Thermally-responsive and reduced glutathione-sensitive folate-targeted nanocarrier based on alginate and pluronic F127 for on-demand release of methotrexate.

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.

Fabrication of carboxymethyl cellulose-based thermo-sensitive hydrogels and inhibition of corneal neovascularization.

Corneal neovascularization (CNV) is a common multifactorial sequela of anterior corneal segment inflammation, which could lead to visual impairment and even blindness. The main treatments available are surgical sutures and invasive drug injections, which could cause serious ocular complications. To solve this problem, a thermo-sensitive drug-loaded hydrogel with high transparency was prepared in this study, which could achieve the sustained-release of drugs without affecting normal vision. In briefly, the thermo-sensitive hydrogel (PFNOCMC) was prepared from oxidized carboxymethyl cellulose (OCMC) and aminated poloxamer 407 (PF127-NH2). The results proved the PFNOCMC hydrogels possess high transparency, suitable gel temperature and time. In the CNV model, the PFNOCMC hydrogel loading bone morphogenetic protein 4 (BMP4) showed significant inhibition of CNV, this is due to the hydrogel allowed the drug to stay longer in the target area. The animal experiments on the ocular surface were carried out, which proved the hydrogel had excellent biocompatibility, and could realize the sustained-release of loaded drugs, and had a significant inhibitory effect on the neovascularization after ocular surface surgery. In conclusion, PFNOCMC hydrogels have great potential as sustained-release drug carriers in the biomedical field and provide a new minimally invasive option for the treatment of neovascular ocular diseases.

Nasal administration of a temozolomide-loaded thermoresponsive nanoemulsion reduces tumor growth in a preclinical glioblastoma model.

Glioblastoma (GB) is the worst and most common primary brain tumor. Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, at least 50% of TMZ treated patients do not respond to TMZ and the development of chemoresistance is a major problem. Here, we designed a lipid nanoemulsion containing a thermoresponsive polymer (poloxamer 407) aiming to improve TMZ release into the brain via nasal delivery. Increasing amounts of poloxamer 407 were added to preformed nanoemulsions (250 nm-range) obtained by spontaneous emulsification. The influence of the polymer concentration (from 2.5% to 12.5%) and temperature on viscosity was clearly evidenced. Such effect was also noticed on the mucoadhesiveness of formulations, as well as TMZ release rate and retention/permeation through nasal porcine mucosa using Franz-type diffusion cells. From these results, a formulation containing 10% of poloxamer (NTMZ-P10) was selected for further experiments by nasal route. A significantly higher TMZ amount was observed in the brain of rats from NTMZ-P10 in comparison with controls. Finally, our results show that formulation reduced significantly tumor growth by three-fold: 103.88 ± 43.67 mm3 (for NTMZ-P10) and 303.28 ± 95.27 mm3 (control). Overall, these results suggest the potential of the thermoresponsive formulation, administered by the non-invasive nasal route, as a future effective glioblastoma treatment.

RGD-decorated PLGA nanoparticles improved effectiveness and safety of cisplatin for lung cancer therapy.

Upon extensive pharmaceutical and biomedical research to treat lung cancer indicates that lung cancer remains one of the deadliest diseases and the leading cause of death in men and women worldwide. Lung cancer remains untreated and has a high mortality rate due to the limited potential for effective treatment with existing therapies. This highlights the urgent need to develop an effective, precise and sustainable solutions to treat lung cancer. In this study, we developed RGD receptor-targeted PLGA nanoparticles for the controlled and targeted co-delivery of cisplatin (CDDP) and upconversion nanoparticles (UCNP) in lung cancer therapy. Pluronic F127-RGD conjugate was synthesized by carbodiimide chemistry method and the conjugation was confirmed by FTIR and 1HNMR spectroscopy techniques. PLGA nanoparticles were developed by the double emulsification method, then the surface of the prepared nanoparticles was decorated with Pluronic F127-RGD conjugate. The prepared formulations were characterized for their particle size, polydispersity index, zeta potential, surface morphology, drug encapsulation efficiency, and in vitro drug release and haemolysis studies. Pharmacokinetic studies and safety parameters in BAL fluid were assessed in rats. Histopathology of rat lung tissue was performed. The obtained results of particle sizes of the nanoparticle formulations were found 100-200 nm, indicating the homogeneity of dispersed colloidal nanoparticles formulations. Transmission Electron Microscopy (TEM) revealed the spherical shape of the prepared nanoparticles. The drug encapsulation efficiency of PLGA nanoparticles was found to range from 60% to 80% with different nanoparticles counterparts. RGD receptor-targeted PLGA nanoparticles showed controlled drug release for up to 72 h. Further, RGD receptor-targeted PLGA nanoparticles achieved higher cytotoxicity in compared to CFT, CFT, and Ciszest-50 (marketed CDDP injection). The pharmacokinetic study revealed that RGD receptor-targeted PLGA nanoparticles were 4.6-fold more effective than Ciszest-50. Furthermore, RGD receptor-targeted PLGA nanoparticles exhibited negligible damage to lung tissue, low systemic toxicity, and high biocompatible and safety in lung tissue. The results of RGD receptor-targeted PLGA nanoparticles indicated that it is a promising anticancer system that could further exploited as a potent therapeutic approach for lung cancer.

Efficacy of a local anesthetic gel infusion kit for pain relief after minimally invasive colorectal surgery: an open-label, randomized clinical trial.

Continuous wound infusion with local anesthesia is an effective method for reducing postoperative pain after laparoscopic colorectal surgery. However, most subcutaneous local anesthesia is delivered through continuous injection, which can be inconvenient for patients. This study compared the effectiveness of postoperative pain relief from the application of a local poloxamer 407-based ropivacaine hydrogel (Gel) to the incision site with continuous infusion-type ropivacaine administration (On-Q) in patients undergoing laparoscopic colorectal surgery. This prospective, randomized, non-inferiority study included 61 patients who underwent laparoscopic colorectal surgery with an incision length of 3-6 cm. All 61 patients were randomly assigned to the Gel group (poloxamer 407-based 0.75% ropivacaine, 22.5 mg) or the On-Q group (0.2% ropivacaine, 4 mg/hour for two days). Postoperative analgesia was induced in all patients with intravenous patient-controlled analgesia (IV-PCA). The outcome measures, which were assessed for 72 h after surgery, included the total amount of fentanyl consumed via IV-PCA (primary endpoint), and the amount of rescue analgesia (pethidine) and postoperative pain intensity assessed using a numeric rating scale (NRS) [secondary endpoints]. The Gel was administered to 31 patients and On-Q was used for 30 patients. There was no significant difference in the total usage of fentanyl between the two groups (Gel group, 1623.98 mcg; On-Q group, 1595.12 mcg; P = 0.806). There was also no significant difference in the frequency of analgesic rescue medication use (P = 0.213) or NRS scores (postoperative 6 h, P = 0.860; 24 h, P = 0.333; 48 h, P = 0.168; and 72 h, P = 0.655) between the two groups. The Gel, which continuously delivers a local anesthetic to operative sites, can thus be considered an effective device for analgesia and pain relief for midline incisions in laparoscopic colorectal surgery.

Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity.

BACKGROUND: Nanomedicine has emerged as a promising strategy for cancer treatment. The most representative nanomedicine used in clinic is PEGylated liposomal doxorubicin DOXIL®, which is first FDA-approved nanomedicine. However, several shortcomings, such as low drug loading capacity, low tumor targeting, difficulty in mass production and potential toxicity of carrier materials, have hindered the successful clinical translation of nanomedicines. In this study, we report a preclinical development process of the carrier-free prodrug nanoparticles designed as an alternative formulation to overcome limitations of conventional nanomedicines in the terms of technical- and industrial-aspects. RESULTS: The carrier-free prodrug nanoparticles (F68-FDOX) are prepared by self-assembly of cathepsin B-specific cleavable peptide (FRRG) and doxorubicin (DOX) conjugates without any additional carrier materials, and further stabilized with Pluronic F68, resulting in high drug loading (> 50%). The precise and concise structure allow mass production with easily controllable quality control (QC), and its lyophilized powder form has a great long-term storage stability at different temperatures (- 4, 37 and 60 °C). With high cathepsin B-specificity, F68-FDOX induce a potent cytotoxicity preferentially in cancer cells, whereas their cytotoxicity is greatly minimized in normal cells with innately low cathepsin B expression. In tumor models, F68-FDOX efficiently accumulates within tumor tissues owing to enhanced permeability and retention (EPR) effect and subsequently release toxic DOX molecules by cathepsin B-specific cleavage mechanism, showing a broad therapeutic spectrum with significant antitumor activity in three types of colon, breast and pancreatic cancers. Finally, the safety of F68-FDOX treatment is investigated after single-/multi-dosage into mice, showing greatly minimized DOX-related toxicity, compared to free DOX in normal mice. CONCLUSIONS: Collectively, these results provide potential preclinical development process of an alternative approach, new formulation of carrier-free prodrug nanoparticles, for clinical translation of nanomedicines.

Mucus-Penetrating Silk Fibroin-Based Nanotherapeutics for Efficient Treatment of Ulcerative Colitis.

Oral nanoparticles have been considered a prospective drug delivery carrier against ulcerative colitis (UC). To enhance the mucus-penetrating capacity and aqueous solubility, and strengthen the anti-inflammatory effect of resveratrol (RSV), we fabricated RSV-loaded silk fibroin-based nanoparticles with the functionalization of Pluronic F127 (PF-127). The obtained PF-127-functionalized RSV-loaded NPs had an average particle size around 170 nm, a narrow size distribution (polydispersity index < 0.2), and negative zeta potential (−20.5 mV). Our results indicated that the introduction of PF-127 strengthened the mucus-penetrating property of NPs. In vitro studies suggested that NPs with PF-127 enhanced the suppression of the secretion of proinflammatory cytokine TNF-α and reactive oxygen species (ROS) from RAW 264.7 macrophages under lipopolysaccharide stimulation in comparison with other counterparts. According to the evaluation of macro symptoms and main inflammatory cytokines, we further report preferable therapeutic outcomes achieved by PF-127 functionalized-NP-treated dextran sulphate sodium (DSS) groups in the colitis model compared with blank silk fibroin NPs and RSV-loaded NPs without the functionalization of PF-127. Taken together, this work suggests that the fabricated PF-127 NPs via the oral route are promising and useful RSV-loaded nanocarriers for UC treatment.

Glycosaminoglycan-based injectable hydrogels with multi-functions in the alleviation of osteoarthritis.

Osteoarthritis (OA), as an "undead cancer", causes a serious burden for both individuals and society. In this study, a glycosaminoglycan-based injectable hydrogel was prepared with hyaluronic acid (HA), chondroitin sulfate E disaccharide (ΔUA-diSE) and thermosensitive Pluronic F127 (PF127) to provide a new strategy for OA alleviation. Both in vitro and in vivo biological evaluations were introduced to investigate the slow-release capacity, related mechanisms, and effectiveness of PF-HA-diSE on OA. The results demonstrated that PF-HA-diSE could alleviate OA effectively by regulating the complement system, especially the formation of C5b-9, and its downstream signals. Interestingly, we also found that PF127 was not only a drug carrier, but may have the potential on inhibiting C5b-9 formation. Altogether, these findings provided a more effective local drug delivery system for glycosaminoglycans in better treatment of OA and related diseases.

Curcumin and Paclitaxel Co-loaded Heparin and Poloxamer P403 Hybrid Nanocarrier for Improved Synergistic Efficacy in Breast Cancer.

INTRODUCTION: Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor targeting and limit the usual side effects of chemotherapy. METHODS: In this research, we developed the amphiphilic Heparin-poloxamer P403 (HSP) nanogel that could load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel were assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its dual drug-loaded platform showed high stability and spherical morphology. RESULTS: The drug release profile indicated fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@CUR@PTX compared to free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR. CONCLUSION: HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.

Development and evaluation of PLA based hybrid block copolymeric nanoparticles for systemic delivery of pirarubicin as an anti-cancer agent.

Pirarubicin (PIRA) is a semi-synthetic anthracycline derivative that is reported to have lesser toxicity and better clinical outcomes as compared to its parental form doxorubicin (DOX). However, long term use of PIRA causes bone marrow suppression and severe cardiotoxicity to the recipients. Herein, we have developed a biodegradable polymeric nano platform consisting of amphiphilic di-block copolymer methoxy polyethylene glycol-polylactic acid and a hydrophobic penta-block copolymer polylactic acid-pluronic L-61-polylactic acid as a hybrid system to prepare PIRA (& DOX) encapsulated nanoparticles (NPs) with an aim to reduce its off targeted toxicity and enhance therapeutic efficacy for cancer therapy. Prepared PIRA/DOX NPs showed uniform particle size distribution, high encapsulation efficiency and sustained drug release profile. Cytotoxicity evaluation of PIRA NPs against TNBC cells and mammospheres showed its superior anti-cancer activity over DOX NPs. Anti-cancer efficacy of PIRA/DOX NPs was found significantly enhanced in presence of penta-block copolymer which confirmed chemo-sensitising ability of pluronic L-61. Most importantly, encapsulation of PIRA/DOX in the NPs reduced their off targeted toxicity and increased the maximum tolerated dose in BALB/c mice. Moreover, treatment of EAC tumor harbouring mice with PIRA NPs resulted in higher tumor regression as compared with the groups treated with free PIRA, free DOX or DOX NPs. Altogether, the results conclude that prepared PIRA NPs exhibits an excellent anti-cancer therapeutic efficacy and has a strong potential for cancer therapy.

Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators.

Deferoxamine (DFO) is an FDA-approved iron-chelating agent which shows good therapeutic efficacy, however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained-release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol-gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half-life 47-fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator-loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.

γ-Cyclodextrin-based polypseudorotaxane hydrogels for ophthalmic delivery of flurbiprofen to treat anterior uveitis.

Anterior uveitis is a sight-threatening inflammation inside the eyes. Conventional eye drops for anti-inflammatory therapy need to be administered frequently owing to the rapid elimination and corneal barrier. To address these issues, polypseudorotaxane hydrogels were developed by mixing Soluplus micelles (99.4 nm) and cyclodextrins solution. The optimized hydrogels exhibited shear-thinning and sustained release properties. The hydrogels exhibited higher transcorneal permeability coefficient (Papp, 1.84 folds) than that of drug solutions. Moreover, animal study indicated that the hydrogels significantly increased the precorneal retention (AUC, 21.2 folds) and intraocular bioavailability of flurbiprofen (AUCAqueous humor, 17.8 folds) in comparison with drug solutions. Importantly, the hydrogels obviously boosted anti-inflammatory efficacy in rabbit model of endotoxin-induced uveitis at a reduced administration frequency. Additionally, the safety of hydrogels was confirmed by cytotoxicity and ocular irritation studies. In all, the present study demonstrates a friendly non-invasive strategy based on γ-CD-based polypseudorotaxane hydrogels for ocular drug delivery.

Randomized Trial of Poloxamer 407-Based Ropivacaine Hydrogel After Thoracoscopic Pulmonary Resection.

BACKGROUND: We conducted a comparative study to evaluate the efficacy of poloxamer 407-based ropivacaine hydrogel at the wound site (Gel) and continuous thoracic paravertebral block using On-Q PainBuster (On-Q; B. Braun Medical) for postoperative pain after thoracoscopic pulmonary resection. METHODS: This prospective, randomized, noninferiority study included 89 patients randomized to the Gel group (poloxamer 407-based 0.75% ropivacaine, 22.5 mg) or the On-Q group (0.2% ropivacaine, 4 mg/h for 48 hours). The primary outcome measure was total fentanyl consumption, and secondary outcome measures were the need for rescue analgesia and pain intensity using the numeric rating scale (NRS). RESULTS: There was no significant difference in total fentanyl consumption between the Gel group and the On-Q group (1504.29 ± 315.72 µg vs 1560.32 ± 274.81 µg, P = .374). Pain intensity using the NRS between the Gel group and the On-Q group demonstrated no statistical differences at 6 hours (3.56 vs 3.55, P = .958), 24 hours (3.21 vs 3.00, P = .25), 48 hours (2.75 vs 2.49, P = .233), and 72 hours (2.39 vs 2.33, P = .811), and there was no significant difference in the frequency of analgesic rescue medication use (3.70 vs 3.33, P = .417). CONCLUSIONS: We confirm the noninferiority of Gel compared with On-Q for acute postoperative pain after thoracoscopic pulmonary resection. Considering a technical simplicity and low systemic toxicity of the local injection of Gel, this analgesic modality may be worthy of further research and is thus considered to have potential as a viable alternative to On-Q for regional analgesia.

Systematic review of studies on drug-delivery systems for management of temporomandibular-joint osteoarthritis.

INTRODUCTION: Temporomandibular-joint osteoarthritis (TMJOA) management is a major challenge. Minimally invasive therapies (based mainly on injections) have been developed to increase local efficacy and limit adverse systemic effects. However, the requirement for repeat injections due to a short duration of action and expensive healthcare costs have pushed researchers to develop, via tissue engineering, drug-delivery systems (DDSs). In this literature systematic review, we aim to provide an overview of studies that tested DDSs on a TMJOA model. MATERIAL AND METHODS: We searched on PubMed for articles published from November 1965 to March 2021 on DDSs using a TMJOA model. We highlighted the different DDSs and the active molecule employed. Route of drug administration, model type, test duration, and efficacy duration were assessed. To evaluate the quality of each study, a protocol bias was tested using QUADAS-2™. RESULTS: Of the 10 studies that were full text-screened, four used a poly(lactic-co-glycolic acid)-based delivery system. The other DDSs employed chitosan-based hydrogels, microneedles patches, nanostructured lipid carriers, or poloxamer micelles. Hyaluronic acid, nonsteroidal anti-inflammatory drugs, and analgesics were used as active molecules in five studies. The main way to administer DDSs was intra-articular injection and the most used model was the rat. DISCUSSION: Various DDSs and active molecules have been studied on a TMJOA model that could aid TMJOA management. Further works using longer test durations are necessary to validate these advances.

A 61-Year-Old Woman with Chronic Iron-Deficiency Anemia Due to a Cameron Lesion and a Response to Oral Application of Combined Poloxamer 407 with Hyaluronic Acid and Chondroitin Sulfate Following Single Treatment with Pantoprazole: A Case Report.

BACKGROUND Cameron lesions are linear erosions and ulcers on the crests of gastric mucosal folds in the neck of a hiatal hernia and can be difficult to diagnose and treat. This report is of a case of chronic iron deficiency in a 61-year-old woman with a late diagnosis of a Cameron lesion, who did not respond to a single treatment with the proton pump inhibitor (PPI) pantoprazole, but was then treated with oral poloxamer 407 with hyaluronic acid and chondroitin sulfate in addition to PPI. CASE REPORT We report the case of a 61-year-old women with recurrent iron-deficiency anemia, first diagnosed 40 years prior to her presentation at our Endoscopy Unit, and an ongoing melena. We discovered an intrahiatal gastric mucosal defect, which we at first treated with proton pump inhibitors and sucralfate. After a follow-up gastroscopy revealed the persistence of the lesion, we decided to incorporate into the treatment a gel-like substance containing, among others, hyaluronic acid and chondroitin sulfate, and observed that the lesion resolved completely. CONCLUSIONS This report highlights that Cameron lesions should be considered in patients with hiatal hernia who have iron-deficiency anemia and can be diagnosed on upper endoscopy. Further clinical studies are required to determine the role of combined poloxamer 407 with hyaluronic acid and chondroitin sulfate in the management of Cameron lesions.

Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis.

Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC50 and CC50, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 µg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 µg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum-infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.

Drug-eluting Vein Graft with Acetylsalicylic Acid-Ticagrelor-Unfractionated Heparin Complex Inhibits Early Graft Thrombosis

Background: Bypass graft surgery remains to be an important treatment option for left main and multivessel coronary artery disease. Approximately 2% of saphenous vein grafts are lost immediately after the coronary artery bypass graft operations and 12% in the first month due to thrombosis. Aims: To administer one anticoagulant and two antiplatelet agents in a way that locally affects the vein graft before the bypass operation and to thereby analyse their effects on early graft thrombosis. Study Design: Animal experimentation. Methods: Since ticagrelor was used locally for the first time in this study, its efficacy in combination with other drugs (acetylsalicylic acid, acetylsalicylic acid and ticagrelor, and acetylsalicylic acid + ticagrelor + unfractionated heparin) was examined on rats including control (untreated) and sham (pluronic gel) group (n=14 for each group). Before the tunica adventitia layer of the femoral veins was bypassed to the femoral artery, it was coated with the drug-eluting pluronic F-127 gel. The presence or absence of thrombus in the vein graft samples was recorded under light microscopy. In vein graft preparations where thrombus was detected, the thrombus area (µm2) was calculated using the Axiovision software. Immunohistochemical staining was performed with the anti-rat von Willebrand factor polyclonal antibody kit. Results: The number of preparations containing thrombus was significantly lower in the acetylsalicylic acid + ticagrelor + unfractionated heparin group than in the acetylsalicylic acid, control, and sham groups, according to the comparisons made on the 1st and 3rd days (p=0.001 and 0.02, respectively). von Willebrand factor staining was significantly lower in the acetylsalicylic acid + ticagrelor + unfractionated heparin group than in the other groups on the 3rd day (p=0.005). Conclusion: Locally effective acetylsalicylic acid-ticagrelor-unfractionated heparin complex has been shown to significantly reduce thrombus formation in vein grafts in this experimental model. Local administration of these drugs, which are routinely administered orally just before stent implantations, on the vein graft before the bypass is performed can prevent the loss of vein grafts due to thrombus, thereby reducing the mortality and morbidity of these patients.

Soft liquid metal nanoparticles achieve reduced crystal nucleation and ultrarapid rewarming for human bone marrow stromal cell and blood vessel cryopreservation.

High warming rates during cryopreservation are crucial and essential for successful vitrification. However, realizing a faster warming rate in low-concentration cryoprotective agents appears to be challenging for conventional warming process through convective heat transfer. Herein, we developed a liquid metal (LM) nanosystem that can act as a spatial source to significantly enhance the warming rates with near-infrared laser irradiation during the warming process. The synthetic Pluronic F127-liquid metal nanoparticles (PLM NPs) displayed multiple performances with uniform particle size, superior photothermal conversion efficiency (52%), repeatable photothermal stability, and low cytotoxicity. Particularly, it is more difficult for the liquid PLM NPs with less surface free energy to form crystal nucleation than other solid NPs such as gold and Fe3O4, which is beneficial for the cooling process during cryopreservation. The viability of human bone marrow-derived mesenchymal stem cells postcryopreservation reached 78±3%, which is threefold higher than that obtained by the conventional warming method (25±6%). Additionally, the cells postcryopreservation maintained their normal attachment, proliferation, surface marker expression, and intact multilineage differentiation properties. Moreover, the results of mouse tails including blood vessel cryopreservation showed a relatively improved intact structure when using PLM NP rewarming compared with the results of conventional warming. The new LM nanosystem provides a universal platform for cryopreservation that is expected to have potential for widespread applications including bioengineering, cell-based medicine, and clinical translation. STATEMENT OF SIGNIFICANCE: In this study, we fabricated soft liquid metal nanoparticles with high photothermal conversion efficiency, repeatable photothermal stability, and low cytotoxicity. Particularly, soft liquid metal nanoparticles with less surface free energy and suppression effects of ice formation were first introduced to mediate cryopreservation. Superior ice-crystallization inhibition is achieved as a result of less crystal nucleation and ultrarapid rewarming during the freezing and warming processes of cryopreservation, respectively. Collectively, cryopreservation of human bone marrow stromal cells (HBMSCs) and mouse tails including blood vessels can be successfully performed using this new nanoplatform, showing great potential in the application of soft nanoparticles in cryopreservation.

Preparation, Optimization, and In Vivo Evaluation of Nanoparticle-Based Formulation for Pulmonary Delivery of Anticancer Drug.

Background and Oobjectives: Lung cancer, a pressing issue in present-day society due to its high prevalence and mortality rate, can be managed effectively by long-term delivery of anticancer agents encapsulated in nanoparticles in the form of inhalable dry powder. This approach is expected to be of strategic importance in the management of lung cancer and is a developing area in current research. In the present investigation, we report on the formulation and characterization of docetaxel inhalable nanoparticles as a viable alternative for effective treatment of non-small cell lung cancer as a long-term delivery choice. Materials and Methods: Poloxamer (PLX-188) coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles containing docetaxel (DTX-NPs) were prepared by simple oil in water (o/w) single emulsification-solvent evaporation process. The nanoparticles were collected as pellet by centrifugation, dispersed in mannitol solution, and lyophilized to get dry powder. Results: Optimized DTX-NPs were smooth and spherical in morphology, had particle size around 200 nm, zeta potential around -36 mV, and entrapment efficiency of around 60%. The invitro anticancer assay was assessed and it was observed that nanoparticle-based formulation exhibited enhanced cytotoxicity when compared to the free form of the drug post 48 h. On examining for invitro drug release, slow but continuous release was seen until 96 h following Higuchi release kinetics. DTX-NPs were able to maintain their desired characteristics when studied at accelerated conditions of stability. Conclusions: In-vivo study indicated that the optimized nanoparticles were well retained in lungs and that the drug level could be maintained for a longer duration if given in the form of DTX-NPs by the pulmonary route. Thus, the non-invasive nature and target specificity of DTX-NPs paves the way for its future use as a pulmonary delivery for treating non-small cell lung cancer (NSCLC).

Effect of a poloxamer-based thermosensitive gel on rotator cuff repair in a rabbit model: a controlled laboratory study.

BACKGROUND: A common complication after rotator cuff repair is postoperative stiffness, which can be reduced by a simple application of an anti-adhesive agent. However, anti-adhesive agents may affect rotator cuff healing by preventing fibrosis. This experimental animal study evaluated the effect of the application of a poloxamer-based thermosensitive anti-adhesive gel and its influence on the healing of an acute rotator cuff repair in a rabbit model. METHODS: Acute rotator cuff repair (supraspinatus tendon) was performed using a transosseous suturing method. One shoulder on a randomly selected side was treated with a local application of the anti-adhesive agent (applied side), and saline was applied to the contralateral side (control side). Biomechanical testing and histological analyses were performed at 4 and 8 weeks postoperatively. Eight rabbits were included for each testing and time point, for a total of 32 rabbits. RESULTS: The failure load at 4 weeks was lower in the experimental group (95.2 ± 19.6 N vs. 110.0 ± 20.5 N; P = 0.017). Conversely, at 8 weeks, the failure load was higher in the experimental group (148.3 ± 16.2 N) than in the control group (122.4 ± 16.9 N; P = 0.002). Histological analyses revealed no statistically significant differences in the tendon maturing scores at 4 and 8 weeks between the two groups (all P > 0.05). The thickness of the fibrosis between the rotator cuff tendon and deltoid was thinner in the experimental group at both time points (0.50 ± 0.25 vs. 1.27 ± 0.47; P = 0.002 at 4 weeks, and 0.37 ± 0.35 vs. 1.39 ± 0.50; P = 0.003 at 8 weeks). CONCLUSIONS: Application of an anti-adhesive agent in this rotator cuff model confirmed the agent's effectiveness at reducing fibrosis in the subacromial space. The healing of the tendon showed interesting results, as the experimental group had poorer biomechanical strength at 4 weeks but superior strength at 8 weeks.