PD-1 monoclonal antibodies enhance the cryoablation-induced antitumor immune response: a breast cancer murine model research.

BACKGROUND: It has been demonstrated that cryoablation (Cryo) causes specific T-cell immune responses in the body; however, it is not sufficient to prevent tumor recurrence and metastasis. In this report, we evaluated changes in the tumor immune microenvironment (TIME) in distant tumor tissues after Cryo and investigated the immunosuppressive mechanisms that limit the efficacy of Cryo. METHODS: Bilateral mammary tumor models were established in mice, and we first observed the dynamic changes in immune cells and cytokines at different time points after Cryo. Then, we confirmed that the upregulation of PD-1 and PD-L1 signaling in the contralateral tumor tissue was closely related to the immunosuppressive state in the TIME at the later stage after Cryo. Finally, we also evaluated the synergistic antitumor effects of Cryo combined with PD-1 monoclonal antibody (mAb) in the treatment of breast cancer (BC) mouse. RESULTS: We found that Cryo can stimulate the body's immune response, but it also induces immunosuppression. The elevated PD-1/PD-L1 expression in distant tumor tissues at the later stage after Cryo was closely related to the immunosuppressive state in the TIME but also created the conditions for Cryo combined with PD-1 mAb for BC mouse treatment. Cryo + PD-1 mAb could improve the immunosuppressive state of tumors and enhance the Cryo-induced immune response, thus exerting a synergistic antitumor effect. CONCLUSIONS: The PD-1/PD-L1 axis plays an important role in suppressing Cryo-induced antitumor immune responses. This study provides a theoretical basis for Cryo combined with PD-1 mAb therapy in clinical BC patients.

Healing Diabetic Ulcers with MoO3-X Nanodots Possessing Intrinsic ROS-Scavenging and Bacteria-Killing Capacities.

Diabetic ulcers (DUs) appearing as chronic wounds are difficult to heal due to the oxidative stress in the wound microenvironment and their high susceptibility to bacterial infection. A routine treatment combining surgical debridement with anti-infection therapy is widely used for treating DUs in the clinic, but hardly offers a satisfying wound healing outcome. It is known that a long-term antibiotic treatment may also lead to the drug resistance of pathogens. To address these challenges, new strategies combining both reactive oxygen species (ROS) scavenging and bacterial sterilization have been proposed for fighting against DUs. Following this idea, oxygen deficient molybdenum-based nanodots (MoO3-X ) for healing the DUs are reported. The ROS scavenging ability of MoO3-X nanodots is investigated and the antibacterial property of the nanodots is also demonstrated. The systematic cell and animal experimental results indicate that the MoO3-X nanodots can effectively reduce inflammation, promote epithelial cell regeneration, accelerate angiogenesis, and facilitate DUs recovery. Most importantly, they present excellent capacity to diminish infection of methicillin-resistant Staphylococcus aureus, manifesting the potent application prospect of MoO3-X nanodots for diabetic wound therapy.

Embedding Co2P nanoparticles in Cu doping carbon fibers for Zn-air batteries and supercapacitors.

Developing highly efficient and non-precious materials for Zn-air batteries (ZABs) and supercapacitors (SCs) are still crucial and challenging. Herein, electronic reconfiguration and introducing conductive carbon-based materials are simultaneously conducted to enhance the ZABs and SCs performance of Co2P. We develop a simple and efficient electrospinning technology followed by carbonization process to synthesize embedding Co2P nanoparticles in Cu doping carbon nanofibers (Cu-Co2P/CNFs). As a result, the 7% Cu-Co2P/CNFs presents high oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) activity (half-wave potential of 0.792 V for ORR, an overpotential of 360 mV for OER). The ZABs exhibit a power density of 230 mW cm-2and excellent discharge-charge stability of 80 h. In addition, the 7% Cu-Co2P/CNFs show the specific capacitance of 558 F g-1at 1 A g-1. Moreover, the 7% Cu-Co2P/CNFs//CNFs asymmetric supercapacitor was assembled applying 7% Cu-Co2P/CNFs electrode and pure CNFs, which exhibits a high energy density (25.9 Wh kg-1), exceptional power density (217.5 kW kg-1) and excellent cycle stability (96.6% retention after 10 000 cycles). This work may provide an effective way to prepared Co2P based materials for ZABs and SCs applications.

Glucose-Sensitive Core-Cross-Linked Nanoparticles Constructed with Polyphosphoester Diblock Copolymer for Controlling Insulin Delivery.

This work aims to construct biocompatible, biodegradable core-cross-linked and insulin-loaded nanoparticles which are sensitive to glucose and release insulin via cleavage of the nanoparticles in a high-concentration blood glucose environment. First, a polyphosphoester-based diblock copolymer (PBYP-g-Gluc)-b-PEEP was prepared via ring-opening copolymerization (ROP) and the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in which PBYP and PEEP represent the polymer segments from 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane, respectively, and Gluc comes from 2-azidoethyl-ß-d-glucopyranoside (Gluc-N3) that grafted with PBYP. The structure and molecular weight of the copolymer were characterized by 1H NMR, 31P NMR, GPC, FT-IR, and UV-vis measurements. The amphiphilic copolymer could self-assemble into core-shell uncore-cross-linked nanoparticles (UCCL NPs) in aqueous solutions and form core-cross-linked nanoparticles (CCL NPs) after adding cross-linking agent adipoylamidophenylboronic acid (AAPBA). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to study the self-assembly behavior of the two kinds of NPs and the effect of different Gluc group contents on the size of NPs further to verify the stability and glucose sensitivity of CCL NPs. The ability of NPs to load fluorescein isothiocyanate-labeled insulin (FITC-insulin) and their glucose-triggered release behavior were detected by a fluorescence spectrophotometer. The results of methyl thiazolyl tetrazolium (MTT) assay and hemolysis activity experiments showed that the CCL NPs had good biocompatibility. An in vivo hypoglycemic study has shown that FITC-insulin-loaded CCL NPs could reduce blood glucose and have a protective effect on hypoglycemia. This research provides a new method for constructing biodegradable and glucose-sensitive core-cross-linked nanomedicine carriers for controlled insulin release.

Application of ultrasound-guided intranodal lymphangiography and embolisation in cancer patients with postoperative lymphatic leakage.

BACKGROUND: Traumatic lymphatic leakage is a rare but potentially life-threatening complication. The purpose of this study was to introduce ultrasound-guided intranodal lymphangiography and embolisation techniques for postoperative lymphatic leakage in patients with cancer. METHODS: From January 2018 through June 2020, seven cancer patients (three males, four females, aged 59-75 years [mean 67.57 ± 6.11 years]) developed lymphatic leakage after abdominal or pelvic surgery, with drainage volumes ranging from 550 to 1200 mL per day. The procedure and follow-up of ultrasound-guided intranodal lymphangiography and embolisation were recorded. This study retrospectively analysed the technical success rate, operative time, length of hospital stay, clinical efficacy, and complications. RESULTS: The operation was technically successful in all patients. Angiography revealed leakage, and embolisation was performed in all seven patients (7/7, 100%). The operative time of angiography and embolisation was 41 to 68 min, with an average time of 53.29 ± 10.27 min. The mean length of stay was 3.51 ± 1.13 days. Lymph node embolisation was clinically successful in five patients (5/7, 71.43%), who had a significant reduction in or disappearance of chylous ascites. The other two patients received surgical treatment 2 weeks later due to poor results after embolisation. All patients were followed for 2 weeks. No serious complications or only minor complications were found in all the patients. CONCLUSIONS: Ultrasound-guided intranodal lymphangiography and embolisation were well tolerated by the patients, who experienced a low incidence of complications. Early intervention is recommended for cancer patients with postoperative lymphatic leakage.

Focal adhesion kinase promotes BMP2-induced osteogenic differentiation of human urinary stem cells via AMPK and Wnt signaling pathways.

Human urine-derived stem cells (hUSCs) serve as favorable candidates for bone transplants due to their efficient proliferative and multipotent differentiation abilities, as well as the capacity to secrete a variety of vasoactive agents to facilitate tissue engineering. The present study aimed to explore the role of focal adhesion kinase (FAK) in bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation of hUSCs and to investigate the underlying mechanism. The degree of osteogenic differentiation and the correlated signals, following BMP2 overexpression and siRNA-mediated silencing of FAK, were determined in vitro. Moreover, hUSCs induced bone formation in a rat model with cranial defects, in vivo. Our findings revealed that alkaline phosphatase production, calcium deposits, osteocalcin and osteopontin expression, and bone formation were upregulated in vitro and in vivo following BMP2-induced osteogenic differentiation, and AMPK and Wnt signaling pathway activation by FAK could effectively regulate BMP2-enhanced osteogenic differentiation of hUSCs. Taken together, these findings indicated that FAK could mediate BMP2-enhanced osteogenic differentiation of hUSCs through activating adenosine 5'-monophosphate-activated protein kinase and Wnt signaling pathways.

BMP9 promotes osteogenic differentiation of SMSCs by activating the JNK/Smad2/3 signaling pathway.

Synovial mesenchymal stem cells (SMSCs) with high proliferation and multi differentiation ability, and low immunogenicity have attracted research attention for their potential application in tissue engineering. Once their ability of osteogenesis is strengthened, it will be of practical value to apply the SMSCs in the field of bone regeneration. The current study aimed to investigate the osteogenic characteristics of SMSCs induced by bone morphogenetic protein 9 (BMP9) both in vitro and in vivo and to elucidate the mechanism underlying these characteristics. Specifically, different BMPs were assessed to determine the protein that would be the most favorable for stimulating osteogenic differentiation of SMSCs following their separation. The BMP9-enhanced osteogenesis of SMSCs was fully investigated in vitro and in vivo, and the c-Jun N-terminal kinase (JNK)/Smad2/3 signaling pathway stimulated by BMP9 was further explored. Our data suggested that BMP9 could significantly promote gene and protein expression of runt-related transcription factor 2, alkaline phosphatase, osteopontin, and osteocalcin, and SP600125, a JNK-specific inhibitor, could effectively decrease this tendency. Similar results were also confirmed in rats with cranial defects. In conclusion, our study indicated that BMP9 promotes bone formation both in vitro and in vivo possibly by activating the JNK/Smad2/3 signaling pathway.

Barbaloin Attenuates Mucosal Damage in Experimental Models of Rat Colitis by Regulating Inflammation and the AMPK Signaling Pathway.

BACKGROUND Barbaloin is one of the main medicinal ingredients of aloe vera, which displays various anti-inflammatory and anti-apoptosis properties in several inflammatory and fibrotic diseases. Our study evaluated its efficacy against dextran sulfate sodium (DSS)-induced colitis in rats. MATERIAL AND METHODS Ulcerative colitis (UC) rat models were established in vivo, and after barbaloin treatment, body weight and inflammation index were measured. Additionally, the signaling mechanism by which barbaloin protects against UC was investigated using LPS-infected Caco-2 cells. RESULTS Barbaloin could significantly reverse UC-induced weight loss and colon injury. Further, it could effectively increase the mRNA expression of IL-4 and IL-10 in colon tissues, while decreasing the expression of IFN-γ, IL-6, IL-1ß, and TNF-alpha. Furthermore, it significantly enhanced UC-inhibited atresia band 1 (ZO-1), occludin, and E-cadherin, and was also found to activate the AMPK signaling pathway. Additionally, si-RAN-induced knockdown, and overexpression assay showed that barbaloin could inhibit the UC-enhanced MLCK signaling pathway by activating the AMPK signaling pathway. CONCLUSIONS Barbaloin can effectively inhibit inflammation and reverse epithelial barrier function to protect against UC, possibly via activation of the AMPK signaling pathway.

Comparison of Ultrasound-Guided Right Brachiocephalic and Right Subclavian Vein Cannulation in Adult Patients.

OBJECTIVES: To compare ultrasound-guided right brachiocephalic vein (BCV) central venous catheter (CVC) placement to right subclavian vein (SCV) CVC insertion in terms of the puncture success rate and complications. METHODS: A retrospective review was performed for all adult patients who received an ultrasound-guided CVC via the right BCV or right SCV access route between January 2016 and March 2018. The puncture success rates and procedure-related complications were analyzed. RESULTS: Data were analyzed from 755 adult patients who underwent 915 CVC insertions. The overall success rate was higher in the BCV group compared to that in the SCV group (98.99% versus 96.87%; P = .019). The first-attempt success rate was higher in the BCV group compared to that in the SCV group (96.64% versus 89.34%; P < .001). Intraoperative complications were observed in 16 cases in the BCV group (2.68%) and in 12 cases in the SCV group (3.76%). The incidence rates of postprocedure complications were 5.20% in the BCV group and 6.58% in the SCV group and included catheter-related infections and thrombosis. CONCLUSIONS: Ultrasound-guided cannulation of the right BCV is an effective and safe method for CVC placement in adult patients and provides an additional option for catheter access.

Ultrasound-guided totally implantable venous access ports via the right innominate vein: a new approach for patients with breast cancer.

BACKGROUND: To evaluate the feasibility and safety of ultrasound-guided totally implantable venous access port (TIVAP) implantation via the right innominate vein in patients with breast cancer. METHODS: Sixty-seven breast cancer patients underwent ultrasound-guided implantation of TIVAPs via the right innominate vein for administration of chemotherapy. Clinical data including technical success, success rate for the first attempt, periprocedural, and postoperative complications were recorded and retrospectively studied. RESULTS: All patients underwent successful surgery. The success rate of the first attempt was 95.52% (64/67). The operation time was 28 to 45 min, with an average of 36 ± 6 min. Periprocedural complications included artery punctures in 1 (1.50%, 1/67) patient. Prior to this study, the mean TIVAP time was 257 ± 3 days (range 41 to 705 days). The rate of postoperative complications was 4.48% (3/67), including catheter-related infections in 1 case and fibrin sheath formation in 2 cases. Up to the present study, three people had unplanned port withdrawal due to complications, and the TIVAPs for 25 patients were still in normal use. CONCLUSIONS: The success rate of ultrasound-guided TIVAPs via the right innominate vein is high with low complications, thus safe and feasible. This technique can provide a new option for chemotherapy of breast cancer patients.

Comparison between ultrasound-guided TIVAD via the right innominate vein and the right internal jugular vein approach.

BACKGROUND: To compare the efficacy and safety of right internal jugular vein (IJV) approach and right innominate vein (INV) approach for US-guided totally implantable venous access devices (TIVADs), and to explore the advantages and disadvantages of the two approaches. METHODS: Six hundred and nineteen adult patients had long-term infusion and chemotherapy needs and inconvenience of peripheral venous infusion. Right INV approach was used to implant 339 cases of TIVADs, and right IJV approach was used to implant 280 cases of TIVADs. The success rate of one-time catheterization and the incidence of complications in the two groups were retrospectively analyzed. RESULTS: All patients were successfully implanted in TIVAD. The success rates of one-time puncture in INV group and IJV approach group were 98.53% (334/339) and 95.36% (267/280), respectively. There was significant difference between the two groups (P = 0.020). The incidence of perioperative complications and long-term complications in the right INV group were 1.18% (4/339) and 3.54% (12/339), respectively, while those in the right IJV group were 1.43% (4280) and 3.93% (11280). There was no significant difference in the incidence of perioperative or long-term complications between the two groups (P = 0.785, P = 0.799, respectively). CONCLUSIONS: US-guided TIVADs via the right INV approach and the right IJV approach are both safe and reliable. The right INV approach improves the one-time puncture success rate, as long as the technique is properly operated, serious complications rarely occur.

A Laser-Based On-Machine Measuring System for Profile Accuracy of Double-Headed Screw Rotor.

Great length, large weight and other factors may cause difficulty in measuring the profile accuracy of the double-headed screw rotor. To solve this problem, an on-machine measuring system based on a laser-displacement sensor (LDS) was designed and implemented in this paper by taking an LXK100 four-axis whirlwind milling machine as the carrier. To improve the measurement accuracy of the system, the generalized variable-structural-element morphological method, polynomial interpolation algorithm and ellipse fitting method were first combined to realize the rapid subpixel centroid extraction from a noise-containing spot image, thus improving the data acquisition accuracy of the LDS, and then the hybrid method was experimentally verified. Next, a wavelet threshold function with high-order differentiability and adaptive wavelet coefficient contractility was constructed based on the hyperbolic tangent function, so as to inhibit the disturbance from random errors and preserve real profile information, and this method was simulated and verified. Subsequently, a smoothing algorithm for point cloud data was proposed based on the Lagrange multiplier method to avoid the defect of the piecewise curve-fitting method, that is, function continuity and differentiability could not be satisfied at piecewise points. Finally, the profile accuracy was calculated in real time according to the data reconstruction result and the machining quality was judged. The measurement experiment of the double-headed screw rotor indicates that the proposed on-machine measuring system can complete the profile accuracy measurement for a screw pitch within 39.7 s with measurement accuracy reaching ±8 µm, and the measurement uncertainties of the major axis, minor axis and screw pitch are 0.72 µm, 0.69 µm and 1.24 µm, respectively. Therefore, the measurement accuracy and efficiency are both remarkably improved.

Measurement of Free-Form Curved Surfaces Using Laser Triangulation.

Laser triangulation (LT) is widely used in many fields due to its good stability, high resolution and fast speed. However, the accuracy in these applications suffers from severe constraints on the data acquisition accuracy of LT. To solve this problem, the optical triangulation principle, the object equation of the optical path relationship and the deviation of the laser spot centroid are applied to deduce a mathematical model. Therefore, the image sensor inclination errors can be quantitatively calculated, and the collected data are compensated in real time. Further, a threshold sub-pixel gray-gravity (GG) extraction algorithm is proposed; the gradient function and Gaussian fit algorithm are used to set thresholds to remove the impact of the spot edge noise area on the center location; and polynomial interpolation is employed to enhance the data density of the traditional GG method, thus improving the data acquisition accuracy of LT. Finally, the above methods are applied to on-machine measurement of the American Petroleum Institute (API) thread and the screw rotor, respectively. The experimental results prove that the proposed method can significantly improve the measurement accuracy of free-form curved surfaces using LT and that the improved laser spot center extraction algorithm is more suitable for free-form curved surfaces with smaller curvature and more uniform curvature changes.

A Fast and On-Machine Measuring System Using the Laser Displacement Sensor for the Contour Parameters of the Drill Pipe Thread.

The inconvenient loading and unloading of a long and heavy drill pipe gives rise to the difficulty in measuring the contour parameters of its threads at both ends. To solve this problem, in this paper we take the SCK230 drill pipe thread-repairing machine tool as a carrier to design and achieve a fast and on-machine measuring system based on a laser probe. This system drives a laser displacement sensor to acquire the contour data of a certain axial section of the thread by using the servo function of a CNC machine tool. To correct the sensor's measurement errors caused by the measuring point inclination angle, an inclination error model is built to compensate data in real time. To better suppress random error interference and ensure real contour information, a new wavelet threshold function is proposed to process data through the wavelet threshold denoising. Discrete data after denoising is segmented according to the geometrical characteristics of the drill pipe thread, and the regression model of the contour data in each section is fitted by using the method of weighted total least squares (WTLS). Then, the thread parameters are calculated in real time to judge the processing quality. Inclination error experiments show that the proposed compensation model is accurate and effective, and it can improve the data acquisition accuracy of a sensor. Simulation results indicate that the improved threshold function is of better continuity and self-adaptability, which makes sure that denoising effects are guaranteed, and, meanwhile, the complete elimination of real data distorted in random errors is avoided. Additionally, NC50 thread-testing experiments show that the proposed on-machine measuring system can complete the measurement of a 25 mm thread in 7.8 s, with a measurement accuracy of ±8 µm and repeatability limit ≤ 4 µm (high repeatability), and hence the accuracy and efficiency of measurement are both improved.

A nanomedicine composed of polymer-ss-DOX and polymer-Ce6 prodrugs with monoclonal antibody targeting effect for anti-tumor chemo-photodynamic synergetic therapy.

Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity and uncontrolled drug release due to their lack of targeting. To improve the bioavailability of drugs and reduce side effects, we have developed a mixed micelle of nanomedicine composed of two prodrugs with surface modified monoclonal antibody for cancer therapy. In this system, Nimotuzumab was used as targeting ligands of the mixed micelles (named as DCMMs) that is composed of polymer-doxorubicin prodrug (abbreviated as PEG-b-P(GMA-ss-DOX)) and maleimide polyethylene glycol-chlorin e6 (abbreviated as Mal-PEG-Ce6). The mixed micelles modified with Nimotuzumab (named as NTZ-DCMMs) bind to overexpressed EGFR receptors on Hepatoma-22 (H22) cells. Disulfide bonds in PEG-b-P(GMA-ss-DOX) are disrupted in tumor microenvironment, inducing the reduction-responsive release of DOX and leading to tumor cell apoptosis. Simultaneously, Chlorin e6 (Ce6) produced plenty of singlet oxygen (1O2) under laser irradiation to kill tumor cells. In vivo biological distribution and antineoplastic effect experiments demonstrate that NTZ-DCMMs enhanced drug enrichment at tumor sites through targeting function of antibody, dramatically suppressing tumor growth and mitigating cardiotoxicity of drugs. All results prove that NTZ-DCMMs have the ability to actively target H22 cells and quickly respond to tumor microenvironment, which is expected to become an intelligent and multifunctional drug delivery carrier for efficient chemotherapy and photodynamic therapy of hepatoma. STATEMENT OF SIGNIFICANCE: Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity due to their lack of targeting. Therefore, it's necessary to develop effective, targeted, and collaborative treatment strategies. We construct a mixed micelle of nanomedicine based on two polymer prodrugs and modified with monoclonal antibody on surface for cancer therapy. Under the tumor cell microenvironment, the disulfide bonds of polymer-ss-DOX were broken, effectively triggering DOX release. The photosensitizer Ce6 could generate a large amount of ROS under light, which synergistically promotes tumor cell apoptosis. By coupling antibodies to the hydrophilic segments of polymer micelles, drugs can be specifically delivered. Compared with monotherapy, the combination of chemotherapy and photodynamic therapy can significantly enhance the therapeutic effect of liver cancer.

Dextran-doxorubicin prodrug nanoparticles conjugated with CD147 monoclonal antibody for targeted drug delivery in hepatoma therapy.

Antibody-drug conjugates (ADCs) are a class of tumor cell-targeting drugs that have developed rapidly in recent years. From the perspective of further improving ADC targeting and developing natural macromolecules as drug carriers, it is still challenging and necessary to try new targeted drug delivery modalities. In this study, we have developed an antibody-modified prodrug nanoparticle based on biomacromolecule dextran (DEX) to delivery antitumour drug doxorubicin (DOX). Firstly, oxidized dextran (ODEX) and DOX were bonded to yield ODEX-DOX via Schiff base reaction, which can self-assemble into nanoparticles (NPs) carrying some aldehyde groups. Subsequently, the amino groups of CD147 monoclonal antibody were bound to the aldehyde groups on the surface of ODEX-DOX NPs, resulting in acid-responsive and antibody-modified CD147-ODEX-DOX NPs with relatively small particle size and high DOX loading. FT-IR, UV-Vis, HPLC, and 1H NMR were used to demonstrate the successful synthesis of polymer prodrug ODEX-DOX NPs and antibody-modified nanomedicine CD147-ODEX-DOX NPs. Dynamic light scattering (DLS) was used to evaluate the stability and the pH responsiveness of ODEX-DOX NPs in different media and tumour microenvironment. The in vitro total release content of DOX reached approximately 70% in PB 5.0 buffer solution after 103 h. Furthermore, the in vivo antitumour efficacy and biodistribution experiments confirmed that CD147-ODEX-DOX NPs could significantly inhibit the growth of HepG2 tumour. All of the results indicate that this acid-sensitive nanomedicine has higher safety and targeting effects. It promises to be an ideal strategy for future targeted drug delivery systems and anticancer therapies.

A CD326 monoclonal antibody modified core cross-linked curcumin-polyphosphoester prodrug for targeted delivery and cancer treatment.

Stimuli-responsive cross-linked micelles (SCMs) are ideal nanocarriers for anti-cancer drugs. Compared with non-cross-linked micelles, SCMs exhibit superior structural stability. At the same time, the introduction of an environmentally sensitive crosslinker into a drug delivery system allows SCMs to respond to single or multiple stimuli in the tumor microenvironment, which can minimize drug leakage during the blood circulation process. In this study, curcumin (CUR) was modified as the hydrophobic core crosslinker by utilizing the bisphenol structure, and redox sensitive disulfide bonds were introduced to prepare the glutathione (GSH) stimulated responsive core crosslinker (abbreviated as N3-ss-CUR-ss-N3). In addition, amphiphilic polymer APEG-b-PBYP was prepared through the ring opening reaction, and reacted with the crosslinker through the "click" reaction. After being dispersed in the aqueous phase, core cross-linked nanoparticles (CCL NPs) were obtained. Finally, monoclonal antibody CD326 (mAb-CD326) was reduced and coupled to the hydrophilic chain ends to obtain the nanoparticles with surface modified antibodies (R-mAb-CD326@CCL NPs) for further enhancing targeted drug delivery. The structures of the polymer and crosslinker were characterized by 1H NMR, UV-Vis, FT-IR, and GPC. The morphology, size and stability of CCL NPs and R-mAb-CD326@CCL NPs were investigated by DLS and TEM. The in vitro drug release behavior of CCL NPs was also studied. The results showed that the CCL NPs exhibited reduction-responsiveness and were able to release the original drug CUR under 10 mM GSH conditions. Additionally, the CCL NPs exhibited excellent stability in both the simulated body fluid environment and organic solvents. Especially, R-mAb-CD326@CCL NPs can actively target tumor cells and showed better therapeutic efficacy in in vivo experiments with a tumor suppression rate of 78.7%. This work provides a new idea for the design of nano-drugs targeting breast cancer.

Albumin pre-opsonized membrane-active iPep nanomedicine potentiates chemo to immunotherapy of cancer.

Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell killings mediated by pore-forming proteins or host defense peptides. Of the similar concept, targeting cancer cell membrane using membrane active peptides is a hopeful therapeutic modality but had long been hindered from in vivo application. Here we report an enabling strategy of pre-opsonizing a membrane penetrating Ir-complexed octa-arginine peptide (iPep) with serum albumin via intrinsic amphipathicity-driven bimodal interactions into nanoparticles (NP). We found that NP triggered stress-mediated 4T1 cell oncosis which induced potent immunological activation, surpassing several well-known immunogenic medicines. Vested with albumin-enhanced in vivo tumor targeting specificity and pharmacokinetic properties, NP showed combined chemo to immunotherapies of s. c. tumors in mice, with decreased percentages of MDSC, Treg, M2-like macrophage and improved infiltration of CTLs in tumor site, caused complete regression of 4T1 and CT26 tumors, outperforming clinical medicines. In a challenging orthotopic breast cancer model, boost i. v. injections of NP acted as in situ tumor vaccine that drastically enhanced 4T1-specific cellular and humoral immunities to reverse disease progression. Thus, with combined effects of direct cytoreduction, immune activation and tumor vaccine, iPep-NP presents the promise and potential of a new modality of cancer medicine.

A hybrid hydrogel constructed using drug loaded mesoporous silica and multiple response copolymer as an intelligent dressing for wound healing of diabetic foot ulcers.

Traditional wound dressings have poor mechanical properties and a single function, which cannot achieve rapid healing of diabetic wounds in a unique physiological microenvironment. In order to develop multifunctional hydrogel dressings with appropriate biological activity to accelerate wound healing and obtain better clinical therapeutic effects, herein we report a hybrid system based on drug loaded mesoporous silica and injectable polymer hydrogels mixed with hypoglycemic drug metformin (Met) as a dressing for diabetic wounds. Firstly, a copolymer with the phenylboronic acid group in the side group, poly(acrylamide-co-dimethylaminopropylacrylamide-co-methacrylamidophenylboronic acid) (abbreviated as PB), was prepared. PB was mixed with polyvinyl alcohol (PVA) to obtain an injectable hydrogel (named PP) with pH/glucose dual responsiveness, which was formed through the combination of the phenylborate group of PB and o-diol of PVA. In another reaction, polydopamine-modified mesoporous silica nanoparticles (MSN@PDA) were prepared and used to adsorb antibiotic tetracycline hydrochloride (TH) to obtain drug-loaded MSN@PDA-TH nanoparticles. Subsequently, the hybrid hydrogel dressing (abbreviated as PP/MSN@PDA-TH/Met) was obtained by mixing PB, PVA, Met and MSN@PDA-TH. The self-healing, rheological and adhesive properties of the hybrid hydrogel were characterized. The results show that the hydrogel dressing has good physical properties. Met and TH were released in vitro in different pH media and glucose environments. The results show that the hydrogel dressing has dual responsiveness towards pH and glucose, and can continuously release metformin and tetracycline, which is conducive to accelerating wound healing. The antimicrobial activity, ROS clearance ability and biocompatibility of the hydrogel dressing were evaluated. The results indicate that the hydrogel dressing was multifunctional. Finally, a full-thickness wound repair model of diabetic mice induced by streptozotocin (STZ) was established. The hybrid hydrogel dressing was applied to the wound surface of mice. The wound healing testing on diabetic mice confirmed that the wound covered with the hybrid hydrogel dressing was completely healed with the formation of the new skin and hair within 9 days to 12 days. Histological analysis indicates that, compared to the PBS control, the hydrogel dressing did not cause significant inflammation in the wound, and a large number of blood vessels, glands and hair follicles appeared. This study provides a good strategy for multi-drug synergistic treatment of diabetic foot ulcers.