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.

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.

Modeling brain pathology to study nose-to-brain drug delivery.

OBJECTIVES: To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain tissueMETHODS: Citicoline, cytidine diphosphocholine, designated as CDP-choline, was purchased as a white powder with the molecular weight of 510.31 g/mol. The triblock copolymers of polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol (PEG-PPG-PEG), branded as Pluronic F127, was used. RESULTS: When instilled into the nasal cavity, Pluronic F127 for intranasal administration is transformed into a gel that remains retained for 45-55 minutes, which promotes better penetration of drugs into the brain tissue. CONCLUSION: The polymer's gelling and adhesive properties performed well, which is crucial for further research at the preclinical stage (Tab. 1, Fig. 5, Ref. 28).

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.

Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know?

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

A journey through the history of PEGylated drug delivery nanocarriers.

This note aims to inspire through providing a personal view of the development and potential Drug Delivery Nanocarriers functionalized with polythyleneglycol (PEG). This polymer has been used extensively in Pharmaceutical Technology in a variety of compositions, including polyethylene oxide (PEO)-based surfactants. However, the concept of PEGylation, which started in the 70's, differs from the functionality of a surfactant, already discloses in the 50's. Here, we strictly adhere to the biological functionality of PEGylated nanocarriers intended to have a reduced interaction with proteins and, therefore, modify their biodistribution as well as facilitate their diffusion across mucus and other biological barriers. We analyze how this concept has evolved over the years and the benefit obtained so far in terms of marketed nanomedicines and provide the readers with a prospect view of the topic.

HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model.

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

An injectable, nanostructured implant for the delivery of adenosine triphosphate: towards long-acting formulations of small, hydrophilic drugs.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.

Efficacy of Polyethylene Glycol Electrolyte Powder Combined With Linaclotide for Colon Cleansing in Patients With Chronic Constipation Undergoing Colonoscopy: A Multicenter, Single-Blinded, Randomized Controlled Trial.

INTRODUCTION: Constipation is an independent risk factor for poor bowel preparation. This study aimed to evaluate the bowel cleansing efficacy and safety of polyethylene glycol (PEG) combined with linaclotide (lin) for colonoscopy in patients with chronic constipation (CC). METHODS: This single-blinded, randomized, controlled, and multicenter study was conducted from July 2021 to December 2022 at 7 hospitals. Patients with CC who underwent colonoscopies were enrolled and randomly assigned to 4 groups with split-PEG regimens: 4L-PEG group, 4L-PEG+1d-Lin group, 3L-PEG+1d-Lin group, and 3L-PEG+3d-Lin group. The primary outcome was rates of adequate bowel preparation, defined as a total BBPS score ≥6 and a score ≥2 for each segment. Secondary outcomes were adverse effects, sleep quality, willingness to repeat the colonoscopy, adenoma detection rate, and polyp detection rate. RESULTS: Five hundred two patients were enrolled. The rates of adequate bowel preparation (80.0% vs 60.3%, P < 0.001; 84.4% vs 60.3%, P < 0.001) and the total Boston Bowel Preparation Scale (BBPS) scores (6.90 ± 1.28 vs 6.00 ± 1.61, P < 0.001; 7.03 ± 1.24 vs 6.00 ± 1.61, P < 0.01) in the 4L-PEG+1d-Lin group and the 3L-PEG+3d-Lin group were superior to that in the 4L-PEG group. Compared with the 4L-PEG group, the 4L-PEG+1d-Lin group (66.7% vs 81.7%, P = 0.008) and the 3L-PEG+3d-Lin group (75.0% vs 81.7%, P = 0.224) had a lower percentage of mild adverse events. No statistically significant difference in willingness to repeat the colonoscopy, sleep quality, polyp detection rate, or adenoma detection rate was observed among groups. DISCUSSION: PEG combined with linaclotide might be an effective method for bowel preparation before colonoscopy in patients with CC.

Chemical pneumonitis secondary to accidental pulmonary polyethylene glycol-electrolyte solution infusion in a cat.

OBJECTIVE: To describe the successful conservative management of chemical pneumonitis and presumed acute respiratory distress syndrome in a cat secondary to inadvertent pulmonary polyethylene glycol-electrolyte solution (PEG-ELS) instillation. CASE SUMMARY: PEG-ELS is commonly used in small animals for bowel cleansing and to treat constipation. There have been several instances of aspiration or accidental instillation of this solution into the lungs of both people and dogs. PEG-ELS was inadvertently infused into the lungs of the cat in the current report. After 10 days in the ICU, during which time treatment with oxygen therapy, antibiosis, diuretics, and corticosteroids was provided, the cat was successfully discharged. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first report of instillation of PEG-ELS in a cat resulting in chemical pneumonitis and lung injury. We describe the successful management of this condition with conservative management and without the need for invasive interventions such as bronchoscopy and lavage or mechanical ventilation.

Metabolic dysfunction-associated steatohepatitis treated by poly(ethylene glycol)-block-poly(cysteine) block copolymer-based self-assembling antioxidant nanoparticles.

Non-alcoholic steatohepatitis (NASH), now known as metabolic dysfunction-associated steatohepatitis (MASH), involves oxidative stress caused by the overproduction of reactive oxygen species (ROS). Small-molecule antioxidants have not been approved for antioxidant chemotherapy because of severe adverse effects that collapse redox homeostasis, even in healthy tissues. To overcome these disadvantages, we have been developing poly(ethylene glycol)-block-poly(cysteine) (PEG-block-PCys)-based self-assembling polymer nanoparticles (NanoCyses), releasing Cys after in vivo degradation by endogenous enzymes, to obtain antioxidant effects without adverse effects. However, a comprehensive investigation of the effects of polymer design on therapeutic outcomes has not yet been conducted to develop our NanoCys system for antioxidant chemotherapy. In this study, we synthesized different poly(L-cysteine) (PCys) chains whose sulfanyl groups were protected by tert-butyl thiol (StBu) and butyryl (Bu) groups to change the reactivity of the side chains, affording NanoCys(SS) and NanoCys(Bu), respectively. To elucidate the importance of the polymer design, these NanoCyses were orally administered to MASH model mice as a model of oxidative stress-related diseases. Consequently, the acyl-protective NanoCys(Bu) significantly suppressed hepatic lipid accumulation and oxidative stress compared to NanoCys(SS). Furthermore, we substantiated that shorter PCys were much better than longer PCys for therapeutic outcomes and the effects related to the liberation properties of Cys from these nanoparticles. Owing to its antioxidant functions, NanoCyses also significantly attenuated hepatic inflammation and fibrosis in the MASH mouse model.

"Click" amphotericin B in prodrug nanoformulations for enhanced systemic fungemia treatment.

Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.

The baicalein amorphous solid dispersion to enhance the dissolution and bioavailability and effects on growth performance, meat quality, antioxidant capacity and intestinal flora in Taihang chickens.

Baicalein (BAI) is a natural flavonoid with antioxidant, antitumor and antibacterial properties. However, the bioavailability of BAI was limited due to low solubility. This study aims to improve the solubility of BAI through the amorphous solid dispersion (ASD) and evaluate changes in its pharmacokinetics and pharmacodynamics in Taihang chickens. Polyethylene caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer (Soluplus) was chosen as the carrier, and ASD was prepared by rotary evaporation and was characterized by powder X-ray diffractions (PXRD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). In vitro dissolution assays were used to screen the optimal ratio of drug to carrier, in vivo pharmacokinetic assays were conducted to investigate the promoting effect on the absorption. In addition, the effects of ASD on the growth performance, meat quality, antioxidant capacity and intestinal flora were investigated. ASD (1:9 and 2:8) did not exhibit crystal diffraction peaks of BAI in PXRD or endothermic peaks in DSC, indicating the successful preparation of ASD. The results of in vitro dissolution assay showed that the cumulative dissolution rate of ASD (2:8) within 600 min was 52.67%, which was 7.84-fold higher than BAI. The pharmacokinetic results showed that the peak concentration (Cmax) and the area under the drug-time curve (AUC0∼24) of ASD (2:8) was (5.20 ± 0.82) µg/mL and (17.03 ± 0.67) µg·h/mL, which was 1.91 and 2.64-fold higher than BAI, respectively. Dietary supplementation of BAI and ASD could increase average daily gain (ADG), while decrease feed conversion ratio (FCR), but there was no significant difference (P > 0.05). The drip loss of BAIASD group was lower than BAI group (P < 0.05). In addition, the antioxidant capacity of Taihang chickens were enhanced, the diversity and the abundance of beneficial bacteria was improved. Results of BAI upon the dietary supplementation tested in Taihang chickens, after preparation of ASD, indicating a superior enhancement effect in growth performance, meat quality, antioxidant capacity and intestinal flora due to an improved solubility and optimized bioavailability.

Anti-inflammatory effect of a novel piperazino-enaminone delivered by liposomes in a mouse model of hemophilic arthropathy.

Hemophilic arthropathy (HA) is a condition caused by recurrent intra-articular bleeding in patients with hemophilia. Pro-inflammatory cytokines play a crucial role in the pathogenesis of HA. Our previous research demonstrated that a novel compound, piperazino-enaminone (JODI), effectively inhibited pro-inflammatory cytokines, including IL-6, MCP-1, MIP-1α, and MIP-1ß, in a mouse model of hemarthrosis. This study aims to enhance the anti-inflammatory effect of JODI by employing nanoparticle delivery systems, which could potentially improve its poor water solubility. Here, we developed liposomes modified with polyethylene glycol (PEG) for the delivery of JODI (JODI-LIP), and found that JODI-LIP exhibited uniform size, morphology, good stability and in vitro release degree. JODI-LIP mitigated cytotoxicity of JODI, and significantly suppressed the production of pro-inflammatory cytokines (TNF-α and IL-1ß) and nitric oxide (NO) release in RAW 264.7 cells stimulated by lipopolysaccharide (LPS), as well as the proliferation of human fibroblast-like synovial (HFLS) cells. In a murine model of HA, JODI-LIP demonstrated superior efficacy in ameliorating joint swelling and synovitis, compared to JODI. Importantly, JODI-LIP markedly reduced pro-inflammatory cytokines (TNF-α, IFN-γ, IL-33, and MCP-1) in injured joints. No hepatic or hematological toxicity was observed in mice treated with JODI-LIP. In summary, our results suggest that JODI-LIP holds promise as a therapeutic intervention for HA by attenuating pro-inflammatory cytokine levels.

Commentary: Is Polyethylene Glycol Toxicity From Intravenous Methocarbamol Fact or Fiction?

Methocarbamol is an antispasmodic muscle relaxant and was the fourth most-prescribed muscle relaxant by volume in the United States in 2021. Intravenous (IV) methocarbamol contains the excipient, polyethylene glycol (PEG), which has been implicated in metabolic acidosis and nephrotoxicity. Intravenous methocarbamol was first approved by the US Food and Drug Administration in 1959 and at that time the IV methocarbamol prescribing information warned of PEG-associated adverse drug events in patients living with renal impairment; however, the manufacturer acknowledged data were lacking to objectively support this claim. Clinicians prescribing and dispensing IV methocarbamol may encounter the warning for PEG-associated metabolic acidosis and nephrotoxicity without knowing the potential risks, or lack thereof, supporting or disavowing this phenomenon. This commentary debates the merits supporting and arguments refuting PEG-associated metabolic acidosis and nephrotoxicity in patients treated with IV methocarbamol.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats.

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Real-life use of ropeg-interferon α2b in polycythemia vera: patient selection and clinical outcomes.

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.