Liposomal Nanoparticles Research Articles

Reparative Efficacy of Liposome-Encapsulated Oleanolic Acid against Liver Inflammation Induced by Fine Ambient Particulate Matter and Alcohol in Mice.

Airborne fine particulate matter (PM2.5) is a severe problem and is associated with health issues including liver diseases. Workers performing manual labor tend to be alcohol consumers during work, where they are also exposed to PM2.5. Long-term PM2.5 exposure can increase oxidative stress, leading to inflammation. Whether long-term exposure to air pollution and alcohol synergistically increases liver fibrosis risk warrants investigation. Oleanolic acid (OA)—a triterpenoid—has antioxidant and anti-inflammatory activities, but its low water solubility and cytotoxicity impair its potential applications. In this study, we fabricated liposomal OA nanoparticles (Lipo-OAs); then, we evaluated the anti-inflammatory effect on exposed cells and the ameliorative effect of Lipo-OAs on PM2.5 and alcohol-induced liver fibrosis in mice. The half maximal inhibitory concentration of PM2.5 for hepatic stellate cells was 900 μg/mL; at a concentration of ≥600 μg/mL, PM2.5 significantly increased interleukin-6 and tumor necrosis factor-α production. OA encapsulation in Lipo-OAs, 353 ± 140 nm in diameter with 79% encapsulation efficiency, significantly reduced OA cytotoxicity. Lipo-OAs treatment significantly reduced alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase levels; histologically, it alleviated steatosis and improved Ishak’s modified HAI score. In conclusion, Lipo-OAs have potential anti-inflammatory and reparative effects for PM2.5 and alcohol-induced liver injury treatment.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Endothelial‐specific nanodelivery of Rho kinase inhibitors: Targeting tumor angiogenesis and metastasis

ObjectiveThe limitations of current vascular endothelial growth factor (VEGF)‐centered anti‐angiogenic therapy include the inhibition of physiological angiogenesis, development of evasive resistance, and increased vascular leakage, which drives the need for a novel therapy for tumor angiogenesis and metastasis. RhoA pathway inhibition blocks VEGF‐ and sphingosine‐1 phosphate (S1P)‐induced angiogenesis and vascular leakage without hindering endogenous angiogenesis. Fasudil, a clinically relevant Rho‐associated kinase (ROCK) inhibitor, blocks the RhoA downstream signaling, but adverse events (hypotension, skin reactions) exist. Here, we propose endothelial ROCK targeting with Fasudil‐containing immune‐related nanodelivery.HypothesisFasudil‐encapsulated CD31‐targeting liposomal formulation is a potential tumor antiangiogenic therapy by blocking RhoA signaling via ROCK inhibition in the endothelial cells.MethodsFasudil‐liposomal nanoparticles were prepared by DPPC, cholesterol, 16:0 PEG2000PE, DSPE‐PEG2000‐mal, DSPE‐PEG‐FITC, and CHCl3: MeOH (4:1) combination, thin‐film formation, downsizing after Fasudil incorporation, filtering, and conjugation with IgG and CD31‐targeting antibodies. We used dynamic light scattering (DLS) for the liposomal characterization, dose‐response experiments on primary Human Umbilical Vein Endothelial Cells (HUVEC) and Bend3 cells for in vitro toxicity evaluation, antibody (Ab)‐to‐liposome binding evaluation and pathway inhibition evaluation by western blot, and UPLC analysis (EE)% for the evaluation of encapsulation efficiency. The binding affinity of the CD31‐conjugated liposomes and their time‐dependent cell incorporation were evaluated by competitive binding assay via immunohistochemistry (IHC) and flow cytometry. Morphometric analysis was assessed by Livecyte imaging analysis.ResultsSize and PDI measurement by DLS confirmed the stability of our formulation, which presented limited toxicity (concentration: 0.625‐5120 µM; IC50 at 43.05 µM [HUVECs over 24 hours of treatment]) with a significantly higher overall survival rate than Fasudil. Efficient CD31 and mouse IgG Ab conjugation to Fasudil liposomes and blockade of the RhoA downstream signaling in endothelial cells were confirmed. The specific binding of CD31‐targeting liposomes on endothelial cells was verified in the presence and absence of excess CD31 Ab. The time‐dependent study confirmed the kinetics of liposome incorporation in endothelial cells and the enhanced uptake of CD31 liposomes compared to IgG. Cell morphometric and physiological analysis revealed comparable alterations caused by Fasudil‐ and endothelial‐specific Fasudil‐containing liposomes.ConclusionWe have successfully developed Fasudil‐encapsulated, CD31‐targeting liposomes. Future studies will be directed to study the formulation’s effect on endothelial physiology in vitro and in vivo, tumor growth, angiogenesis, and metastasis.

Delivery of TAPI‐1 via Neutrophil Membrane Fusogenic Liposomal Nanoparticles Can Effectively Ameliorate Cardiac Dysfunction in Heart Failure

Nanomedicine has been widely employed as a site‐specific and target‐oriented drug delivery tactic in treating heart failure (HF). Ischemia‐induced inflammation plays a robust role in the development of HF and neutrophil is one of the main immune cell types that rapidly infiltrate into the inflamed tissues after myocardial infarction (MI). In the present study, we examined the efficacy of a formation of biomimetic nanoparticles that were prepared by fabricated TAPI‐1 loaded liposomes coated with neutrophil membranes in the treatment of HF. Male SD rats underwent coronary artery ligation (CL) to induce HF. These HF rats were treated with intravenous injection of TAPI‐1‐loaded biomimetic nanoparticles (n=6) or TAPI‐1 alone (n=6) for 4 weeks. The left ventricular (LV) function was assessed by echocardiography within 24 hours and 4 weeks after CL. The nanoparticles were evaluated prior to the treatments. Compared with non‐coated formation, neutrophil membrane‐coated nanoparticles have high uptake into LPS‐stimulated cardiac cells or endothelial cells. Moreover, the coated nanoparticles exhibited higher cell‐specific targeting potential and internalization capacity than non‐coated nanoparticles in LPS‐stimulated endothelial cells. Small animal imaging showed that DiR‐labeled nanoparticles were mainly accumulated in the injured heart after MI. Compared with HF rats treated with TAPI‐1 alone, the HF rats treated with TAPI‐1‐loaded nanoparticles had significantly (* p<0.05) improved anatomic indicators with reduced ratio (%) of heart/body weight (0.34 ± 0.042* vs. 0.48± 0.11) and lung/body weight (0.84 ± 0.19* vs. 1.14 ± 0.15). Additionally, one 4‐week treatment with TAPI‐1‐loaded biomimetic nanoparticles reduced LV end systolic volume (0.67±0.032* vs. 0.83±0.036, mL) when compared with the TAPI‐1 alone. While LV stroke volume (LVSV) did not change significantly in IV TAPI‐1‐treated HF animals, LVSV (0.47±0.043* vs. 0.27±0.029, mL) was significantly increased in HF rats treated with TAPI‐1‐loaded nanoparticles at 4 weeks vs. 24 hours after CL. LV end diastolic volume, LV ejection fraction, and LV infarction zone didn’t exhibit significant differences between two treatment groups. Cardiac hemodynamic measurements revealed that the HF rats treated with TAPI‐1‐loaded nanoparticles had decreased LV end diastolic pressure (10.53±1.67* vs. 19.01±3.32, mmHg) and elevated dP/dtmax(8202.65±658.09* vs. 5994.47±630.81) compared with the HF rats‐treated with TAPI‐1 alone. Histological evaluation indicated that the fibrosis areas surrounding the infarction scar were significant reduced (15.97±1.84* vs. 22.86±2.27, %) in HF rats treated with TAPI‐1‐loaded nanoparticles vs. TAPI alone. Flow cytometric analysis also demonstrated that treatment with TAPI‐1‐loaded nanoparticles improved inflammatory conditions indicated by increased ratio of CD4+/CD8+ T Cells (2.40±0.67* vs. 1.56±0.21) in the blood and reduced percentage of leukocytes in the heart of HF. These data indicate that neutrophil membrane fusogenic liposomal nanoparticle is an effective drug delivery approach in treating this devastating disease. (Supported by NIH grants R01 HL‐139521 & HL‐155091 to SGW, S10 OD019941 to RW)

Liposome-Encapsulated Tobramycin and IDR-1018 Peptide Mediated Biofilm Disruption and Enhanced Antimicrobial Activity against Pseudomonas aeruginosa.

The inadequate eradication of pulmonary infections and chronic inflammation are significant complications in cystic fibrosis (CF) patients, who usually suffer from persistent and frequent lung infections caused by several pathogens, particularly Pseudomonas aeruginosa (P. aeruginosa). The ability of pathogenic microbes to protect themselves from biofilms leads to the development of an innate immune response and antibiotic resistance. In the present work, a reference bacterial strain of P. aeruginosa (PA01) and a multidrug-resistant isolate (MDR 7067) were used to explore the microbial susceptibility to three antibiotics (ceftazidime, imipenem, and tobramycin) and an anti-biofilm peptide (IDR-1018 peptide) using the minimum inhibition concentration (MIC). The most effective antibiotic was then encapsulated into liposomal nanoparticles and the IDR-1018 peptide with antibacterial activity, and the ability to disrupt the produced biofilm against PA01 and MDR 7067 was assessed. The MIC evaluation of the tobramycin antibacterial activity showed an insignificant effect on the liposomes loaded with tobramycin and liposomes encapsulating tobramycin and IDR-1018 against both P. aeruginosa strains to free tobramycin. Nevertheless, the biofilm formation was significantly reduced (p < 0.05) at concentrations of ≥4 μg/mL and ≤32 μg/mL for PA01 and ≤32 μg/mL for MDR 7067 when loading tobramycin into liposomes, with or without the anti-biofilm peptide compared to the free antibiotic, empty liposomes, and IDR-1018-loaded liposomes. A tobramycin concentration of ≤256 µg/mL was safe when exposed to a lung carcinoma cell line upon its encapsulation into the liposomal formulation. Tobramycin-loaded liposomes could be a potential candidate for treating lung-infected animal models owing to the high therapeutic efficacy and safety profile of this system compared to the free administration of the antibiotic.

A Revolutionary Blueprint for Mitigation of Hypertension via Nanoemulsion.

Hypertension is one of the most important causes of mortality, affecting the health status of the patient. At the same time, hypertension causes a huge health and economic burden on the whole world. The incidence and prevalence of hypertension are rising even among young people in both urban as well as rural communities. Although various conventional therapeutic moieties are available for the management of hypertension, they have serious flaws such as hepatic metabolism, reduced dose frequency, poor aqueous solubility, reduced bioavailability, and increased adverse effects, making the drug therapy ineffective. Therefore, it is required to design a novel drug delivery system having the capability to solve the constraints associated with conventional treatment of hypertension. Nanotechnology is a new way of using and manipulating the matter at the molecular level, whose functional organization is measured in nanometers. The applications of nanotechnology in the field of medicine provide an alternative and novel direction for the treatment of cardiovascular diseases and show excellent performance in the field of targeted drug therapy. Various nanotechnologies based drug delivery systems, such as solid lipid nanoparticles, nanosuspension, nanoemulsion, liposome, self-emulsifying systems, and polymeric nanoparticles, are available. Among them, nanoemulsion has provided a niche to supplement currently available therapeutic choices due to numerous benefits like stability, ease of preparation, enhanced drug absorption, reduced hepatic metabolism, increased dose frequency, enhanced bioavailability, and encapsulation of hydrophilic as well as hydrophobic drugs. This present review provides an in-depth idea about progression in treatment of hypertension, constraints for antihypertensive drug therapy, need of nanoemulsions to overcome these constraints, comparative analysis of nanoemulsions over other nanostructure drug delivery systems, pharmacodynamics studies of nanoemulsions for treatment of hypertension, recent patents for drug-loaded nanoemulsions meant for hypertension, and marketed formulations of nanoemulsions for hypertension.

Quantification of Available Ligand Density on the Surface of Targeted Liposomal Nanomedicines at the Single-Particle Level.

Active targeting has been hailed as one of the most promising strategies to further enhance the therapeutic efficacy of liposomal nanomedicines. Owing to the critical role of ligand density in mediating cellular uptake and the intrinsic heterogeneity of liposomal formulations, precise quantification of the surface ligand density on a single-particle basis is of fundamental importance. In this work, we report a method to simultaneously measure the particle size and the number of ligands on the same liposomal nanoparticles by nanoflow cytometry. Then the ligand density for each individual liposome can be determined. With an analysis rate up to 10 000 particles per minute, a statistically representative distribution of ligand density could be determined in minutes. By utilizing fluorescently labeled recombinant receptors as the detection probe against the conjugated ligands, only those available for cell targeting can be exclusively detected. The influence of ligand input, conjugation strategy, and the polyethylene glycol spacer length on the available ligand density of folate-modified liposomes was investigated. The correlation between the available ligand density and cell targeting capability was assessed in a quantitative perspective for liposomes modified with three different targeting moieties. The optimal ligand density was determined to be 0.5-2.0, 0.7, and 0.2 ligand per 100 nm2 for folate-, transferrin-, and HER2-antibody-conjugated liposomes, respectively. These optimal values agreed well with the spike density of the natural counterparts, viruses. The as-developed approach is generally applicable to a wide range of active-targeting nanocarriers.

MiR-100-loaded liposomal nanoparticles inhibit migration and invasion of gastric cancer cells through targeting trefoil factor 1 to mediate stromal cell derived factor-1a/C-X-C chemokine receptor type 4 signaling pathway

Abnormal expression of miR-100 is indicated to influence the progression of gastric cancer (GC). As a carrier of miR-100, liposomal nanoparticles (LNPs) can accelerate the entry of miR-100 into cells and improve drug effectiveness. In this study, we investigated the underlying mechanism whereby LNPs carrying miR-100 impact invasiveness of GC cells to provide a new strategy for managing the disorder. Human GC cells were treated with empty vectors, miR-100 mimic, and miR-100-loaded LNPs. SDF-1a/CXCR4 inhibitor was established as control group. Upon treatments, RT-qPCR was used to determine miR-100 expression in GC cells and Transwell and scratch assay was used to assess cell migration and invasion. Luciferase-reporter gene assay and Western blot analysis detected the interaction between miR-100 and SDF-1a/CXCR4 signaling pathway. Treatment with miR-100-loaded LNPs obtained the highest expression of miR-100, even higher than transfection with miR-100 mimic (P &lt; 0.05), without difference between miR-100 mimic group and empty vector group (P &gt; 0.05). With amplified bands of 610 bp detected in the miR-100-loaded LNPs, the nanoparticles dramatically decreased cell migration and invasion with the lowest number of migrated cells and migration speed and healing rate among all the groups. Empty vector and miR-10 mimic exerted similar effect on cell migration and invasion (P &gt; 0.05). With binding regions between them, miR-100 was indicated as the target gene of TFF1. The fluorescence intensity of mutant plasmid was greater than that of wild-type plasmid (P &lt; 0.05). Moreover, the miR-100-loaded LNPs resulted in decreased SDF-1a/CXCR4 expression, lower than that of the other groups. Isolated overexpression of miR-100 or empty vector similarly down-regulated SDF-1a/CXCR4.Collectively, the miR-100 loaded with LNPs effectively up-regulates miR-100 expression and inhibits GC cell progression through targeting TFF1 protein and regulating the SDF-1a/CXCR4 signaling pathway.

Protective effect of liposomal nanoparticles-loaded with miR-499 antagonist on cardiomyocyte following acute myocardial infarction through suppression of CDC25A

Abnormal expression of miR-499 is related to progression of acute myocardial infarction (MI). This study aimed to explore the effect of liposomal nanoparticles carrying miR-499 antagonist on proliferation of cardiomyocytes and myocardial injury, to provide evidence for in-depth analysis of pathogenesis. With 10 sham-operated rats as control group, 10 rats were induced MI. The cardiac function and myocardial tissue morphology were detected. Myocardial cells were transfected with liposomal nanoparticles (blank group), miR-499 agonist (agonist group), liposomal nanoparticles carrying miR-499 agonist (carrier+antagonist group), or CDC25A activator and inhibitor. CDC25A, Akt, and mTOR expressions were determined in the myocardial cells upon treatments, as targeting relationships between miR-499 and CDC25A were detected by dualluciferase reporter gene assay. Myocardial cell proliferation and apoptosis were detected by flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Myocardial infarction (MI) rats exhibited myocardial damage and had irregular cardiac function indexes, and oxidative stress indexes with inflammatory cell infiltration and disordered myocardial architecture. miR-499 antagonist-loaded liposomal nanoparticles significantly elevated the ratio of viable cells, while cell viability was not altered in the other groups (P &lt; 0.05). The miRNA-loaded nanomaterials induced decreased cell apoptosis, and overexpression of miR-499 increased apoptosis (P &lt; 0.05). The expressions of CDC25A, Akt and mTOR proteins were increased by presence of miR-499 antagonist-loaded liposomal nanoparticles. However, silencing of CDC25A induced decreased viability, while the ratio of viable cells was increased in the CDC25A activator group (P &lt; 0.05). There was a direct targeting relationship between miR-499 and CDC25A. It was found that Liposomal nanoparticles carrying miR-499 antagonist down-regulated the expression of CDC25A by down-regulating the expression of miR-499 to activate the Akt/mTOR signaling pathway, and enhanced the cardiomyocyte proliferation following MI.

Nanoparticle albumin-bound paclitaxel is superior to liposomal paclitaxel in the neoadjuvant treatment of breast cancer.

Aim: The present study aimed to retrospectively compare the efficacy and safety between liposomal paclitaxel (Lps-P) and nanoparticle albumin-bound paclitaxel (Nab-P) in neoadjuvant systemic treatment (NST) of breast cancer. Materials & methods: Two hundred thirty-five patients who were diagnosed with invasive breast cancer and then received dose-dense NST with epirubicin and cyclophosphamide followed by paclitaxel were enrolled. Results: Nab-P has an advantage in improving the total and axillary-only pathologic complete response rate over Lps-P. Although Nab-P can cause a higher incidence and severity of peripheral sensory neuropathy (PSN), most symptoms are temporary and reversible. In the Lps-P group, the proportion of patients with residual irreversible PSN is larger. Conclusion: Nab-P might be superior to Lps-P in NST of breast cancer.

Photosensitized co-generation of nitric oxide and singlet oxygen Enhanced toxicity against ovarian cancer cells.

Near micromolar concentrations of nitric oxide (NO) induce tumor cells death. However, an appropriate NO load has to be delivered selectively to the tumor site in order to avoid NO loss and secondary NO-induced effects. The encapsulation of millimolar concentrations of a NO source and an appropriate trigger of NO release within phospatidylcholine-based liposomes should provide an efficient tool for the selective release of the needed NO payload. In this work we report the photosensitized generation of singlet oxygen and NO from folate-targeted PEGylated liposomes, containing AlPcS4 as the sensitizer and S-nitrosoglutathione (GSNO), in millimolar amounts, as the NO source. Amounts of singlet oxygen detected outside the liposome when using PEGylated liposomes are near 200 % larger when GSNO is present inside the liposomes as compared to its absence. These liposomes, conjugated to folate, were found to enhance the photosensitized cytotoxicity to A2780CP20 ovarian cancer cells as compared to liposomes containing the sensitizer but no GSNO (30 % as compared to 70 % cell viability) under the conditions of this work. Fluorescense of AlPcS4 was observed inside cells incubated with folate-conjugated liposomes but not with liposomes without folate. The photosensitized activity enhancement by GSNO increased when light fluence or liposome concentration were increased. The majority of ovarian cancer patients are initially diagnosed with disseminated intra-abdominal disease (stages III-IV) and have a 5-year survival of less than 20%. This work suggests a novel ovarian cancer nodules treatment via the use of tumor-targeted liposome nanoparticles with the capability of generating simultaneously reactive oxygen and nitrogen species upon illumination with near-infrared light.

Starvation therapy enabled “switch-on” NIR-II photothermal nanoagent for synergistic in situ photothermal immunotherapy

Tumor photonic hyperthermia in the second near-infrared biowindow (NIR-II) represents the distinct therapeutic modality owing to the high tissue penetration and excellent spatiotemporal controllability. However, the non-specific “always on” nature of conventional NIR-II photothermal agents and the photothermal therapy (PTT)-associated tumor metastasis have restricted the progress of photonic hyperthermia. In this study, a cascade nanoreactor (denoted as LGT) based on clinically transformable liposomal nanoparticles is rationally engineered by encapsulating a pro-photothermal agent, 3,3′,5,5′-tetramethylbenzidine (TMB), and a tumor starvation mediator, glucose oxidase (GOD), for starvation therapy activated in-situ photothermal immunotherapy in inhibiting primary and metastasized tumors. Accompany with GOD-mediated intratumoral glucose depletion and hydrogen peroxide generation, the pro-photothermal agent is in-situ converted into the NIR-II absorbing charge transfer complex (CTC) in tumor microenvironment (TME). Collaboratively, glucose deprivation not only cuts the energy supply to tumor cells but also makes LGT sensitive to photothermal ablation. Upon NIR-II laser irradiation, LGT-mediated in-situ PTT ablates primary tumors, and further elicits the exposure of tumor-associated antigens. Importantly, the combination of starvation therapy enabled in situ PTT with anti-CTLA-4 checkpoint blockade therapy effectively inhibits distant tumor growth and tumor metastasis. Therefore, the present work provides a representative paradigm for tumor starvation therapy activated “switch-on” photothermal immunotherapy of cancer.

Influence of Acetaminophen on Molecular Adsorption and Transport Properties at Colloidal Liposome Surfaces Studied by Second Harmonic Generation Spectroscopy.

Time-resolved second harmonic generation (SHG) spectroscopy is used to investigate acetaminophen (APAP)-induced changes in the adsorption and transport properties of malachite green isothiocyanate (MGITC) dye to the surface of unilamellar 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes in an aqueous colloidal suspension. The adsorption of MGITC to DOPC liposome nanoparticles in water is driven by electrostatic and dipole–dipole interactions between the positively charged MGITC molecules and the zwitterionic phospholipid membranes. The SHG intensity increases as the added MGITC dye concentration is increased, reaching a maximum as the MGITC adsorbate at the DOPC bilayer interface approaches a saturation value. The experimental adsorption isotherms are fit using the modified Langmuir model to obtain the adsorption free energies, adsorption equilibrium constants, and the adsorbate site densities to the DOPC liposomes both with and without APAP. The addition of APAP is shown to increase MGITC adsorption to the liposome interface, resulting in a larger adsorption equilibrium constant and a higher adsorption site density. The MGITC transport times are also measured, showing that APAP decreases the transport rate across the DOPC liposome bilayer, especially at higher MGITC concentrations. Studying molecular interactions at the colloidal liposome interface using SHG spectroscopy provides a detailed foundation for developing potential liposome-based drug-delivery systems.

Nanoparticle-Delivered microRNA-153-3p Alleviates Myocardial Infarction-Induced Myocardial Injury in a Rat Model.

Although microRNA-153-3p (miR-153-3p) has been demonstrated to confer protective roles in ischemia/reperfusion injury, its potential role in myocardial infarction (MI) remains undefined. Small-molecule modifiers and nanoparticles loaded with microRNAs (miRNAs) have emerged as potential therapeutic reagents for MI treatment. In this study, we prepared liposome nanoparticles, hyaluronic acid (HA)-cationic liposomes (CLPs) complex, for the delivery of miR-153-3p and delineated the mechanistic actions of miR-153-3p modified by nHA-CLPs in MI-induced injury. Our data suggested that nHA-CLPs-loaded miR-153-3p protected cardiomyocytes against MI-induced cardiomyocyte apoptosis and myocardial injury. miR-153-3p was bioinformatically predicted and experimentally verified to bind to Krüppel-like factor 5 (KLF5) 3'UTR and negatively regulate its expression. Hypoxia was adopted to stimulate MI-induced injury to cardiomyocytes in vitro, in which miR-153-3p presented anti-apoptotic potential. However, restoration of KLF5 reversed this anti-apoptotic effect of miR-153-3p. Furthermore, KLF5 was demonstrated to be an activator of the NF-κB pathway. KLF5 enhanced cardiomyocyte apoptosis and inflammation under hypoxic conditions through NF-κB pathway activation, while nHA-CLPs-loaded miR-153-3p suppressed inflammation by blocking the NF-κB pathway. Collectively, our findings suggested the cardioprotective role of miR-153-3p against MI and the successful delivery of miR-153-3p by nHA-CLPs. The identification of KLF5-mediated activation of NF-κB pathway as an apoptotic and inflammatory mechanism aids in better understanding of the biology of MI and development of novel therapeutic strategies for MI.

Stimuli-responsive Polymeric Nanosystems for Therapeutic Applications

Recent studies have been reported emerging polymeric nanoparticles as a promising particulate carrier system for controlled and targeted drug delivery. Stimuli-responsive nanocarriers have shown characteristics, such as high drug uptake at specific sites or targeted cells with an advantage of no drug leakage. These stimuli-responsive polymeric systems are used to functionalize nanocarriers, such as dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, and quantum dots. The study reviews the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli, like pH, temperature, redox, light, and magnetic field. These stimuli- responsive drug delivery systems exhibit different drug release patterns in in vitro and in vivo studies. Stimuli- responsive nanocarriers are useful for both hydrophilic and hydrophobic drugs and release them on applied stimulus. This review highlights the recent development in the physical properties of polymeric materials and their application in stimuli-responsive specific drug delivery. The stimuli (smart, intelligent, programmable) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, and lifestyle disorders. The stimuli-responsive- based nanocarriers are developing at a fast pace, and there is a huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.

Simvastatin-loaded liposome nanoparticles treatment for uterine leiomyoma in a patient-derived xenograft mouse model: a pilot study

Uterine leiomyomas are complex tumours with limited medical treatment options. Simvastatin is used to treat hypercholesterolaemia and has shown promising effects as a treatment option for leiomyomas. Previously, our group demonstrated a promising effect of simvastatin treatment in a patient-derived xenograft mouse model. Here, we tested the efficacy of simvastatin liposomal nanoparticles (NPs). After bilateral leiomyoma xenograft implantation, mice (N = 12) were divided into three treatment arms: control, simvastatin and simvastatin-loaded liposome NPs (simvastatin-NPs). Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP; however, the results were not significant. Due to low bioavailability and short half-life of simvastatin, liposomal NPs have the potential to enhance drug delivery, however, in this study NP did not provide improvement over simvastatin, but did demonstrate their potential for the delivery of simvastatin. Impact statement What is already known on this subject? Simvastatin treatment in a patient-derived xenograft mouse model reduced tumour growth and decreased proliferation. What do the results of this study add? Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP, however, it did not improve the efficacy of simvastatin at reducing tumour growth and proliferation. What are the implications of these findings for clinical practice and/or further research? More studies are needed to optimise the formulation of NPs to further enhance the sustainable delivery of simvastatin.

Nanotherapeutics in autophagy: a paradigm shift in cancer treatment.

Autophagy is a catabolic process in which an organism responds to its nutrient or metabolic emergencies. It involves the degradation of cytoplasmic proteins and organelles by forming double-membrane vesicles called "autophagosomes." They sequester cargoes, leading them to degradation in the lysosomes. Although autophagy acts as a protective mechanism for maintaining homeostasis through cellular recycling, it is ostensibly a cause of certain cancers, but a cure for others. In other words, insufficient autophagy, due to genetic or cellular dysfunctions, can lead to tumorigenesis. However, many autophagy modulators are developed for cancer therapy. Diverse nanoparticles have been documented to induce autophagy. Also, the highly stable nanoparticles show blockage to autophagic flux. In this review, we revealed a general mechanism by which autophagy can be induced or blocked via nanoparticles as well as several studies recently performed to prove the stated fact. In addition, we have also elucidated the paradoxical roles of autophagy in cancer and how their differential role at different stages of various cancers can affect its treatment outcomes. And finally, we summarize the breakthroughs in cancer disease treatments by using metallic, polymeric, and liposomal nanoparticles as potent autophagy modulators.

Replacing cholesterol with sterol modified lipids results in improved liposomal stability

Liposomal nanoparticles are excellent candidates for vaccine and drug delivery applications, including the delivery of mRNA vaccines. However, a central challenge is the liposomal stability under physiological conditions that often result in uncontrolled drug release. The development of stable and long-circulating liposomes is, therefore, needed for protecting the encapsulated payload from degradation and premature release. Traditionally, this issue has been addressed through the incorporation of cholesterol in liposomal compositions.

Retraction Note to: Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the Co-Delivery of KRAS-siRNA and Gemcitabine for Pancreatic Cancer Treatment.

Retraction Note to: Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the Co-Delivery of KRAS-siRNA and Gemcitabine for Pancreatic Cancer Treatment.

Formulation and Evaluation of Rosuvastatin Calcium Polymeric Nanoparticles-Loaded Transdermal Patch

Background: Transdermal drug delivery systems (TDDS) have been rapidly developed as a promising alternative to the oral delivery systems to provide controlled drug delivery and avoid the first-pass metabolism of drugs. Recently, various nanocarriers such as liposome and lipid nanoparticles have been used to enhance dermal and transdermal penetration of drugs. The aim of this study is to formulate and evaluate a polymeric nanoparticle (PNPs)-loaded transdermal patch of the antihyperlipidemic drug rosuvastatin. Materials and Methods: Rosuvastatin PNPs were prepared by nanoprecipitation method, and evaluated for particle size, zeta-potential and polydispersity index. PNPs-loaded patch and PNPs-free patch (control) of rosuvastatin were prepared by solvent casting method using hydroxyl polymethyl cellulose K15 (HPMC K 15) as film-forming polymer and polyethylene glycol 200 (PEG 200) as a plasticizer and evaluated for physical appearance, thickness, folding endurance, surface pH, in-vitro release and ex-vivo permeability. Results: The particle size, zeta-potential, and polydispersity index of rosuvastatin-loaded PNPs were 68.69 nm, - 7.5 mV, and 0.294, respectively. The prepared transdermal films showed acceptable appearance, thickness, and folding endurance as well as surface pH values. In vitro release study showed 65% and 82% cumulative release after 24 hrs for the polymeric nanoparticle-loaded patch and control patch, respectively. However. ex vivo permeation results showed that a significantly higher amount of rosuvastatin permeated via rat skin from the PNPs-loaded patch in comparison to the control patch (P-value ˂ 0.05). Conclusion: Rosuvastatin PNPs-loaded transdermal patch was successfully prepared and revealed promising releasing and permeation properties comparing to control patch.