Four-Point Scleral Fixation of An Akreos Adapt AO Intraocular Lens Using Double-Strand 9-0 Polypropylene Suture.

PURPOSE: To report the results of a novel surgical four-point transscleral suture fixation of intraocular lens (IOL) with four hollow haptics using the double-suture technique. METHODS: We retrospectively reviewed the medical records of 15 eyes of 15 patients who underwent 4-point transscleral suture fixation of a foldable IOL using the double-suture technique. Preoperative data and follow-up data for at least 4 months were collected for all patients. RESULTS: The IOLs were fixed and centered well. The mean preoperative corrected distance visual acuity was 0.70 ± 0.54 logarithm of the minimum angle of resolution (Snellen 20/102), and it improved to 0.29 ± 0.26 logarithm of the minimum angle of resolution (Snellen 20/39) at the final follow-up ( P = 0.001). No vitreous hemorrhage, hypotony, suture breakage, retinal detachment, IOL dislocation, and iris capture was detected during the follow-up period in any of the patients. CONCLUSION: We have developed a novel technique for 4-point transscleral suture fixation of IOL using the double-suture technique with 9-0 polypropylene suture. This technique seemed to be safe and it may not require the surgeon to learn any new technique.

Nanoscale cationic micelles of amphiphilic copolymers based on star-shaped PLGA and PEI cross-linked PEG for protein delivery application.

To enhance the bioavailability of protein therapeutants and improve the stability of storage and delivery, a series of branched amphiphilic block copolymers consisting of cholic acid (CA) initiated poly(D,L-lactide-co-glycolide) (CA-PLGA) and water-soluble polyethyleneimine cross-linked polyethylene glycol (PEI-PEG) denoted as CA-PLGA-b-(PEI-PEG) were synthesized and characterized. CA-PLGA-b-(PEI-PEG) presented low cytotoxicity by MTT and cck-8 assay. The cationic CA-PLGA-b-(PEI-PEG) micelles (diameter about 100 nm and zeta potential 34-61 mV) were prepared through self-assembly method, and complexed with insulin via electrostatic interaction to obtain nanoscale micelle/insulin complexes. The micelle/insulin complexes-loaded CA-PLGA microspheres (MIC-MS, 10.4 ± 3.85 µm) were manufactured by employing a double emulsion (W1/O/W2) method. The in vitro insulin release behavior and in vivo hypoglycaemic effect of MIC-MS on streptozotocin (STZ) induced diabetic rats were compared with those of the insulin-loaded CA-PLGA microspheres (INS-MS, 7.8 ± 2.57 µm). The initial burst in vitro release of MIC-MS was markedly lower than that of INS-MS (P < 0.01), and the pharmacological availability of MIC-MS via subcutaneous administration was 148.9% relative to INS-MS. Therefore, the cationic CA-PLGA-b-(PEI-PEG) micelles can effectively increase the bioavailability of insulin in CA-PLGA microspheres and can be considered as a potential protein carrier.

PDL regeneration via cell homing in delayed replantation of avulsed teeth.

BACKGROUND: This study was aimed to investigate whether regeneration of periodontal ligament (PDL) like tissue could be promoted by stromal cell-derived factor-1 (SDF1) and bone morphogenetic protein-7 (BMP7) induced cell homing in delayed replantation of avulsed teeth. METHODS: Canine mandibular premolar teeth were first extracted and air-dried for 2 h followed by complete detachment of their PDL tissues. The crown and pulp of the teeth were also removed. Twenty-four roots divided into two groups (n = 12/group) were used for the following in vivo transplantation. The roots of Group A were treated with 17 % EDTA for 24 h to achieve demineralization, and then coated with SDF1 and BMP7 supplemented collagen solution. The roots of Group B were similarly treated except being coated with a pristine collagen solution. The above roots were transplanted in the sockets that formed previously during tooth extraction. At 6 months' post-operation, PDL-like tissue composed of spindle-shaped cells, capillaries and highly organized collagen fibers was observed in the interstitial space between the avulsed root surface and surrounding alveolar bone in Group A. The neo-fibers inserted deeply and perpendicularly into the cementum and adjacent bone. The periodontium-like characteristics of the neo-tissue was confirmed by immunohistochemical staining for collagen I, fibronectin and osteocalcin. RESULTS: A high incidence of PDL re-establishment as 42 % was achieved for samples of Group A. However, no PDL-like tissue was found but root ankylosis and replacement resorption as well as inflammatory resorption was observed in the replanted roots of Group B. CONCLUSIONS: It can be confirmed that avulsed teeth could be successfully rescued even in delayed transplantation to avoid dentoalveolar ankylosis or replacement resorption via the current developed cell homing method.

Nanoliposomes Encapsulated Rapamycin/Resveratrol to Induce Apoptosis and Ferroptosis for Enhanced Colorectal Cancer Therapy.

OBJECTIVES: Monotherapy is often ineffective for treating colorectal cancer. In this study, we developed PEG-modified liposomes loaded with rapamycin (Rapa) and resveratrol (Res) (Rapa/Res liposomes, or RRL) to investigate their therapeutic potential in colorectal cancer. METHODS: RRL were constructed using the reversed-phase evaporation method. We assessed the cytotoxicity, apoptosis, and ferroptotic effects of RRL on colorectal cancer HCT116 cells. The anti-tumor efficacy of RRL was evaluated in HCT116 xenograft mice. RESULTS: RRL had a particle size of 86.67 ± 1.10 nm and a zeta potential of -33.13 ± 0.49 mV. The coloaded formulation demonstrated satisfactory performance both in vitro and in vivo, resulting in increased cytotoxicity to HCT116 cells and significant suppression of HCT116 xenografts tumor growth. Mechanically, RRL significantly increased the apoptosis rate of HCT116 cells, induced ROS accumulation in tumor cells, and effectively downregulated the expression of the ferroptosis-associated proteins GPX4 and SLC7A11, demonstrating its superior efficacy compared to that of Rapa liposomes (Rapa/Lps) or Res liposomes (Res/Lps) alone. CONCLUSION: Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer.

Targeted co-delivery of rapamycin and oxaliplatin by liposomes suppresses tumor growth and metastasis of colorectal cancer.

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.

Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation.

Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of ɑ-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer.

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.

Colorimetric immunosensing using liposome encapsulated MnO2 nanozymes for SARS-CoV-2 antigen detection.

Development of specific signal reporters with signal amplification effect are highly needed for sensitive and accurate detection of pathogen. Herein, we design a colorimetric immunosensing nanosystem based on liposome encapsulated quantum dots-sized MnO2 nanozyme (MnO2QDs@Lip) as a signal reporter for ultrasensitive and fast detection of SARS-CoV-2 antigen. The pathogenic antigens captured and separated by antibody-conjugated magnetic beads (MBs) are further connected with antibody-modified MnO2QDs@Lip to form a sandwich-like immunocomplex structure. After triggered release, MnO2 QDs efficiently catalyze colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxidized TMB, which can be qualitatively observed by naked eyes and quantitatively analyzed by UV-Vis spectra or smartphone platforms. By taking advantages of immuno-magnetic separation, excellent peroxidase-like catalytic activity of MnO2 QDs, and high encapsulation efficiency of MnO2QDs@Lip, ultrasensitive detection of SARS-CoV-2 antigen ranging from 0.1 pg/mL to 100 ng/mL is achieved within 20 min. The limit of detection (LOD) is calculated to be 65 fg/mL in PBS buffer. Furthermore, real clinical samples of SARS-CoV-2 antigens can be effectively identified by this immunosensing nanosystem with excellent accuracy. This proposed detection nanosystem provides a strategy for simple, rapid and ultrasensitive detection of pathogens and may shed light on the development of new POCT detection platforms for early diagnosis of pathogens and surveillance in public health.

Rapamycin Liposomes Combined with 5-Fluorouracil Inhibits Angiogenesis and Tumor Growth of APC (Min/+) Mice and AOM/DSS-Induced Colorectal Cancer Mice.

Background: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro. Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs. Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration. Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.

Control of membrane fouling during hyperhaline municipal wastewater treatment using a pilot-scale anoxic/aerobic-membrane bioreactor system.

Membrane fouling limits the effects of long-term stable operation of membrane bioreactor (MBR). Control of membrane fouling can extend the membrane life and reduce water treatment cost effectively. A pilot scale anoxic/aerobic-membrane bioreactor (A/O-MBR, 40 L/hr) was used to treat the hyperhaline municipal sewage from a processing zone of Tianjin, China. Impact factors including mixed liquid sludge suspension (MLSS), sludge viscosity (micro), microorganisms, extracellular polymeric substances (EPS), aeration intensity and suction/suspended time on membrane fouling and pollution control were studied. The relationships among various factors associated with membrane fouling were analyzed. Results showed that there was a positive correlation among MLSS, sludge viscosity and trans-membrane pressure (TMP). Considering water treatment efficiency and stable operation of the membrane module, MLSS of 5 g/L was suggested for the process. There was a same trend among EPS, sludge viscosity and TMP. Numbers and species of microorganisms affected membrane fouling. Either too high or too low aeration intensity was not conducive to membrane fouling control. Aeration intensity of 1.0 m3/hr (gas/water ratio of 25:1) is suggested for the process. A long suction time caused a rapid increase in membrane resistance. However, long suspended time cannot prevent the increase of membrane resistance effectively even though a suspended time was necessary for scale off particles from the membrane surface. The suction/suspended time of 12 min/3 min was selected for the process. The interaction of various environmental factors and operation conditions must be considered synthetically.

Delivery of Rapamycin by Liposomes Synergistically Enhances the Chemotherapy Effect of 5-Fluorouracil on Colorectal Cancer.

BACKGROUND: Rapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer. METHODS: We prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo. RESULTS: The prepared rapamycin liposomes had a particle size of 100±5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways. CONCLUSION: Collectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin's antitumor effect but also synergistically enhances 5-FU's chemotherapy effect.

A novel magnetic fluorescent molecularly imprinted sensor for highly selective and sensitive detection of 4-nitrophenol in food samples through a dual-recognition mechanism.

In this study, surface imprinting, magnetic separation, and fluorescent detection were integrated to develop a dual-recognition sensor (MF-MIPs), which was used for highly selective and sensitive detection of 4-nitrophenol (4-NP) in food samples. Silane-functionalized carbon dots (Si-CDs) participated in the imprinting process and were uniformly distributed into the MIPs layers. MF-MIPs sensor exhibited a high fluorescence response and selectivity based on the dual-recognition mechanism of imprinting recognition and fluorescence identification. The relative fluorescence intensity of MF-MIPs sensor presented a good linear relationship in the range of 0.08-10 µmol·L-1 with a low limit of detection (23.45 nmol·L1) for 4NP. MF-MIPs sensor showed high anti-interference, as well as excellent stability and reusability. The 4-NP recovery from spiked food samples ranged from 93.20 to 102.15%, and the relative standard deviation was lower than 5.0%. Therefore, MF-MIPs sensor may be a promising method for 4-NP detection in food samples.

Curcumin-Loaded Poly(L-lactide-co-glycolide) Microbubble-Mediated Sono-photodynamic Therapy in Liver Cancer Cells.

Sono-photodynamic therapy (SPDT) activates the same photo-/sonosensitizer and exerts more marked antitumor effects than sonodynamic therapy or photodynamic therapy. We aimed to explore the utilization of curcumin (CUR)-loaded poly(L-lactide-co-glycolide) microbubble (MB)-mediated SPDT (CUR-PLGA-MB-SPDT) in HepG2 liver cancer cells. The cytotoxicity and intracellular accumulation of CUR were determined. We used 40 µM CUR as the photo-/sonosensitizer for 3 h. In a comparison of CUR-SDT or CUR-PDT, HepG2 cell viability decreased and apoptotic rate increased in CUR-SPDT. The CUR-PLGA MBs had round spheres with smooth surfaces and an average size of 3.7 µm. In CUR-PLGA MBs, drug entrapment efficiency and drug-loading capacity were 74.29 ± 2.60% and 17.14 ± 0.60%, respectively. CUR-loaded PLGA MBs (CUR-PLGA MBs) had good biocompatibility with normal L02 cells and were almost non-cytotoxic to HepG2 cells. Among CUR-SDT, CUR-PDT, CUR-SPDT or CUR-PLGA-MB-SDT, the cell CUR-PLGA-MB-SPDT had the lowest viability. Transmission electron microscopy revealed pyroptosis and apoptosis in the CUR-PLGA-MB-SPDT group; the potential mechanism was related to the mitochondrial membrane potential loss and increased production of intracellular reactive oxygen species. These findings suggested that CUR-PLGA-MB-SPDT may be a promising treatment for liver cancer.

Zipper-like magnetic molecularly imprinted microspheres for on/off-switchable recognition and extraction of 17ß-estradiol from food samples.

Zipper-like on/off-switchable and magnetic molecularly imprinted microspheres (SM-MIMs) were constructed using acrylamide (AAm) and 2-acrylamide-2-methyl propanesulfonic acid (AMPS) as functional monomers for 17ß-estradiol (17ß-E2) recognition and extraction. The imprinted polymer interactions between poly(AAm) (PAAm) and poly(AMPS) (PAMPS) with on/off-switchable property to temperature, exhibited dissociation at relatively higher temperatures (such as 30 °C) and helped 17ß-E2 enter into imprinted sites, leading to higher binding capability. Conversely, the interpolymer complexes between PAAm and PAMPS formed and blocked 17ß-E2 access to imprinted sites at lower temperature (such as 20 °C). SM-MIMs were used as dispersive solid phase extraction (SPE) adsorbent with HPLC for 17ß-E2 pretreatment and detection in food samples, and low limit detection (2.52 µg L-1) and quantification (10.76 µg L-1) with higher recovery were obtained. Therefore, SM-MIMs may be a promising adsorbent for 17ß-E2 pretreatment in food samples owing to its advantages of on/off-switchable recognition, eco-friendly elution, and efficient separation.

Delivery of curcumin by directed self-assembled micelles enhances therapeutic treatment of non-small-cell lung cancer.

BACKGROUND: It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. MATERIALS AND METHODS: In this study, CUR-loaded methoxy polyethylene glycol-polylactide (CUR/mPEG-PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. RESULTS: The average size of CUR/mPEG-PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067-0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG-PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG-PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG-PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG-PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. CONCLUSION: The mPEG-PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG-PLA micelles have promising clinical potential in treating NSCLC.