Search Results (199)

Background/Objectives: Polyethylene glycol (PEG) is widely used to enhance the stability and pharmacokinetics of nanomedicines, including lipid nanoparticle (LNP)-based mRNA vaccines. However, both pre-existing and vaccine-induced anti-PEG antibodies may compromise the efficacy and safety of PEGylated therapeutics. Methods: In this study, we analyzed the specificity and avidity of anti-PEG antibodies in human blood donor samples from Unvaccinated individuals and recipients of PEGylated mRNA-LNP vaccines (Comirnaty and Spikevax), polysorbate-containing vaccines, or vaccines lacking both PEG and polysorbates. Quantitative ELISA was used to characterize anti-PEG and anti-polysorbate IgM and IgG responses in 325 plasma samples, while an equilibrium titration method was applied to assess IgG binding to PEG molecules, micelles, and PEGylated liposomes with defined structural features in 36 plasma samples. Results: Vaccination with PEGylated mRNA-LNPs was associated with increased anti-PEG antibody levels and qualitative changes in antibody binding behavior. Anti-PEG IgG antibodies displayed progressively higher avidity toward larger and structurally more complex PEG-containing antigens, with the strongest binding observed for PEGylated liposomes. Notably, vaccinated individuals, particularly those who received Spikevax, showed increased end-group and backbone-specific avidity, as well as an enhanced ability of antibody paratopes to engage shorter PEG chains. In contrast, polysorbate-containing or PEG-free vaccines did not elicit comparable effects. Conclusions: These findings suggest that vaccination with PEGylated mRNA-LNPs is associated with the emergence of altered antibody populations with increased end-group reactivity and higher avidity toward PEG-directed immune responses, despite PEG being a synthetic, nonprotein polymer. Antibody binding to LNPs, accompanied by the emergence of high-avidity anti-PEG IgG seems to be consistent with an increased risk of adverse events, particularly following repeated vaccinations, including complement activation-related pseudoallergy (CARPA) and anaphylaxis. It may also contribute to altered immune protection against the vaccine target, underscoring the need for avidity-aware risk-benefit assessment of PEGylated therapeutics. Full article

Cutaneous infections and chronic inflammatory wounds remain difficult to treat because antimicrobial resistance, polymicrobial biofilms, excessive protease activity, oxidative stress, and impaired barrier repair collectively reduce the effectiveness of conventional topical therapies. Plant-derived antimicrobial peptides (AMPs) and peptide-associated bioactives offer antimicrobial, antibiofilm, immunomodulatory, and tissue reparative potential; however, their clinical translation is limited by proteolytic instability, poor stratum corneum penetration, short cutaneous residence time, formulation variability, cytotoxicity risks and limited human evidence. The key research gap is the lack of an integrated translational framework linking plant-derived peptide bioactivity with polymer engineering, advanced delivery systems, skin microenvironment biology, manufacturability, and regulatory feasibility. This review aims to critically evaluate the design principles, therapeutic mechanisms, delivery platforms, and translational barriers of plant-based peptide–polymer therapeutics for cutaneous infection and inflammation. We summarize major classes of plant-derived antimicrobial peptides, including defensins, cyclotides, thionins, hevein-like peptides, snakins, lipid transfer proteins, and knottin-type scaffolds, and examine engineering strategies such as self-assembly, aromatic N-capping, PEGylation, lipidation, dendritic architectures, and stimuli-responsive conjugation. We further discuss topical matrices, nanocarriers, liposomes, electrospun fibers, and surface-tethered biomaterials as delivery platforms for improving peptide stability, local retention, and controlled release. Finally, we identify key translational bottlenecks, including selectivity, toxicity, scalability, batch reproducibility, regulatory classification, and insufficient clinical validation. Mechanism-driven peptide optimization, quality-by-design manufacturing, standardized preclinical models, and controlled clinical trials will be essential for advancing these systems toward safe and effective dermatological therapies. Full article

Objectives: Current liposomal drug delivery studies remain largely formulation-specific and descriptive, with limited predictive capability. This study aimed to develop co-loaded nanoliposomes and establish an integrated framework for predictive analysis of drug release. Methods: PEGylated nanoliposomes co-loaded with bendamustine and rutin were prepared using the thin-film hydration method. Physicochemical properties, encapsulation efficiency, and in vitro release were evaluated. An integrated analytical approach combining data augmentation, monotonicity-constrained denoising, Weibull kinetic modeling, and machine learning was applied to characterize and predict release behavior. Results: Co-loaded formulations exhibited higher encapsulation efficiency (up to 77.75%) and distinct release profiles compared to single-drug systems. Weibull modeling adequately described nonlinear release kinetics (R² ≈ 0.90–0.94). Machine learning enabled within-formulation prediction of later-stage release from early time points (R² > 0.98; MAE ≈ 0.83–1.00%), although leave-one-formulation-out cross-validation confirmed that cross-formulation generalization remains limited. Reconstructed release curves captured overall formulation-dependent trends, despite variable accuracy in individual kinetic parameters. Conclusions: The proposed hybrid framework enables early prediction of drug release and reveals that curve-level behavior may be approximated without precise parameter estimation, though this reflects parameter compensability rather than robust prediction. This work provides a proof-of-concept framework for analyzing nanoliposomal drug delivery systems. Full article

Background: Neuroblastoma (NB) causes about 15% of cancer deaths in childhood. Recently, we suggested cell-surface nucleolin (NCL) as a novel target for preclinical therapy against NB. Methods: Here, a broad range of human NB cell lines were evaluated for NCL expression. PEGylated liposomal nanoparticles, co-encapsulating C6- or C18-ceramides and doxorubicin (DXR) and functionalized with the F3 peptide (F3-lipo[C6-DXR] or F3-lipo[C18-DXR]), were tested against NCL-expressing NB cell lines, grown in monolayers (2D) and as multicellular tumor spheroids (3D). Untargeted liposomes were used as the control. Cytotoxicity and apoptotic/necrotic deaths were evaluated. Results: All NB cell lines expressed cell-surface NCL. Compared to untargeted formulations, F3-lipo[C6-DXR] and F3-lipo[C18-DXR] showed enhanced cellular association and antitumor effects against NB cells. Compared to F3-lipo[C18-DXR], F3-lipo[C6-DXR] was significantly more effective in reducing 2D and 3D NB cell lines’ viability (2D: IC50 range 313–995 nM and 239–629 nM, respectively; 3D: IC50 range 202–416.2 nM and 62.61–398.6 nM, respectively) and in inducing apoptotic cell death. F3-lipo[C6-DXR] also led to a greater cytotoxicity compared to liposomal DXR alone, highlighting the benefit of co-encapsulation. Conclusions: NCL is a promising target in NB, and F3-targeted liposomes enable the selective delivery of their cargo. F3-lipo[C6-DXR] showed superior antitumor activity, supporting ceramide–DXR co-encapsulation as a potential treatment strategy, which needs to be further validated. Full article

Curcumin, a natural polyphenol derived from Curcuma longa, is widely recognized for its therapeutic properties. However, its clinical utility is limited because of poor solubility, rapid degradation and hence low bioavailability. To overcome these issues, nanoformulation approaches, especially PEGylated liposomes, have been explored as advanced delivery systems. PEGylation, which involves attaching polyethylene glycol (PEG) to the liposomal surface, enhances circulation time by creating a steric shield that reduces protein interactions and clearance by the mononuclear phagocyte system (MPS). However, PEG can alter lipid membrane properties, which may in turn affect curcumin’s solubility and distribution within the liposomal bilayer, ultimately reducing its loading efficiency. To ensure that PEG-modified liposomes can be effectively loaded with curcumin, we investigated curcumin–membrane interactions in saturated (DMPC) and unsaturated (POPC) liposomes, both in the presence and absence of PEG. Based on dissociation constants (K_d) obtained from fluorescence spectroscopy measurements, we found that PEGylated DMPC liposomes exhibit the strongest binding affinity for curcumin. Fluorescence quenching experiments showed that curcumin adopts a transbilayer orientation in all membranes examined. Curcumin’s location within PEGylated and non-PEGylated liposomal membranes was further confirmed by examining its effects on membrane properties, including fluidity, polarity, and oxygen transport. These effects were investigated using electron paramagnetic resonance (EPR) spectroscopy with spin labels. The results indicate that PEG does not impose major changes on membrane properties. Curcumin, however, was found to reinforce the liposomal membranes, increase their polarity, and reduce oxygen availability. Overall, the findings suggest that liposomes, particularly those composed of PEGylated DMPC, are effective vehicles for curcumin delivery. Full article

The development of effective inhalable drugs remains a key challenge in the treatment of pulmonary diseases, due to the physiological barriers of the respiratory tract and the lack of predictive models that accurately reproduce the human lung environment. In this context, liposomes (LP) have emerged as promising nanocarriers for pulmonary drug delivery due to their high biocompatibility, surfactant-like composition, capacity to encapsulate both hydrophilic and lipophilic drugs, and potential to provide sustained drug release while reducing systemic toxicity. This study evaluates the influence of size and PEGylation on their physicochemical properties, cytotoxicity, interaction with the pulmonary mucus, and cellular internalisation. LP of 100 nm (LP 100), 200 nm (LP 200), and 600 nm (LP 600) were characterised physiochemically and evaluated in pulmonary cell lines (A549 and Calu-3) exposed in liquid–liquid interface (LLI) and air–liquid interface (ALI) by nebulisation. In addition, artificial pulmonary mucus (APM) was employed to analyse LP penetration through the pulmonary mucus barrier. Results indicate that LP 100 exhibits greater colloidal stability, lower cytotoxicity, and sustained migration through the APM over time with respect to larger particles. PEGylation of LP 100 (LP-PEG) further increases their stability and ability to penetrate the APM, although cellular internalisation is reduced due to the steric effect of the PEG coating. These findings highlight the importance of adjusting the size and surface modifications of LPs according to the therapeutic target of the drug, optimising their persistence on the epithelial surface or their cellular uptake. Full article

Background/Objectives: This pilot study investigates the feasibility of using patient-derived microtumors (PDMs) to assess chemotherapy response in epithelial ovarian cancer. Methods: Fresh tissue from 10 patients was used to develop PDMs, which were then tested against carboplatin/paclitaxel, carboplatin/docetaxel, and carboplatin/pegylated liposomal doxorubicin (PLD). Of the 10 PDMs, 3 were obtained from primary debulking surgery (PDS), and 7 were obtained at the time of interval debulking surgery following neoadjuvant chemotherapy. Results: When looking at PDMs derived from tissue collected at the time of PDS, we found that 100% of PDMs demonstrated a full response to carboplatin/PLD, while 30% showed a full response to all regimens, all of which were derived from high-grade serous carcinoma during PDS. The remaining PDMs showed moderate responses to carbo/taxol and carbo/doce. Conclusions: This study suggests that PDMs can be used to assess the efficacy of chemotherapy regimens, as a hypothesis-generating step toward future predictive validation. Full article

The nano-technological approach and supramolecular chemistry principles relation to the encapsulation of enzymes pave the way for creating next-generation nano-system-functionalized nano-compartments. The most promising approach for prophylaxis and the treatment of organophosphate (OP) poisoning is the use of stable, bioavailable nano-compartments containing OP-scavenging enzymes. Such enzymes, like butyrylcholinesterase (BChE), wild type and mutants, could also be used for the detoxification of other poisonous esters. There are two types of IRD-labeled human BChE-containing nano-scavengers: PEGylated liposomes and polyethyleneglycol–polypropylenesulfide polymersomes, which were developed with diameter close to 100 nm. BChE-polymersomes have higher encapsulation efficiency (95%) and slower release rate of enzymes (more than 7 days) compared to BChE-liposomes. The catalytic properties of encapsulated enzymes were analyzed for nano-compartment formulations, lipophilicity, the structure of block copolymers, and for different ester substrate polarity: positively charged butyrylthiocholine iodide, neutral phenyl acetate, and negatively charged aspirin. The highest k_cat (more than three times) compared to non-encapsulated BChE was for polymersomes based on diblock PEG-PPS polymersomes towards the neutral phenyl acetate substrate. Full article

Evidence on the therapeutic use of nanoparticles for traumatic brain injury (TBI) remains limited. This study aimed to evaluate the neuroprotective potential of atorvastatin-loaded polyethylene glycol (PEG)-conjugated liposomes (LipoStatin) in a mouse model of repetitive TBI. TBI was induced using five controlled head impacts with a 120 g weight at 12-h intervals. Mice were randomly assigned to Sham, Control (saline-treated), Statin (free atorvastatin), Liposome (empty PEGylated liposomes without atorvastatin), and LipoStatin (atorvastatin-loaded PEGylated liposome) groups. LipoStatin (10 mg/kg/day) was intravenously administered for 5 days post-injury. Neurological function was evaluated using the neurological severity score (NSS), while blood–brain barrier (BBB) integrity and neuroinflammation were assessed on day 5, and cellular apoptosis on day 12. LipoStatin-treated mice exhibited the lowest NSSs. IVIS^® imaging indicated significantly attenuated BBB disruption (p < 0.001), and Western blot analysis revealed restored caveolin-1 protein levels (p < 0.01), which are associated with BBB integrity. TNF-α levels were reduced considerably in the LipoStatin group compared to both the Control (p < 0.001) and Statin (p < 0.05) groups. Immunofluorescence showed reduced co-localization of caspase-3 with PDGFR-β and GFAP, indicating decreased pericyte and astrocyte apoptosis. These findings suggest that LipoStatin may confer neuroprotection in TBI by stabilizing BBB integrity, reducing inflammation, and mitigating cell death, supporting its potential as an improved nanocarrier-based therapeutic approach. Full article

Liposomes started to be studied for drug delivery in 1970s, taking advantage of their ability to encapsulate hydrophilic and hydrophobic drugs using biodegradable and biocompatible molecules. Nowadays, they remain one of the most promising strategies for drug delivery not only in cancer treatment but also in gene therapies and vaccines. The design and development of liposomal systems have evolved significantly over the past decades, moving from conventional formulations to advanced, stimulus-responsive, and multifunctional nanocarriers. Analogous to the myth of the Trojan Horse, liposomes must mislead the host immune system to reach the interior of cancer cells in order to deliver the therapeutic payload. There are many barriers that liposomes have to overcome to circulate through the bloodstream and specifically target cancer cells without damaging other tissues. Crucial parameters such as lipid composition, particle size, zeta potential, and PEGylation have been systematically optimized to enhance pharmacokinetics and biodistribution and to improve delivery efficiency. Furthermore, conjugation with antibodies, peptides, or small molecules has enabled active targeting, while stimuli such as pH, temperature, and enzymatic activity have been exploited for controlled drug release within the tumor microenvironment. Such innovations have laid the groundwork for translating liposomal formulations from the bench to clinical applications. In this paper, we evaluate the physicochemical features of liposomal design that underpin their suitability and efficacy for anticancer drug delivery. We aimed to focus on two main aspects: conducting an exhaustive review of the physicochemical parameters of liposomal drugs that have already been approved by regulatory agencies, while maintaining a pedagogical approach when explaining the key design parameters for the optimal design of liposomes in oncology in detail. Full article

Background: Betulins (betulin, betulinic acid and lupeol) demonstrated antitumor and chemopreventive activity but showed low bioavailability due to their self-aggregation in hydrophilic environments. To overcome these disadvantages, their incorporation into lipid nanoformulations (PEGylated liposomes and Lipid Nanostructured Carriers (NLCs)) has proven to represent a viable solution. Objectives: The purpose of this study is to evaluate the size and incorporation rate of these molecules in nanoformulations, as well as their delivery and metabolic fate (pure betulinic acid versus a standardized extract, TT) relative to Doxorubicin using an in vivo protocol. The investigation extended our previous in vitro investigations towards an in vivo evaluation of antitumor activity, metabolic fate and toxicity in Wistar rats bearing Walker 256 carcinoma tumors over 21 days. Since previous studies used oral or intratumor administration, this exploratory study applied intravenous administration via microbubble-assisted sonoporation, considering its higher relevance for translational studies. Methods: The delivery and metabolic fate of the parent molecules, the identification of their fragments and metabolites using UHPLC-QTOF-ESI⁺MS were investigated, along with the identification of some toxicity biomarkers in rat plasma, tumor tissues and urine. Results: Preferential accumulation of Doxorubicin in tumors was observed compared to betulinic acid and TT components, as well as their persistence in plasma or elimination in urine. Compared to PEGylated liposomes, NLC formulations (especially NLC Doxo) induced a lower survival rate, a decreased bioavailability and increased toxicity by around 20%. Conclusions: These data are a starting point and complement the contrast-enhanced imaging and histology evaluations, which may contribute to the actual knowledge about the in vivo fate of betulins. Full article

Objectives: Endometrial cancer is the most common gynaecologic malignancy, and its mortality rate is rising. Advanced or recurrent disease remains challenging because historically there have been limited therapeutic options. We aim to describe a complete and durable response to the HER2-directed antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in a heavily pretreated patient with HER2-positive, mismatch-repair-deficient metastatic serous endometrial cancer. Methods: A 72-year-old woman underwent hysterectomy, bilateral salpingo-oophorectomy, and staging procedures for FIGO stage IIIA, high-grade serous papillary endometrial carcinoma. Tumour profiling revealed dMMR, a p53 abnormal pattern, and HER2 overexpression (IHC 3+). She received carboplatin/paclitaxel plus avelumab, followed by pegylated liposomal doxorubicin and weekly paclitaxel. After progression on paclitaxel, off-label T-DXd was initiated. Molecular data (FoundationOne CDx) were collected, along with and serial imaging and CA125 assessments. Results: The patient developed cough after two cycles of T-DXd; interstitial lung disease was excluded, and treatment resumed with steroid cover. By December 2024, PET/CT demonstrated complete metabolic response, with resolution of vaginal-vault and para-aortic lesions and normalisation of CA125. Real-world progression-free survival exceeded eight months, with ongoing symptom improvement. Treatment was generally well tolerated; the principal adverse event was grade 3 neutropenia requiring dose reduction. No cardiotoxicity or interstitial lung disease occurred. Conclusions: This case illustrates that T-DXd can induce deep and durable remission in HER2-positive, dMMR metastatic serous endometrial cancer after multiple lines of therapy. It adds real-world evidence supporting further investigation of HER2-directed antibody–drug conjugates in gynaecologic malignancies, and underscores the need for confirmatory trials and refined biomarker-driven patient selection. Full article

Lutein is one of carotenoids in the human brain that is consistently associated with all cognitive performance indicators, and its levels are closely linked to age-related cognitive decline. However, lutein application is limited by its poor stability and low bioaccessibility. In this study, a lutein-loaded delivery system was developed to enhance stability and achieve brain-targeting effects. Using high-speed shear and ethanol hydration methods, PEGylated lutein liposomes with lactoferrin (Lf-LLips) were constructed and characterized. The morphology was observed using TEM and AFM. Particle sizes and lutein retention rates were evaluated under different temperatures (4 °C, 25 ± 2 °C, 50 °C), light (diffusion light, DL; light shielding, LS), and storage durations at 28 d. Compared with free lutein, the in vitro release behavior and permeability across the blood–brain barrier of the systems were investigated. Lf-LLips exhibited a particle size of 186.63 ± 2.04 nm and a potential of −30.53 ± 1.65 mV, and the lutein encapsulation efficiency was 83.11 ± 1.67%. When stored under LS, the particle size of Lf-LLips remained under 190 nm at 4 °C for 28 days, and the retention rate of lutein exceeded 80%. The release curve of Lf-LLips in vitro over 72 h followed the Weibull model. Furthermore, the permeability across the blood–brain barrier model within 12 h was 22.73 ± 1.42%. These results demonstrate that Lf-LLips significantly improve the stability of lutein and exhibit sustained-release properties along with brain-targeting efficiency. The findings demonstrate the promising future of lutein for applications in brain health enhancement. Full article

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

Background/Objectives: To compare oncologic outcomes of second-line chemotherapy regimens in relapsed high-grade serous ovarian cancer (HGSOC) by platinum sensitivity. Methods: We retrospectively reviewed HGSOC patients treated at two centers (June 2003–December 2020), classified by platinum-free interval (6- and 12-month cut-offs). Outcomes were progression-free survival (PFS, primary) and objective response and disease control rates (secondary). Regimens administered to ≥10% of patients or with favorable outcomes were compared using multivariable Cox analyses. Results: Among 468 patients (41.2% sensitive, 32.9% partially sensitive, 25.9% resistant), platinum-sensitive patients were younger (p = 0.024), diagnosed earlier, and more likely to undergo primary debulking surgery (both p < 0.001), achieving best outcomes after second-line chemotherapy (median PFS 14.8 vs. 10.5 and 5.2 months, p < 0.001). In both sensitive groups, the most common regimens were taxane + platinum ± bevacizumab, followed by pegylated liposomal doxorubicin + carboplatin, which was associated with shorter PFS in platinum-sensitive patients (hazard ratio (HR) 1.67, p = 0.016). Second-line maintenance with bevacizumab or poly(ADP-ribose) polymerase inhibitors was associated with improved PFS in both groups (p < 0.001). In platinum-resistant patients, the omission of bevacizumab (HR 2.01, p < 0.001) and a primary treatment history without cytoreduction (HR 4.43, p = 0.044) were associated with inferior outcomes. Conclusions: In platinum-sensitive patients with a favorable prognosis, taxane + platinum regimens were most commonly used and outperformed PLD + carboplatin. Maintenance therapy also conferred a meaningful benefit. In platinum-resistant disease, bevacizumab use and prior cytoreductive surgery may improve outcomes, underscoring the importance of treatment selection and surgical approach. Full article