here, we propose a lymph node delivery strategy to modulate the immune response by activating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells simultaneously. Novel pH/redox dual-sensitive micelles were prepared using poly(l-histidine)-poly(ethylene glycol) (PLH-PEG) as a skeleton, which can effectively deliver immunomodulators to the lymph nodes due to their suitable particle size. At 48 h after subcutaneous injection, the accumulation efficiency in lymph nodes increased 8.12-fold compared with the control group. Subsequently, Trp2/CpG-coloaded pH/redox dual-sensitive micelles (Trp2/CpG-NPs) acted on antigen-presenting cells, fully promoting CTL activation through dendritic cell antigen cross-presentation and macrophage repolarization. IL-15-loaded pH/redox dual-sensitive micelles (IL-15-NPs) were developed to activate the killing effect of NK cells by interacting with IL-15 receptors. In the tumor-bearing mice model, this lymph node delivery strategy showed significant antitumor efficiency and the tumor inhibition rate reached 93.76%. Meanwhile, the infiltration of CTLs and NK cells in tumor tissues increased, and the immunosuppressive microenvironment was relieved by the repolarization of macrophages from M2-type to M1-type. Overall, this study highlighted the potential of the lymph node delivery strategy for cancer immunotherapy.

Gas-blasting nanocapsules to accelerate carboplatin lysosome release and nucleus delivery for prostate cancer treatment.

To improve therapeutic effect and reduce severely side effects of carboplatin (CBP), the gas-generating nanocapsules were developed to accelerate CBP lysosome release and nucleus delivery. CBP/SB-NC was prepared by co-loading CBP and NaHCO3 (SB) in nanocapsules using w/o/w emulsification solvent evaporation. They exhibited vesicle-like spherical morphology, uniform particle size and negative zeta potential. Reaching the tumor site with a relatively high concentration is the first step for CBP delivery and the results showed that CBP/SB-NC could effectively increase drug accumulation at tumor site. After that, the drug delivery carriers need to be internalized into tumor cells and the in vitro cellular uptake ability results showed CBP/SB-NC could be internalized into RM-1 cells more efficient than CBP solution. After internalized by RM-1 cells, the gas-blasting release process was tested in acid environment. It was demonstrated that 5 mg/ml NaHCO3 was optimal to achieve pH-responsive gas-blasting release. In vitro release results showed that CBP significantly rapid release in acid environment (pH 5.0) compared to neutral pH (pH 7.4) (P < 0.05). Meanwhile, TEM and the change of the concentration of H+ results exhibited that the explosion of CBP/SB5-NC was more easily happened in lysosome acid environment (pH 5.0). The blasting release can accelerate CBP lysosome release to cytoplasm. Furthermore, the nucleus delivery results showed CBP/SB5-NC can promote pH-triggered rapid nucleus delivery. And the results of Pt-DNA adduct assay showed that the binding efficiency between CBP and DNA of CBP/SB5-NC was higher than CBP solution. At last, in vitro and in vivo anti-tumor efficacy proved that CBP/SB5-NC could enhance anti-tumor activity for prostate cancer therapy. CBP/SB5-NC also showed superior safety in vitro and in vivo by hemolysis assay and histopathological study. All of the results demonstrate that CBP/SB5-NC would be an efficient gas-blasting release formulation to enhance prostate cancer treatment.

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern.

Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH-triggered charge and size dual switchable nanocage co-loaded with abemaciclib and IMD-0354 (PA/PI-ND) is reported, exhibiting a novel triple-interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR-poly(ethylene glycol)-poly(l-lysine)-dimethylmaleic anhydride (NGR-PEG-PLL-DMA, ND) in PA/PI-ND promotes the pH-triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI-ND triple-interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD-0354. The dual anti-tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD-0354 promoting tumor-associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI-ND has improved anti-tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI-ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.