Endoscopic polidocanol foam sclerobanding for the treatment of grade II-III internal hemorrhoids: A prospective, multi-center, randomized study.

BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.

Oral sulfate solution versus polyethylene glycol for bowel preparation before colonoscopy, meta-analysis and trial sequential analysis of randomized clinical trials.

BACKGROUND: This study aimed to compare oral sulfate solution (OSS) with polyethylene glycol (PEG) for bowel preparation before colonoscopy. METHODS: A literature search was performed on PubMed, Ovid, and Cochrane Databases for randomized clinical trials (RCT) comparing OSS with PEG for bowel preparation before colonoscopy. The last search was performed on 22 August 2023. The primary outcome was the quality of bowel preparation. The outcomes were compared by meta-analysis and trial sequential analysis (TSA). RESULTS: A total of 14 RCTs with 4526 patients were included. OSS was comparable with PEG regarding adequate bowel preparation [P = 0.16, odds ratio (OR) = 1.19, 95% confidence interval (CI) [0.93, 1.51], I2 = 0%]. However, OSS showed obvious priority in excellent bowel preparation (P < 0.001, OR = 1.62, 95% CI [1.27, 2.05], I2 = 0%) and total Boston bowel preparation scale (BBPS) [P = 0.02, weighted mean difference (WMD) = 0.27, 95% CI [0.05, 0.50], I2 = 84%]. Additionally, the detection rate of polyps (P = 0.001, OR = 1.44, 95% CI [1.15, 1.80], I2 = 0%) and adenoma (P = 0.007, OR = 1.22, 95% CI [1.06, 1.42], I2 = 0%) was significantly higher in the OSS group. The two groups showed comparable incidence of adverse events except for a higher incidence of dizziness (P = 0.02, OR = 1.74, 95% CI [1.08, 2.83], I2 = 11%) was indicated in the OSS group. Moreover, OSS was associated with a higher satisfaction score (P = 0.02, WMD = 0.62, 95% CI [0.09, 1.15], I2 = 70%). In the TSA, the cumulative Z-curve crossed both the conventional boundary and trial sequential monitoring boundary and the required information size has been reached for excellent bowel preparation and total BBPS. CONCLUSION: The current data demonstrated that OSS was associated with better quality of bowel preparation. More clinical trials are still needed to confirm other outcomes.

Efficacy and safety of polyethylene glycol loxenatide in treating mild-to-moderate diabetic kidney disease in type 2 diabetes patients: a randomized, open-label, clinical trial.

Objective: This study aimed to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEG-Loxe) compared to those of dapagliflozin in patients with mild-to-moderate diabetic kidney disease (DKD), a prevalent microvascular complication of type 2 diabetes mellitus (T2DM). The study is set against the backdrop of increasing global diabetes incidence and the need for effective DKD management. Methods: This study constituted a single-center, randomized, open-label, clinical trial. The trial included patients with mild-to-moderate DKD and suboptimal glycemic control. Eligible participants were randomly allocated to one of the two groups for treatment with either PEG-Loxe or dapagliflozin. The primary endpoint was the change in UACR from baseline at 24 weeks. Results: Overall, 106 patients were randomized and 80 patients completed the study. Following 24 weeks of treatment, the PEG-Loxe group exhibited a mean percent change in baseline UACR of -29.3% (95% confidence interval [CI]: -34.8, -23.7), compared to that of -31.8% in the dapagliflozin group (95% CI: -34.8, -23.7). Both PEG-Loxe and dapagliflozin showed similar efficacy in reducing UACR, with no significant difference between the groups (p = 0.336). The HbA1c levels decreased by -1.30% (95% CI: -1.43, -1.18) in the PEG-Loxe group and by -1.29% (95% CI: -1.42, -1.17) in the dapagliflozin group (p = 0.905). The TG levels decreased by -0.56 mmol/L (95% CI: -0.71, -0.42) in the PEG-Loxe group and -0.33 mmol/L (95% CI: -0.48, -0.19) in the dapagliflozin group (p = 0.023). Differences in TC, HDL-C, LDL-C, SBP, and DBP levels between the groups were not statistically significant (all p > 0.05). Safety profiles were consistent with previous findings, with gastrointestinal adverse events being more common in the PEG-Loxe group. Conclusions: PEG-Loxe is as effective as dapagliflozin in improving urine protein levels in patients with mild-to-moderate DKD and offers superior benefits in improving lipid profiles. These findings support the use of PEG-Loxe in DKD management, contributing to evidence-based treatment options. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300070919.

Sennoside A+B Is as Effective as Polyethylene Glycol in Preparation for Small Intestine Capsule Endoscopy.

BACKGROUND/AIMS:  We aimed to compare the effectiveness of the polyethylene glycol (PEG) and sennoside A+B regimens after clear fluid diet and fasting in bowel preperation of capsule endoscopy. MATERIALS AND METHODS:  In this retrospective single-center study, patients who were consecutively examined with small bowel capsule endoscopy (SBCE) between May 2010 and March 2023 were evaluated. Patients who underwent PEG 4 L and sennoside A+B calcium 250 mL for small bowel preparation were assigned. The quality of the small bowel cleaning and the diagnostic yield in detecting of small bowel lesions were compared. RESULTS:  Two hundred forty-two patients who underwent SBCE for various indications (PEG 74.4%, sennoside A+B 25.6%) were included in the study. The mean proximal small bowel cleaning scores was 1.97 ± 0.77 for PEG and 1.98 ± 0.04 (P = .83) for sennoside A+B; the mid small bowel cleaning scores was 1.76 ± 0.84 for PEG and 1.59 ± 0.05 (P = .108) for sennoside A+B; the mean distal small bowel cleaning scores was 1.27 ± 0.08 for PEG and 1.3 ± 0.54 (P = .805) for sennoside A+B; and the total small bowel cleaning scores was 1.66 ± 0.06 and 1.62 ± 0.04 (P = .622) for PEG and sennoside A+B, respectively. There were no significant differences regarding small bowel cleaning scores both segmentally and totally. At the same time, the diagnostic value of SBCE was similar in both groups. CONCLUSION:  The effectiveness of sennoside A+B in SBCE preparation is similar to that of PEG and can be used in intestinal cleansing.

Efficacy and safety outcomes in Japanese patients with low-risk polycythemia vera treated with ropeginterferon alfa-2b.

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis. A phase 2 study reported that ropeginterferon alfa-2b is a well-tolerated and effective treatment for PV in Japanese patients. This post hoc analysis of the phase 2 data further evaluated outcomes in patients at low risk of thrombosis (low-risk PV). Among 20 patients with low-risk PV, 60.0% (12/20) and 85.0% (17/20) achieved < 45% hematocrit by weeks 24 and 52, respectively. The proportion of responders with complete hematologic response (CHR) was 60.0% (12/20) at week 52, and the median time to response was 11.9 months. The mean JAK2 V617F allele burden decreased from 75.8% at baseline to 53.7% at week 52. No patient experienced thrombosis or bleeding episodes. All patients experienced treatment-emergent adverse events (TEAEs) related to ropeginterferon alfa-2b, but no grade ≥ 3 TEAEs or deaths related to ropeginterferon alfa-2b occurred, and no new safety concerns arose. This analysis indicated that ropeginterferon alfa-2b may be an effective treatment option for Japanese patients with low-risk PV.

Dexamethasone-loaded ROS stimuli-responsive nanogels for topical ocular therapy of corneal neovascularization.

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin ß1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance.

Retrospective multicenter study of elderly patients with platinum-sensitive relapsed ovarian cancer treated with trabectedin and pegylated liposomal doxorubicin (pld) in a real-world setting: a geico study.

BACKGROUND: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting. METHODS: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible. RESULTS: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%). CONCLUSIONS: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients.

Polyethylene Glycol-Fusion Repair of Peripheral Nerve Injuries.

Axons successfully repaired with polyethylene glycol (PEG) fusion tecnology restored axonal continuity thereby preventing their Wallerian degeneration and minimizing muscle atrophy. PEG fusion studies in animal models and preliminary clinical trials involving patients with digital nerve repair have shown promise for this therapeutic approach. PEG fusion is safe to perform, and given the enormous potential benefits, there is no reason not to explore its therapeutic potential.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

Anti-EGFR immunoliposomes for cabazitaxel delivery: From formulation development to in vivo evaluation in prostate cancer xenograft model.

Liposomes functionalized with monoclonal antibodies offer targeted therapy for cancer, boasting advantages like sustained drug release, enhanced stability, passive accumulation in tumors, and interaction with overexpressed receptors on cancer cells. This study aimed to develop and characterize anti-EGFR immunoliposomes loaded with cabazitaxel and assess their properties against prostate cancer in vitro and in vivo. Using a Box-Behnken design, a formulation with soy phosphatidylcholine, 10% cholesterol, and a 1:20 drug-lipid ratio yielded nanometric particle size, low polydispersity and high drug encapsulation. Immunoliposomes were conjugated with cetuximab through DSPE-PEG-Maleimide lipid anchor. Characterization confirmed intact antibody structure and interaction with EGFR receptor following conjugation. Cabazitaxel was dispersed within the liposomes in the amorphous state, confirmed by solid-state analyses. In vitro release studies showed slower cabazitaxel release from immunoliposomes. Immunoliposomes had enhanced cabazitaxel cytotoxicity in EGFR-overexpressing DU145 cells without affecting non-tumor L929 cells. Cetuximab played an important role to improve cellular uptake in a time-dependent fashion in EGFR-overexpressing prostate cancer cells. In vivo, immunoliposomes led to significant tumor regression, improved survival, and reduced weight loss in xenograft mice. While cabazitaxel induced leukopenia, consistent with clinical findings, histological analysis revealed no evident toxicity. In conclusion, the immunoliposomes displayed suitable physicochemical properties for cabazitaxel delivery, exhibited cytotoxicity against EGFR-expressing prostate cancer cells, with high cell uptake, and induced significant tumor regression in vivo, with manageable systemic toxicity.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study.

BACKGROUND: This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. METHODS: In this prospective, single-center, single-arm study, we enrolled patients (18-70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48-72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3-4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2-4, time to complete radiotherapy, and safety. RESULTS: Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3-4 neutropenia was 28.8%, with an average duration of grade 3-4 neutropenia persistence of 3.85 days (1-7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2-4, respectively. The incidences of grade 3-4 neutropenia for cycles 1-4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41-56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. CONCLUSION: PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Efficacy of linaclotide in combination with polyethylene glycol for bowel preparation in Chinese patients undergoing colonoscopy polypectomy: protocol for a randomised controlled trial.

BACKGROUND: Adequate bowel preparation is essential for successful colonoscopy and polypectomy procedures. However, a significant proportion of patients still exhibit suboptimal bowel preparation, ranging from 18% to 35%. The effectiveness of bowel preparation agents can be hampered by volume and taste, adversely affecting patient compliance and tolerance. Therefore, exploring strategies to minimise laxative volume and improve patient tolerance and adherence is imperative to ensure optimal bowel preparation quality. METHODS AND ANALYSIS: This study is a two-arm, single-blinded, parallel-group randomised controlled trial designed to compare the efficacy of 2 L polyethylene glycol (PEG) combined with linaclotide with 4 L PEG in bowel cleansing. A total of 422 participants will be randomly assigned in a 1:1 ratio to either the intervention group (2 L PEG combined with 580 µg linaclotide) or the control group (4 L PEG). The primary outcome measure is bowel cleansing efficacy, which is assessed using the Boston Bowel Preparation Scale. Secondary outcomes include evaluating the tolerability and safety of the bowel preparation regimens, bowel diary assessments, postpolypectomy complications (such as bleeding and perforation) and the size and number of removed polyps. ETHICS AND DISSEMINATION: The study has received approval from the Clinical Research Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine. The findings of this trial will serve as a valuable resource for clinicians and patients undergoing colonoscopy polypectomy by guiding the selection of appropriate bowel preparation regimens. Study findings will be disseminated to participants, presented at professional society meetings, and published in peer-reviewed journals. This trial was registered on the Chinese Clinical Trial Registry with registration number ChiCTR2300075410.

Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.

Dual immunotherapy alternating with anti-PD-1 antibody plus liposomal doxorubicin show good efficacy in prostate epithelioid hemangioendothelioma: a case report.

Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.

A novel chitosan-PEG hydrogel embedded with in situ silver nanoparticles of Clerodendrum glandulosum Lindl. extract: evaluation of its in vivo diabetic wound healing properties using an image-guided machine learning model.

The pathophysiology of chronic wounds related to diabetes mellitus is a result of a series of complications induced by hyperglycemia. The symptoms include impaired growth factor production, decreased keratinocyte proliferation and migration, reduced angiogenesis and cytokine synthesis, lowered matrix metalloproteinase (MMP) production, neuropathy, reduced nitric oxide synthase production, decreased fibroblast synthesis and migration, and impaired inflammatory cell functions. This multifaceted mechanism of diabetic wounds needs a suitable novel topical formulation that can deliver the active constituent by a controlled means, target the various stages of wound healing, absorb the wound exudates, and prevent secondary infections. To meet the above requirements, the Clerodendrum glandulosum (CG) extract reduced silver nanoparticle (AgNP) impregnated chitosan-polyethylene glycol (PEG) hydrogel was synthesized. The findings of the physicochemical characterization studies suggested that the hydrogel exhibited excellent formulation characteristics and showed controlled release for seven days, making it suitable for chronic wound healing studies. In subsequent studies, these formulations showed good antioxidant and antimicrobial properties, and hemocompatibility, with the least cytotoxic properties. The results of the diabetic wound healing studies showed a faster wound closure rate and improved extracellular matrix formation. These antioxidant, antimicrobial, anti-inflammatory and wound-healing properties suggest that the CG-AgNP loaded chitosan-PEG hydrogel is a promising material for novel topical formulation of diabetic wounds.

Improved anti-breast cancer activity by doxorubicin-loaded super stealth liposomes.

PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron phospholipids can decrease the detachment of polyethylene glycol (PEG) from the liposomal surface owing to an increased hydrophobic anchoring effect on the phospholipid bilayer of liposomes and thus generating super stealth liposomes that are suitable for the systemic delivery of anticancer drugs. Herein, doxorubicin hydrochloride-loaded super stealth liposomes were studied for the treatment of breast cancer lung metastasis in an animal model. The results demonstrated that the super stealth liposomes had suitable physicochemical properties for in vivo administration and could significantly increase the efficacy of doxorubicin in breast cancer lung metastasis tumor-bearing mice compared to the free drug. The super stealth liposomes also increased doxorubicin accumulation inside the tumor tissue. The permanence of PEG on the surface of the super stealth liposomes favored the formation of a depot of therapeutic nanocarriers inside the tumor tissue by improving their permanence after stopping treatment. The doxorubicin-loaded super stealth liposomes increased the survival of the mouse tumor model. These promising results demonstrate that the doxorubicin-loaded super stealth liposomes could be an effective nanomedicine to treat metastatic breast cancer.

Enhancing myocardial infarction treatment through bionic hydrogel-mediated spatial combination therapy via mtDNA-STING crosstalk modulation.

Myocardial infarction (MI)-induced impaired cardiomyocyte (CM) mitochondrial function and microenvironmental inflammatory cascades severely accelerate the progression of heart failure for compromised myocardial repair. Modulation of the crosstalk between CM mitochondrial DNA (mtDNA) and STING has been recently identified as a robust strategy in enhancing MI treatment, but remains seldom explored. To develop a novel approach that can address persistent myocardial injury using this crosstalk, we report herein construction of a biomimetic hydrogel system, Rb1/PDA-hydrogel comprised of ginsenoside Rb1/polydopamine nanoparticles (Rb1/PDA NPs)-loaded carboxylated chitosan, 4-arm-PEG-phenylboronic acid (4-arm-PEG-PBA), and 4-arm-PEG-dopamine (4-arm-PEG-DA) crosslinked networks. An optimized hydrogel formulation presents not only desired adhesion properties to the surface of the myocardium, but also adaptability for deep myocardial injection, resulting in ROS scavenging, CM mitochondrial function protection, M1 macrophage polarization inhibition through the STING pathway, and angiogenesis promotion via an internal-external spatial combination. The enhanced therapeutic efficiency is supported by the histological analysis of the infarcted area, which shows that the fibrotic area of the MI rats decreases from 58.4% to 5.5%, the thickness of the left ventricular wall increases by 1-fold, and almost complete recovery of cardiac function after 28 days of treatment. Overall, this study reported the first use of a strong adhesive and injectable hydrogel with mtDNA and STING signaling characteristics for enhanced MI treatment via an internal-external spatial combination strategy.

Ultra-pH-sensitive nanoparticle of gambogenic acid for tumor targeting therapy via anti-vascular strategy plus immunotherapy.

Although the combination of anti-vascular strategy plus immunotherapy has emerged as the optimal first-line treatment of hepatocellular carcinoma, lack of tumor targeting leads to low antitumor efficacy and serious side effect. Here, we report an ultra-pH-sensitive nanoparticle of gambogenic acid (GNA) encapsulated by poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA) for tumor-targeting combined therapy of anti-vascular strategy plus immunotherapy. PEG-PAEMA-GNA nanoparticle was quite stable at pH 7.4 for 30 d. In contrast, it exerted size shrinkage, charge reversal and the release of GNA at pH 6.7 within 24 h. Moreover, PEG-PAEMA-GNA significantly enhanced the anti-vascular activity, membrane-disruptive capability and pro-apoptosis when pH changed from 7.4 to 6.7. Western blot analysis exhibits that PEG-PAEMA and its GNA nanoparticle facilitated the phosphorylation of STING protein. In vivo assays show that PEG-PAEMA-GNA not only displayed much higher tumor inhibition of 92 % than 37 % of free GNA, but also inhibited tumor vasculature, promoted the maturation of dendritic cells and recruited more cytotoxic t-lymphocytes for sufficient anti-vascular therapy and immunotherapy. All these results demonstrate that PEG-PAEMA-GNA displayed tumor-targeting combined treatment of anti-vascular therapy and immunotherapy. This study offers a simple and novel method for the combination of anti-vascular therapy and immunotherapy with high selectivity towards tumor.

In vitro and in vivo studies of ocular topically administered NLC for the treatment of uveal melanoma.

Uveal melanoma is one of the most common and aggressive intraocular malignancies, and, due to its great capability of metastasize, it constitutes the most incident intraocular tumor in adults. However, to date there is no effective treatment since achieving the inner ocular tissues still constitutes one of the greatest challenges in actual medicine, because of the complex structure and barriers. Uncoated and PEGylated nanostructured lipid carriers were developed to achieve physico-chemical properties (mean particle size, homogeneity, zeta potential, pH and osmolality) compatible for the ophthalmic administration of (S)-(-)-MRJF22, a new custom-synthetized prodrug for the potential treatment of uveal melanoma. The colloidal physical stability was investigated at different temperatures by Turbiscan® Ageing Station. Morphology analysis and mucoadhesive studies highlighted the presence of small particles suitable to be topically administered on the ocular surface. In vitro release studies performed using Franz diffusion cells demonstrated that the systems were able to provide a slow and prolonged prodrug release. In vitro cytotoxicity test on Human Corneal Epithelium and Human Uveal Melanoma cell lines and Hen's egg-chorioallantoic membrane test showed a dose-dependent cytotoxic effect of the free prodrug on corneal cells, whose cytocompatibility improved when encapsulated into nanoparticles, as also confirmed by in vivo studies on New Zealand albino rabbits. Antiangiogenic capability and preventive anti-inflammatory properties were also investigated on embryonated eggs and rabbits, respectively. Furthermore, preliminary in vivo biodistribution images of fluorescent nanoparticles after topical instillation in rabbits' eyes, suggested their ability to reach the posterior segment of the eye, as a promising strategy for the treatment of choroidal uveal melanoma.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).