Search

[Display omitted] Cancers are increasing in prevalence and many challenges remain for their treatment, such as chemoresistance and toxicity. In this context, siRNA-based therapeutics have many potential advantages for cancer therapies as a result of their ability to reduce or prevent expression of specific cancer-related genes. However, the direct delivery of naked siRNA is hindered by issues like enzymatic degradation, insufficient cellular uptake, and poor pharmacokinetics. Hence, the discovery of a safe and efficient delivery vehicle is essential. This review explores various lipid and polymer-based delivery systems for siRNA in cancer treatment. Both polymers and lipids have garnered considerable attention as carriers for siRNA delivery. While all of these systems protect siRNA and enhance transfection efficacy, each exhibits its unique strengths. Lipid-based delivery systems, for instance, demonstrate high entrapment efficacy and utilize cost-effective materials. Conversely, polymeric-based delivery systems offer advantages through chemical modifications. Nonetheless, certain drawbacks still limit their usage. To address these limitations, combining different materials in formulations (lipid, polymer, or targeting agent) could enhance pharmaceutical properties, boost transfection efficacy, and reduce side effects. Furthermore, co-delivery of siRNA with other therapeutic agents presents a promising strategy to overcome cancer resistance. Lipid-based delivery systems have been demonstrated to encapsulate many therapeutic agents and with high efficiency, but most are limited in terms of the functionalities they display. In contrast, polymeric-based delivery systems can be chemically modified by a wide variety of routes to include multiple components, such as release or targeting elements, from the same materials backbone. Accordingly, by incorporating multiple materials such as lipids, polymers, and/or targeting agents in RNA formulations it is possible to improve the pharmaceutical properties and therapeutic efficacy while reducing side effects. This review focuses on strategies to improve siRNA cancer treatments and discusses future prospects in this important field. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hydrophobic deep eutectic solvent (HDES) is developed as a novel oil phase for LBFs. • Phase diagrams are modeled to describe the thermodynamic behavior of the HDES. • Molecular dynamics simulations are performed to examine the formulation architecture. • The HDES solubilized more venetoclax compared to conventional oil-phase candidates. • Combined with Tween 80, the HDES resulted in supersaturated venetoclax release. There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release. [ABSTRACT FROM AUTHOR]

[Display omitted] Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilisation enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilisation of drug and their oral bioavailability. [ABSTRACT FROM AUTHOR]

[Display omitted] Doxorubicin hydrochloride (DOX) is an anticancer agent used in cancer chemotherapy. The purpose of this study was to design nanostructured lipid carriers (NLCs) of DOX as smart chemotherapy to improve its photostability and anticancer efficacy. The characteristics of DOX and DOX-loaded NLCs were investigated using UV–Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, particle size, and zeta potential study. The cytotoxicity of DOX was evaluated against three cancer cell lines (HeLa, A549, and CT-26). The particle size and zeta potential were in the range 58.45-94.08 nm and −5.80 mV - −18.27 mV, respectively. The chemical interactions, particularly hydrogen bonding and van der Waals forces, between DOX and the main components of NLCs was confirmed by FTIR. NLCs showed the sustained release profile of DOX. The photostability results revealed that the NLC system improved the photostability of DOX. Cytotoxicity results using the three cell lines showed that all formulations improved the anticancer efficacy of free DOX, and the efficacy was dependent on cell type and particle size. These results suggest that DOX-loaded NLCs are promising chemotherapeutic agents for cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC 50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5–10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49–1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects. [ABSTRACT FROM AUTHOR]

[Display omitted] The precise delivery of therapeutic agents to specific cell populations, including cancer cells, remains a target in modern medicine, to enhance treatment efficacy, while minimizing unintended side effects. This study presents a strategy utilizing bispecific antibodies for the targeted delivery of nucleic acid drugs to the surface of glucose-regulated protein 78 (GRP78)-overexpressing cancer cells. Strong binding affinity of the bispecific antibodies to GRP78-overexpressing cancer cells, including HEPG2 cells, confirmed the tumor-targeting potential of this platform. Functional analyses demonstrated the role of the bispecific antibodies in enhancing lipid nanoparticle (LNP) uptake, causing increased gene expression levels of nucleic acid drugs loaded within LNPs. In vivo imaging confirmed the potency of the bispecific-antibody-modified LNPs in delivering nucleic acid drugs to tumors and sustaining therapeutic expression levels. In vivo therapy results indicated that the bispecific antibodies improved the antitumor activity of PE38 -loaded LNPs in tumors overexpressing surface GRP78. This study pioneered a bispecific-antibody-centered platform for the targeted delivery of nucleic acid drugs. The robust antigen–antibody binding affinity, tumor-selective interactions, enhanced cellular uptake, and proficient gene expression promise to advance precision therapeutics in oncology. Continued refinement and translation of this drug delivery strategy are important to unlock its full clinical potential. [ABSTRACT FROM AUTHOR]

[Display omitted] Solid lipid microparticles (SLMs) represent a promising approach for drug delivery in anti-acne applications. In this study, asiatic acid-loaded SLMs (AASLMs) were prepared by melt emulsification method in conjunction with freeze-drying. Comprehensive evaluations comprised particle size, %entrapment efficiency (%EE), %labeled amount (%LA), surface morphology, stability, %release, %skin permeation, and anti-acne activity. The AASLMs exhibited an average particle size ranging from 7.46 to 38.86 µm, with %EE and %LA falling within the range of 31.56 to 100.00 and 90.43 to 95.38, respectively. The AASLMs demonstrated a spherical shape under scanning electron microscopy, and maintained stability over a 3-month period. Notably, formulations with 10 % and 15 % cetyl alcohol stabilized with poloxamer-188 (specifically F6 and F12) displayed a minimum inhibitory concentration (MIC) value of 75 mg/ml against Cutibacterium acnes. Furthermore, F12 exhibited a higher %release and %skin permeation compared to F6 over 24 h. In a single-blind clinical trial involving fifteen participants with mild-to-moderate acne, F12 showcased its potential not only in reducing porphyrin intensity and enhancing skin barriers but also in significantly improving skin hydration and brightness. However, further investigations with larger subject cohorts encompassing diverse age groups and genders are necessary to thoroughly establish the performance of the developed AASLMs. [ABSTRACT FROM AUTHOR]

Magnetic Lipid-Based Hybrid Nanosystems (M-LC NPs ) is a novel nanoplatform that can respond to magnetic stimulus and are designed for delivering L-carnosine (CN), a challenging dipeptide employed in the treatment of breast cancer. CN exhibits considerable water solubility and undergoes in-vivo degradation, hence restricting its application. Consequently, it is anticipated that the developed M-LC NPs will enhance the effectiveness of CN. To ensure the physical stability of MNPs, they were initially coated with a mixture of oleic acid and oleylamine before being included in pegylated liquid crystalline nanoparticles (PLCNPs). The proposed M-LC NPs exhibited promising in-vitro characteristics, notably a small particle size (143.5 nm ± 1.25) and a high zeta potential (-39.5 mV ± 1.54), together with superparamagnetic behavior. The in-vitro release profile exhibited a prolonged release pattern. The IC 50 values of M-LC NPs were 1.57 and 1.59 times lower than these of the CN solution after 24 and 48 hours, respectively. Female BALB/C female mice with an induced breast cancer (Ehrlich Ascites tumor [EAT] model) were used to study the influence of an external magnetic field on the chemotherapeutic activity and toxicity of CN loaded in the developed M-LC NPs . Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LC NPs and CN solution, as evidenced by a reduction of % tumor growth (11.7%), VEGF levels (22.95 pg/g tissue), and cyclin D1 levels (27.61 ng/g tissue), and an increase in caspase-3 level (28.9 ng/g tissue). Ultimately, the developed stimuli-responsive CN loaded M-LC NPs presented a promising nanoplatform for breast cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer stands as the foremost health issue and the principal reason for mortality worldwide. It is projected that India will see over 1.73 million new cases and more than 880,000 deaths related to cancer, with lung cancer being a significant contributor. The efficiency of existing chemotherapy procedures is not optimal because of less soluble nature and short half-life of anticancer substances. More precipitated toxicity and non-existence of targeting propensity can lead to severe side effects, non-compliance, and inconvenience for patients. Nonetheless, the domain of nanomedicine has undergone a revolution in the past few years with the advent of novel drug delivery mechanisms that tackle the drawbacks of conventional approaches. Diverse nanoparticle-based drug delivery methods, including liposomes, nanoparticles, nanostructured lipid carrier and solid lipid nanoparticle that encapsulated chemotherapy drugs, are currently employed for efficient lung cancer therapy. NLCs, recognized as the second-generation lipid nanocarriers, are a focused drug delivery mechanism that has garnered significant interest owing to their multitude of advantages such as increased stability, minimal toxicity, prolonged shelf life, superior encapsulation capability, and biocompatible nature. This review focuses on the NLCs carrier system, discussing its preparation methods, types, characterization, applications, and future prospects in lung cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The oral bioavailability of therapeutic peptides is generally low. To increase peptide transport across the gastrointestinal barrier, permeation enhancers are often used. Despite their widespread use, mechanistic knowledge of permeation enhancers is limited. To address this, we here investigate the interactions of six commonly used permeation enhancers with lipid membranes in simulated intestinal environments. Specifically, we study the interactions of the permeation enhancers sodium caprate, dodecyl maltoside, sodium cholate, sodium dodecyl sulfate, melittin, and penetratin with epithelial cell-like model membranes. To mimic the molecular composition of the real intestinal environment, the experiments are performed with two peptide drugs, salmon calcitonin and desB30 insulin, in fasted-state simulated intestinal fluid. Besides providing a comparison of the membrane interactions of the studied permeation enhancers, our results demonstrate that peptide drugs as well as intestinal-fluid components may substantially change the membrane activity of permeation enhancers. This highlights the importance of testing permeation enhancement in realistic physiological environments and carefully choosing a permeation enhancer for each individual peptide drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

[Display omitted] • DC is verified as a novel and efficient method for lipodisk production. • Preparation by means of DC results in disks with small and homogeneous size. • No need for pre-mixing of the lipids in organic solvent. • Model drugs doxorubicin and curcumin were successfully formulated in the disks. • Optimized protocols enabled high drug loading efficiencies. Polyethylene glycol (PEG)-stabilized lipodisks have emerged as innovatiive, promising nanocarriers for several classes of drugs. Prior research underscores the important role of lipid composition and preparation method in determining the lipodisk size, uniformity, and drug loading capacity. In this study, we investigate dual centrifugation (DC) as a novel technique for the production of PEG-stabilized lipodisks. Moreover, we explore the potential use of DC for the encapsulation of two model drugs, curcumin and doxorubicin, within the disks. Our results show that by a considerate choice of experimental conditions, DC can be used as a fast and straightforward means to produce small and homogenous lipodisks with a hydrodynamic diameter of 20–30 nm. Noteworthy, the technique works well for the production of both cholesterol-free and cholesterol-containing disks and does not require pre-mixing of the lipids in organic solvent. Furthermore, our investigations confirm the efficacy of DC in formulating curcumin and doxorubicin within these lipodisks. For doxorubicin, careful control and optimization of the experimental conditions resulted in formulations displaying an encouraging encapsulation efficiency of 84 % and a favourable drug-to-lipid ratio of 0.13 in the disks. [ABSTRACT FROM AUTHOR]

[Display omitted] Successful oral delivery of liposomes requires formulations designed to withstand harsh gastrointestinal conditions, e.g., by converting to solid-state followed by loading into gastro-resistant delivery devices. The hypothesis was that the use of dextran-trehalose mixtures for spray drying would improve the rehydration kinetics of dried liposomes. The objectives were to determine the protective capacity of trehalose-dextran dehydration precursors and to increase the concentration of liposomes in the dry formulation volume. The study successfully demonstrated that 8.5% dextran combined with 76.5% trehalose protected CAF®04 liposomes during drying, with the liposome content maintained at 15% of the dry powder. Accordingly, the rehydration kinetics were slightly improved in formulations containing up to 8.5% dextran in the dry powder volume. Additionally, a 2.4-fold increase in lipid concentration (3 mM vs 7.245 mM) was achieved for spray dried CAF®04 liposomes. Ultimately, this study demonstrates the significance of trehalose as a primary carrier during spray drying of CAF®04 liposomes and highlights the advantage of incorporating small amounts of dextran to tune rehydration kinetics of spray-dried liposomes. [ABSTRACT FROM AUTHOR]

[Display omitted] A library of 16 lipid nanoparticle (LNP) formulations with orthogonally varying lipid molar ratios was designed and synthesized, using polyadenylic acid [poly(A)] as a model for mRNA, to explore the effect of lipid composition in LNPs on (i) the initial size of the resultant LNPs and encapsulation efficiency of RNA and (ii) the sensitivity of the LNPs to various conditions including cold storage, freezing (slow vs. rapid) and thawing, and drying. Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify the optimal lipid molar ratios and interactions that favorably affect the physical properties of the LNPs and enhance their stability in various stress conditions. LNPs exhibited distinct responses under each stress condition, highlighting the effect of lipid molar ratios and lipid interactions on the LNP physical properties and stability. It was then demonstrated that it is feasible to use thin-film freeze-drying to convert poly(A)-LNPs from liquid dispersions to dry powders while maintaining the integrity of the LNPs. Importantly, the residual moisture content in LNP dry powders significantly affected the LNP integrity. Residual moisture content of ≤ 0.5% or > 3–3.5% w/w negatively affected the LNP size and/or RNA encapsulation efficiency, depending on the LNP composition. Finally, it was shown that the thin-film freeze-dried LNP powders have desirable aerosol properties for potential pulmonary delivery. It was concluded that Design of Experiments can be applied to identify mRNA-LNP formulations with the desired physical properties and stability profiles. Additionally, optimizing the residual moisture content in mRNA-LNP dry powders during (thin-film) freeze-drying is crucial to maintain the physical properties of the LNPs. [ABSTRACT FROM AUTHOR]

CRISPR-Cas genome editing technology holds great promise for wide-ranging biomedical applications. However, the development of efficient delivery system for CRISPR-Cas components remains challenging. Herein, we synthesized a series of ionizable lipids by conjugation of alkyl-acrylate to different amine molecules and further assembled ionizable lipid nanoparticles (iLNPs) for co-delivery of Cas9 mRNA and sgRNA. Among all the iLNP candidates, 1A14-iLNP with lipids containing spermine as amine head, demonstrated the highest cellular uptake, endosomal escape and mRNA expression in vitro. Co-delivery of Cas9 mRNA and sgRNA targeting EGFP by 1A14-iLNP achieved the highest EGFP knockout efficiency up to 70% in HeLa-EGFP cells. In addition, 1A14-iLNP displayed passive liver-targeting delivery of Cas9 mRNA in vivo with good biocompatibility. Moreover, we developed a simple method of lyophilization-mediated reverse transfection of CRISPR-Cas9 components for efficient genome editing. Therefore, the developed 1A14-iLNP and the lyophilization formulation, represent a potent solution for CRISPR-Cas9 delivery, which might broaden the future of biomedical applications of both mRNA and CRISPR-based therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we present a novel approach for overcoming intestinal barriers by utilizing heparanase-responsive charge-converting nanocarriers (NCs). These NCs are designed to undergo charge conversion in response to the activity of heparanase (HPSE), an enzyme commonly overexpressed in cancer cells. Nanostructured lipid carriers (NLCs) and solid lipid nanocarriers (SLNs) with a positively charged core were coated with heparin (Hep), resulting in a negative surface charge and a size between 195 and 220 nm. However, upon encountering heparanase, heparin undergoes enzymatic cleavage, resulting in zeta potential shift from -22.1 to +8.3 mV for NLC-Hep and from -19.8 to +5.1 mV for SLN-Hep. Heparin-coated NCs showed more than 6-fold higher mucus permeating properties compared to the uncoated NCs. In vitro experiments using the heparanase-expressing cancer cell line HT29 demonstrated an up to 4-fold improved cellular uptake of the heparin coated NCs compared to co-incubation with the HPSE inhibitor suramin. Furthermore, cellular uptake was investigated on Caco-2 cells and on a Caco-2/HT29-MTX co-culture. Overall, this study highlights the potential of heparanase-responsive charge-converting NCs as a promising strategy for overcoming intestinal barriers and enhancing cellular uptake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

[Display omitted] • Environmentally friendly synthesis of 6 nm gold nanoparticles with curcumin (AuNP-C). • AuNP-C showed no cytotoxicity in fibroblast and macrophage cells. • Decreased lipid peroxidation and ROS levels in embryo hearts treated with AuNP-C. • AuNP-C restored activities of antioxidants in embryos exposed to oxidative damage. • Increased overall antioxidant capacity in treated embryos with AuNP-C. Gold nanoparticles (AuNPs) have gained considerable attention due to their biocompatibility, customizable optical properties and ease of synthesis. In this study, an environmentally friendly method was used for synthesize curcumin-functionalized AuNPs (AuNP-C). AuNP-C exhibited a spherical shape, uniformity, and an average diameter of 6 nm. The in vitro antioxidant activity was analyzed, and cytotoxicity properties of AuNP-C were assessed in fibroblast and macrophage cells. Additionally, the effects of AuNP-C on oxidative stress in chicken embryo liver and hearts were investigated. AuNP-C demonstrated potent free radical scavenging properties without exhibiting cytotoxicity and hepatotoxicity effects. Administration of 300 µg/mL of AuNP-C in chicken embryos, subjected to oxidative damage induced by 2,2′-azobis(2-amidinopropane) dihydrochloride, significantly reduced lipid peroxidation and reactive oxygen species levels in the cardiac tissue. Moreover, the activities of cardiac superoxide dismutase, catalase, and glutathione reductase were restored, accompanied by an increase in overall antioxidant capacity. Furthermore, at higher concentrations, AuNP-C normalized the reduced glutathione content. AuNP-C preserved the normal structure of blood vessels; however, it resulted in an increase in protein carbonylation. This study provides initial evidence for the modulation of antioxidant defense mechanisms by green-synthesized AuNPs and underscores the importance of investigating the in vivo safety of phytoantioxidant-functionalized nanoparticles. [ABSTRACT FROM AUTHOR]

[Display omitted] Alzheimer's disease (AD) is a neurodegenerative disorder and the most relevant form of dementia affecting people worldwide. AD was reported to be associated with increased oxidative stress ending up with neuronal damage. 18β-Glycyrrhetinic acid (GA), triterpenoid aglycone of glycyrrhizin, was reported for its powerful antioxidant activities. However, its high molecular weight and lipophilicity are two major obstacles that limit its use and cause very low brain bioavailability. The aim of the present study was to formulate the GA in lipid nanocapsules (LNCs) for enhanced nose-to-brain delivery, as well as to elucidate its potential neuroprotective effect in AD. The optimized GA-loaded LNCs exhibited nanometric size range, good stability over 6 months, sustained drug release over 24 h and high steady state flux and permeability coefficient across nasal mucosa over 8 h. In-vivo studies were conducted on five groups; control, scopolamine (SCOP)-treated, SCOP + GA-LNCs, SCOP + oral GA suspension, and SCOP + intranasal GA suspension groups. Intranasal administration of GA-LNCs, at a reduced dose of 1 mg/kg, improved scopolamine-induced memory impairment in rats evidenced by behavioral testing, histological examination, and oxidative stress markers; catalase and superoxide dismutase. Collectively, GA-loaded LNCs (with 50 times lower dose) may provide a promising remedy for AD patients worldwide. [ABSTRACT FROM AUTHOR]

Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Targeting mRNA formulations to achieve cell specificity is one of the challenges that must be tackled to mettle their therapeutic potential. Here, lipopolyplexes (LPR) bearing tri-mannose-lipid (TM) are used to target mannose receptor on dendritic cells. We investigated the impact of the net charge and percentage of TM units on the binding, uptake, transfection efficiency (TE) and RNA sensors activation. Binding and uptake capacities of naked and targeted LPR increase with the percent of cationic lipid, but the latter are 2-fold more up taken by the cells. Cationic LPR bearing 5 % and 10 % TM were localized in acidic compartments in contrast to naked LPR and 2.5 % TM-LPR. The drawback is the dramatic decrease of TE as the number of TM-units increases. Cationic LPR bearing 5 % and 10 % TM strongly induced NF-κB and PKR phosphorylation at 6 h. Conversely, mTOR is less activated in line with their low TE. Those side effects are overcome by using 5-methoxyuridine mRNA resulting in an improved TE due to non-phosphorylation of NF-κB and PKR and mTOR activation. Our results point out that targeting DC via mannose receptor triggers a higher uptake of cationic LPRs and fast routing to acidic compartments, and that efficient TE requires low number of TM units use or modified mRNA to escape RNA sensors activation to enhance the translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Preparation of lipid-based drug delivery systems by microfluidics has been increasingly popular, due to the reproducible, continuous and scalable nature of the microfluidic process. Despite exciting development in the field, versatility and superiority of microfluidics over conventional methods still need further evidence, since preparing clinically-relevant sterically stabilised liposomes has been lacking. The present study describes the optimisation of PEGylated liposomal formulations of various rigidity using staggered herringbone micromixer (SHM). The effect of both processing parameters (total flow rate (TFR) and aqueous-to-ethanol flow rate ratio (FRR)) and formulation parameters (lipid components and composition, initial lipid concentration and aqueous media) was investigated and discussed. Liposomal formulations consist of 1,2-dioleoyl- sn -glycero-3-phosphatidylcholine (DOPC), 1,2-dipalmitoyl- sn -glycero-3-phosphatidylcholine (DPPC) or 1,2-distearoyl- sn -glycero-3-phosphatidylcholine (DSPC), with cholesterol and PEGylated lipid (DSPE-PEG 2000) were successfully prepared with the desired size (∼100 nm) and dispersity (<0.2). Doxorubicin was successfully encapsulated in these liposomes at high (>80%) encapsulation efficiency using the pH-gradient remote loading method, illustrating their bilayer integrity and capability as drug delivery systems. We demonstrated that clinically-relevant PEGylated liposomal formulations could be prepared with properties comparable to conventional techniques. Limitations and recommendations on the microfluidic production of PEGylated liposomes were also discussed. [ABSTRACT FROM AUTHOR]

Cefuroxime Axetil (CA) is a poorly soluble, broad spectrum antibiotic which undergoes enzymatic degradation in gastrointestinal tract. The objective of the present study was to develop lipid-based gastro-retentive floating drug delivery systems containing CA using hot-melt extrusion (HME) to improve absorption. Selected formulations of CA and lipids were extruded using a twin screw hot-melt extruder. Milled extrudates were characterized for dissolution, floating strength, and micromeritic properties. Solid-state characterization was performed using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and hot-stage microscopy. In vitro characterization demonstrated that the formulations exhibited a sustained drug release profile for 12 h. All formulations showed desired floating and flow properties. Solid-state characterization revealed no phase separation and no chemical interactions between the drug and excipients. Based on in vitro study results, an optimized formulation (F8) was further evaluated for in vivo performance. Oral bioavailability (C max and AUC 0–24h) of F8 was significantly higher than that of pure CA. This study describes the use of lipid-based gastro-retentive floating drug delivery systems to achieve desired sustained release profile for more complete dissolution which could potentially reduce enzymatic degradation. This study also highlights the effectiveness of HME technology to improve dissolution and bioavailability. [ABSTRACT FROM AUTHOR]

Lipid nanocarriers incorporating glycerides, polyethylene glycol (PEG)-stearates and phospholipids have attracted great attention for in vivo diagnostic, in vivo imaging, activated or non-activated targeted drug delivery. For quality control purposes, the development of appropriate methods for the quantification of their lipid components is needed. In the present study, we developed an analytical method for lipid quantification in formulated nanoparticles. PEG-stearates and glycerides were analyzed in a single run by RP-UPLC-ELSD using a two-step gradient elution program, while the analysis of phospholipids was accomplished by HILIC-UPLC-ELSD after isolation using an SPE silica column. Using both isolated compounds and commercial lipid standards, calibration curves were produced using second-order polynomials to attain the quantitative evaluation of each lipid excipient. Relative standard deviation of all analytes was between 0.9% and 5.3% for intra-day precision and recovery ranged from 83.5% to 112.2%. The presented method was successfully implemented to study the manufacturing process and stability of the formulated lipid excipients during long-term storage and accelerated conditions. The formulation lipid yield was determined and found equal to 82.5%. [ABSTRACT FROM AUTHOR]

The occurrence of lung cancer is linked with tobacco smoking, mainly through the generation of polycyclic aromatic hydrocarbons (PAHs). Elevated activity of cytochrome P4501A1 (CYP1A1) plays an important role in the metabolic processing of PAHs and its carcinogenicity. The present work aimed to investigate the role of CYP1A1 gene in PAH-mediated growth and tumor development in vitro and using an in vivo animal model. RNAi strategy was utilized to inhibit the overexpression of CYP1A1 gene using cationic liposomes generated using a lipid film-coated proliposome microparticles. Treatment of PAH-induced human alveolar adenocarcinoma cell line with cationic liposomes carrying CYP1A1 siRNA resulted in down regulation of CYP1A1 mRNA, protein as well as its enzymatic activity, triggering apoptosis and inhibiting multicellular tumor spheroids formation in vitro. Furthermore, silencing of CYP1A1 gene in BALB/c nude xenografts inhibited tumor growth via down regulation of CYP1A1 expression. Altogether, our findings showed that liposome-based gene delivery technology is a viable and stable approach for targeting cancer causing genes such as CY1PA1. This technology facilitated by the use of sugar particles coated with lipid films has demonstrated ability to generate anticancer effects that might be used in the future for therapeutic intervention and treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Peptides are rarely orally administrated due to rapid degradation in the gastrointestinal tract and low absorption at the epithelial border. The objective of this study was to encapsulate a model water-soluble peptide in biodegradable and biocompatible solid lipid-based nanoparticles, i.e. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) in order to protect it from metabolic degradation. Leuprolide (LEU) and a LEU-docusate Hydrophobic Ion Pair (HIP) were encapsulated in SLN and NLC by High Pressure Homogenization. The particles were characterized regarding their Encapsulation Efficiency (EE), size, morphology, peptide release in FaSSIF-V2, and protective effect towards proteases. Nanoparticles of 120 nm with platelet structures were obtained. Formation of HIP led to a significant increase in LEU EE. Particle size was moderately affected by the presence of simulated fluids. Nonetheless, an important burst release was observed upon dispersion in FaSSIF-V2. NLC were able to improve LEU-HIP resistance to enzymatic degradation induced by trypsin but presented no advantages in presence of α-chymotrypsin. SLN provided no protection regarding both proteases. Despite an increased amount of encapsulated peptide in solid lipid-based nanoparticles following HIP formation, the important specific surface area linked to their platelet structures resulted in an important peptide release upon dispersion in FaSSIF-V2 and limited protection towards enzymatic degradation. [ABSTRACT FROM AUTHOR]

Solvent-free hot melt coating (HMC) provides a safer and more economic process compared to the conventional solvent coating techniques. However, drug release instability and the lack of fundamental understanding on it are limiting factors for application of HMC for industrial productions. In this work, we investigated glyceryl dibehenate, glyceryl monostearate and behenoyl polyoxyl-8 glyceride as HMC materials. The microstructure and solid state alteration of lipids were studied via polarized light microscopy, DSC and powder x-ray diffraction. Microcapsules of N-acetylcysteine particles were provided with these excipients and stored under long term and accelerated conditions for 3 months. The feasibility of selected lipids as HMC excipients was confirmed. The drug release from freshly coated microcapsules was dictated by microstructure, solid state and HLB of lipid coating. Alterations in the release profiles after storage under accelerated conditions were correlated with time-dependent structural alterations of selected lipids. The faster drug release from glyceryl dibehenate and behenoyl polyoxyl-8 glyceride microcapsules was correlated with a low-melting small fraction composed by mixed phases in glyceryl dibehenate and the amorphous region of polyoxyl part in behenoyl polyoxyl-8 glyceride, respectively. The slower drug release from glyceryl dibehenate after storage was explained by the transition of lipid crystals to the β-form with dense crystalline structure. The gained information can be used to design effective tempering strategies for providing stable pharmaceutical products. [ABSTRACT FROM AUTHOR]

Hair follicles are a promising target for the administration of drugs to treat diseases associated with the pilosebaceous unit, such as acne. For solid lipid microparticle dispersions a successful and selective delivery of adapalene via targeted erosion of the particles in sebum has been shown. By embedding nanoparticulate benzoyl peroxide in lipid microparticles, the therapeutic potency of adapalene can be further increased by improving follicular deposition of benzoyl peroxide and minimizing direct contact between benzoyl peroxide and stratum corneum, which is responsible for the irritating potential of this active agent. The aim of this study was to develop a novel nanoparticulate formulation for benzoyl peroxide suitable for the incorporation in solid lipid microparticles. In this contribution, a wet grinding process using liposomal dispersions of fully hydrated phosphatidylcholine was developed, upscaled and optimized for solid content and stabilizer concentration. The resulting novel nanosuspension was characterized by particle size and morphology and examined for chemical and physical stability as well as solubility and polymorphism. During the process development a dependency between the colloidal microstructure of the stabilizer dispersion and milling efficiency was found: while physical mixtures fail to deliver nanosuspensions, liposomal dispersions succeed with the same amount of stabilizer. [ABSTRACT FROM AUTHOR]

Rational design of novel ionizable lipids for development of lipid-nucleic acid nanoparticles (LNP) is required for safe and effective systemic gene delivery for osteoporosis. LNPs require suitable characteristics for intravenous administration and effective accumulation in bone marrow for enhanced transfection. Hence, lipids with C18 tail and ionizable headgroup (Boc-His-ODA/BHODA and His-ODA/HODA) were synthesized and characterized physicochemically. LNPs were prepared with bone morphogenetic protein-9 gene (BHODA-LNP, HODA-LNP, and bone-homing peptide targeted HODA-LNP – HODA-LNPT). Thorough physicochemical (electrolyte stability, DNase I and serum stability) and biological (hemolysis, ROS induction, cytotoxicity and transfection) characterization was carried out followed by acute toxicity studies and therapeutic performance studies in ovariectomized rat model. Lipids with pH dependent ionization were successfully synthesized. LNPs thereof were ∼100 nm size with stability against electrolytes, DNase I and serum and exhibited low hemolytic potential demonstrating suitability for intravenous administration. LNPs exhibited minimal cytotoxicity, non-significant ROS induction and high transfection. In vivo studies demonstrated safety and improved bone regeneration in OVX rats with HODA-LNPT showing significantly better performance. Synthesized ionizable lipids offer safe and effective alternative for preparation of LNPs for gene delivery. Targeted BMP-9 LNP show potential for systemic osteoporosis treatment. [ABSTRACT FROM AUTHOR]

This research attempts to bring together the positive aspects of lipid nanoparticles and Quality by Design (QbD) approach for developing a novel drug delivery system for skin cancers and aktinic keratosis. Lipid nanoparticles which is one of the most efficacious options for topical treatment of skin diseases were prepared due to their ability to overcome the complex structure of skin barrier and to enhance the skin penetration. Since the formulation development contains complex variables of active ingredients, raw materials or production method; all the variables of the product should be elaborated. QbD approach which refers to design and develop formulations and manufacturing processes to maintain the prescribed product quality was also successfully adopted to achieve a time- and cost-saving process ensuring a high-quality product. 5-Fluorouracil (5-FU) loaded lipid nanoparticles, both solid lipid nanoparticles and nanostructured lipid carriers, were developed and characterized by following QbD steps. Optimal lipid nanoparticle formulation with guaranteed quality which was within the design space has been reached through the artificial neural networks. The optimal lipid nanoparticle formulation which is a NLC formulation with a mean particle size of 205,8 ± 9,34 nm, narrow size distribution (0.279 ± 0.01) and negative zeta potantial −30,20 ± 0,92 was produced by high pressure homogenization method. Cytotoxicity profiles of the optimal NLC was determined by cell culture studies on epidermoid carcinoma cells and human keratinocyte cells. Optimal NLC showed significantly higher anticancer effect on epidermoid carcinoma cells than free 5-FU and also less cytotoxicity towards human keratinocyte cells. Optimal NLC was formulated in hydrogel formulation for ease of application which has suitable occlusive and mechanical properties, viscocity and pH for patient complience. The cumulative amount of 5-FU in dermal tissues of rat skin was found 20.11 ± 2.14 μg/cm2 and 9.73 ± 0.87 μg/cm2 after application of NLC enriched hydrogel and 5-FU hydrogel respectively. In conclusion, this study showed that a time and cost saving process ensuring a high-quality product can be obtained by QbD guided formulation development study with the help of artificial neural networks. A novel semisolid dosage form enriched by NLC which is promising for topical treatment of skin cancers was developed. [ABSTRACT FROM AUTHOR]

The present work reports the development, optimization and characterization of novel lipid based nanoformulations viz., Liquid crystalline nanoparticles (LCNP), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and liposomes loaded with Tacrolimus (Tac) for topical delivery. Different nanoformulations were developed after screening lipids and suitable surfactants depending upon emulsification ability. The various nanoformulations were then optimized (to achieve higher entrapment efficacy, lower particle size, PDI and zeta potential), characterized and loaded into gel. The gels loaded with nanoformulations were also characterized depending upon rheology and viscosity. The gels were analyzed for in vitro drug release, HaCaT cell lines studies and skin permeation studies. The in vivo efficacy studies were carried out using mouse tail model and skin irritation studies using Draize patch test and measurement of TEWL. The developed nanoformulations showed optimum particle size (<200 nm), polydispersity index (PDI < 0.3), zeta potential (≥−10 mV) and higher entrapment efficiency (>85%). The nanoformulations showed higher penetration of Tac into skin. Tac-LCNP, Tac-SLN, Tac-NLC and Tac-liposomes loaded gels showed 14, 11.5, 12.5 and 3.7 folds increment in dermal bioavailability respectively, in comparison to free Tac loaded gel and 2.5, 2 and ∼2 folds augmentation in dermal bioavailability respectively as compared to Tacroz™ Forte. In case of Tac-liposomes, the dermal bioavailability was lower as compared with the marketed formulation, Tacroz™ Forte. Despite, the increased bioavailability into the skin, the developed nanoformulations showed no significant skin irritation. The above mentioned nanoformulations were able to achieve greater penetration of Tac into the skin as compared to marketed ointment of Tac, Tacroz™ Forte. [ABSTRACT FROM AUTHOR]

In this study, authors adapt the Quality by Design (QbD) concept as well as the Risk Assessment (RA) method to the early development phase of a new nano-sized liposomal formulation for nasal administration with brain target. As a model active agent, a BCS II class drug was chosen to investigate the behaviour of the drugs with lipophilic character. This research presents how to apply this risk-focused approach and concentrates on the first four stages of the QbD implementation. In this way the quality target product profile was defined, the critical factors were identified and an RA was performed. The RA results helped in the factorial design-based liposome preparation by the lipid film hydration method. The prepared liposomes were evaluated (vesicle size, size distribution, and specific surface area). The surface characteristics were also investigated to verify the exactness of the RA and critical factors based theoretical prediction. The results confirm that the QbD approach in liposome development can improve the formulation process. The RA focused predictive approach resulted in a decreased number of studies in practice but in an effective product preparation. Using such innovative design and development models can help to optimise and rationalise the development of liposomes. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The objective of current study was to develop solid lipid nanoparticles-loaded with simvastatin (SIM-SLNs) and investigate their in vivo anti-hyperlipidemic activity in poloxamer-induced hyperlipidemia model. Nano-template engineering technique was used to prepare SIM-SLNs with palmityl alcohol as lipid core and a mixture of Tween 40/Span 40/Myrj 52 to stabilize the core. The prepared SIM-SLNs were evaluated for physicochemical parameters including particle diameter, surface charge, morphology, incorporation efficiency, thermal behaviour and crystallinity. In vitro release profile of SIM-SLNs in simulated gastric and intestinal fluids was evaluated by using dialysis bag technique and anti-hyperlipidemic activity was assessed in hyperlipidemia rat model. SIM-SLNs revealed uniform particle size with spherical morphology, zeta potential of −24.9 mV and high incorporation efficiency (∼85%). Thermal behaviour and crystallinity studies demonstrated successful incorporation of SIM in the lipid core and its conversion to amorphous form. SIM-SLNs demonstrated a sustained SIM release from the lipid core of nanoparticles. SIM-SLNs significantly reduced the elevated serum lipids as indicated by ∼3.9 and ∼1.5-times decreased total cholesterol compared to those of untreated control and SIM dispersion treated hyperlipidemic rats. In conclusion, SIM-SLNs showed a great promise for improving the therapeutic outcomes of SIM via its effective oral delivery. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Recently, promising strategies of plexes include the complexation of nucleic acids with lipids (lipoplexes) and different kinds of polymers (polyplexes) for delivery of actives and genetic material in abnormal conditions like cancer, cystic fibrosis and genetic disorders. The present review article focuses on the comparative aspects of lipoplexes and polyplexes associated with molecular structure, cellular transportation and formulation aspects. The major advantages of lipoplexes and polyplexes over conventional liposomes involve non-immunogenic viral gene transfer, facile manufacturing and preservation of genetic material encapsulated within the nanocarriers. Lipoplexes and polyplexes enhance the transfection of DNA into the cell by stepwise electrostatic cationic-anionic interaction with DNA backbones. The ease and cost-effective formation of complexes extend their applications in the treatment of cancer and genetic disorders. Lipoplexes and polyplexes necessitate intensive research in the fields of quality, toxicity and methods of preparation for commercialization. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Electrospun nanofibrous dressings present suitable characteristics to be used in wound healing, such as high porosity and high surface area-to-volume ratio. In this study, a wound dressing based on PLGA and Aloe vera containing lipid nanoparticles (NLCs) was developed. NLCs were added in order to add a lipid component that could avoid the adhesion of the dressing to the wound and improve its handling. Membranes with and without NLCs were composed of uniform fibers of about 1 µm in diameter. Their porosity was above 80% and their thickness was about 160 µm. Both dressings showed similar water vapour transmission rate 1100 g/m2day. The formulation containing NLCs presented a higher ultimate tensile strength (2.61 ± 0.46 MPa) and a higher water uptake. Both formulations were biocompatible in vitro. Furthermore, the cell adhesion assay demonstrated that both membranes had a low adherence profile, although it was lower with the dressing containing NLCs. Finally, their efficacy was evaluated in a full thickness wound healing assay conducted in db/db mice, where both enhanced healing similarly. Accordingly, the PLGA-AV-NLC membrane might be a promising strategy for the treatment of chronic wounds, since it improved handling in comparison to the formulation without NLCs. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Nanostructured lipid carriers (NLC) are biocompatible and biodegradable nanoscale systems with extensive application for controlled drug release. However, the development of optimal nanosystems along with a reproducible manufacturing process is still challenging. In this study, a two-step experimental design was performed and databases were successfully modelled using Artificial Intelligence techniques as an innovative method to get optimal, reproducible and stable NLC. The initial approach, including a wide range of values for the different variables, was followed by a second set of experiments with variable values in a narrower range, more suited to the characteristics of the system. NLC loaded with rifabutin, a hydrophobic drug model, were produced by hot homogenization and fully characterized in terms of particle size, size distribution, zeta potential, encapsulation efficiency and drug loading. The use of Artificial Intelligence tools has allowed to elucidate the key parameters that modulate each formulation property. Stable nanoparticles with low sizes and polydispersions, negative zeta potentials and high drug loadings were obtained when the proportion of lipid components, drug, surfactants and stirring speed were optimized by FormRules® and INForm®. The successful application of Artificial Intelligence tools on NLC formulation optimization constitutes a pioneer approach in the field of lipid nanoparticles. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Essential oils containing monoterpenes are widely used in pharmaceuticals and cosmetic products on account of their wide range of bioactive properties (including anti-cancer activity). Two monoterpenes (citral and geraniol) were firstly tested for their anti-inflammatory activity in a RAW 264.7 cell line, demonstrating citral to have enhanced capacity to inhibit NO production (ca. 84% for citral and 52% for geraniol at the lowest tested concentration of 5 µg/ml). As citral showed higher NO inhibitory activity than geraniol, to measure the level of cytotoxicity of citral, AlamarBlue reduction assay was run in two cell models (non-tumoral HaCaT and tumoral A431). Citral exhibited a strong cytotoxic effect in both cell lines, i.e. cell viability lower that 10% after 24 h exposure at 100 µg/ml of monoterpene. An optimized solid lipid nanoparticles (SLNs) formulation for citral was further developed by design of experiments (22 factorial design), followed by accelerated stability testing (LUMiSizer®). An optimal SLN composed of 1 wt% of citral, 4 wt% of lipid and 2.5 wt% surfactant were successfully produced by hot high pressure homogenization (hot HPH) showing a mean particle size (Z-Ave) of 97.7 nm and polydispersity index of 0.249. The produced formulations were analyzed in a high-end dispersion analyzer LUMiSizer® to characterize any demixing phenomena, demonstrating to be long-term stable at room temperature (25 °C), exhibiting very low instability indices (0.032 after production and 0.042 after one month of storage). [ABSTRACT FROM AUTHOR]

[Display omitted] Lipid excipients are favorable materials in pharmaceutical formulations owing to their natural, biodegradable, low-toxic and solubility/permeability enhancing properties. The application of these materials with advanced manufacturing platforms, particularly filament-based 3D-printing, is attractive for personalized manufacturing of thermolabile drugs. However, the filament's weak mechanical properties limit their full potential. In this study, highly flexible filaments were extruded using PG6-C16P, a lipid-based excipient belonging to the group of polyglycerol esters of fatty acids (PGFAs), based on tuning the ratio between its major and minor composition fractions. Increasing the percentage of the minor fractions in the system was found to enhance the relevant mechanical filament properties by 50-fold, guaranteeing a flawless 3D-printability. Applying a novel liquid feeding approach further improved the mechanical filament properties at lower percentage of minor fractions, whilst circumventing the issues associated with the standard extrusion approach such as low throughput. Upon drug incorporation, the filaments retained high mechanical properties with a controlled drug release pattern. This work demonstrates PG6-C16 P as an advanced lipid-based material and a competitive printing excipient that can empower filament-based 3D-printing. [ABSTRACT FROM AUTHOR]

[Display omitted] The goal of this study was the development and evaluation of semisolid caffeine (CAF) loaded nanostructured lipid carriers (NLCs) for topical treatment of cellulite. CAF-loaded NLC formulations were prepared via high-speed homogenization followed by ultrasonication. A 32 full factorial design was employed for formulation optimization. The total lipid content (%) and the liquid lipid content per total lipids (%) were chosen as factors, whereas particle size (PS), polydispersity index (PDI), zeta potential (|ZP|) and viscosity (VIS) were selected as responses. The design suggested CAF-NLC3 as the optimum formulation consisting of a total lipid content of 15% w/w (palmitic acid and soft paraffin/isopropyl myristate, 7:3 w/w) and a surfactant content of 10% w/w (Tween 80/lecithin, 8:1.2 w/w). CAF-NLC3 revealed PS, PDI, ZP, VIS and CAF content values of 318.8 nm, 0.253, −41.1 mV, 18.0 Pa.s and 97.57%, respectively. It showed a pseudoplastic rheological behavior, acceptable pH value (5.25), good spreadability (1.12 mm2/g) and spherical shape employing transmission electron microscopy. Differential scanning calorimetry and X-ray diffraction demonstrated the amorphization of CAF in CAF-NLC3. CAF-NLC3 remained stable for 3 months at room and refrigeration conditions. A single topical application of CAF-NLC3 on shaved abdominal skins of Wistar rats revealed enhanced skin retention of CAF by 2-fold and 1.4-fold after 4 h when compared with plain CAF gel (CAF-P) and marketed CAF gel (CAF-M), respectively. Furthermore, CAF-NLC3 exhibited a superior anti-cellulite activity in comparison with CAF-P and CAF-M through elevating extracellular matrix components (collagen 1, elastin and hyaluronic acid) and stimulating the brown adipose tissue thermogenesis via up-regulating UCP1 and PPAR-γ expression. In addition, CAF-NLC3 prominently increased lipolysis through HSL activity and decreased pro-inflammatory cytokines such as ICAM-1 and VCAM-1 after 30 days of treatment on a high fat diet-induced cellulite rat model. These findings were further confirmed by histopathological examination supported by morphometric analysis. Therefore, incorporation of CAF in a semisolid NLC formulation would be a promising cosmetic approach for the topical treatment of cellulite. [ABSTRACT FROM AUTHOR]

[Display omitted] Breast cancer remains the leading cause of cancer-associated mortality in women. Research investigating novel therapeutic approaches is thus crucial, including phytotherapeutics. Pterostilbene (PTS) is a phytochemical agent with promising efficacy against breast cancer. Poor solubility, low bioavailability and chemical instability are major drawbacks compromising PTS functionality. Herein, novel PTS-loaded solid lipid nanoparticles (PTS-SLNs) were fabricated using the ultrasonication technique. Dual-functionalization with lactoferrin (Lf) and chondroitin-sulfate (CS; CS/Lf/PTS-SLNs) was adopted as active-targeting approach. CS/Lf/PTS-SLNs demonstrated nanoparticle-size (223.42 ± 18.71 nm), low PDI (0.33 ± 0.017), acceptable zeta potential (-11.85 ± 0.07 mV) and controlled release (72.93 ± 2.93% after 24 h). In vitro studies on triple-negative MDA-MB-231 revealed prominent cytotoxicity of CS/Lf/PTS-SLNs (2.63-fold IC 50 reduction), higher anti-migratory effect and cellular uptake relative to PTS-solution. The in vivo anti-tumor efficacy in an orthotopic cancer model verified the superiority of CS/Lf/PTS-SLNs; achieving 2.4-fold decrease in tumor growth compared to PTS-solution. On the molecular level, CS/Lf/PTS-SLNs enhanced suppression of VEGF, down-regulated cyclin D1 and upregulated caspase-3 and BAX, compared to PTS-solution. Also, immunohistochemical assay confirmed the higher anti-tumorigenic effect of CS/Lf/PTS-SLNs (5.87-fold decrease in Bcl-2 expression) compared to PTS-solution. Our findings highlight CS/Lf/PTS-SLNs as a promising nanoplatform for phytotherapeutic targeted-breast cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] In view of the strong anti-inflammatory activity of glucocorticoids (GC) they are used in the treatment of almost all inflammatory lung diseases. In particular, inhaled GC (IGC) allow high drug concentrations to be deposited in the lung and may reduce the incidence of adverse effects associated with systemic administration. However, rapid absorption through the highly absorbent surface of the lung epithelium may limit the success of localized therapy. Therefore, inhalation of GC incorporated into nanocarriers is a possible approach to overcome this drawback. In particular, lipid nanocarriers, which showed high pulmonary biocompatibility and are well known in the pharmaceutical industry, have the best prospects for pulmonary delivery of GC by inhalation. This review provides an overview of the pre-clinical applications of inhaled GC-lipid nanocarriers based on several key factors that will determine the efficiency of local pulmonary GC delivery: 1) stability to nebulization, 2) deposition profile in the lungs, 3) mucociliary clearance, 4) selective accumulation in target cells, 5) residence time in the lung and systemic absorption and 6) biocompatibility. Finally, novel preclinical pulmonary models for inflammatory lung diseases are also discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Benznidazole, a poorly soluble in water drug, is the first-line medication for the treatment of Chagas disease, but long treatment periods at high dosages cause several adverse effects with insufficient activity in the chronic phase. According to these facts, there is a serious need for novel benznidazole formulations for improving the chemotherapy of Chagas disease. Thus, this work aimed to incorporate benznidazole into lipid nanocapsules for improving its solubility, dissolution rate in different media, and permeability. Lipid nanocapsules were prepared by the phase inversion technique and were fully characterized. Three formulations were obtained with a diameter of 30, 50, and 100 nm and monomodal size distribution with a low polydispersity index and almost neutral zeta potential. Drug encapsulation efficiency was between 83 and 92 % and the drug loading was between 0.66 and 1.04 %. Loaded formulations were stable under storage for one year at 4 °C. Lipid nanocapsules were found to protect benznidazole in simulated gastric fluid and provide a sustained release platform for the drug in a simulated intestinal fluid containing pancreatic enzymes. The small size and the almost neutral surface charge of these lipid nanocarriers improved their penetration through mucus and such formulations showed a reduced chemical interaction with gastric mucin glycoproteins. LNCs. The incorporation of benznidazole in lipid nanocapsules improved the drug permeability across intestinal epithelium by 10-fold compared with the non-encapsulated drug while the exposure of the cell monolayers to these nanoformulations did not affect the integrity of the epithelium. [ABSTRACT FROM AUTHOR]

The nasal route has been investigated as a promising alternative for drug delivery to the central nervous system, avoiding passage through the blood-brain barrier and improving bioavailability. In this sense, it is necessary to develop and test the effectiveness of new formulations proposed for the management of neurological disorders. Thereby, the aim of this work was to develop and characterize an ion sensitive in situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nasal delivery in the treatment of epilepsy. Physical characterization of the developed formulations was performed and included the evaluation of rheological features, particle size, polydispersity index (PDI) and zeta potential (ZP) of an in situ hydrogel containing DZP-NLC. Afterwards, in vitro drug release, in vitro mucoadhesion and biocompatibility studies with RPMI 2650 nasal cells were performed. The in situ hydrogel containing DZP-NLC was aerosolized with a nasal spray device specifically designed for nose-to-brain delivery (VP7 multidose spray pump with a 232 N2B actuator) and characterized for droplet size distribution and spray cone angle. Finally, the deposition pattern of this hydrogel was evaluated in a 3D-printed human nasal cavity model. The developed in situ hydrogel containing DZP-NLC presented adequate characteristics for nasal administration, including good gelling ability, mucoadhesiveness and prolonged drug release. In addition, after inclusion in the hydrogel net, the particle size (81.79 ± 0.53 nm), PDI (0.21 ± 0.10) and ZP (-30.90 ± 0.10 mV), of the DZP-NLC remained appropriate for nose-to-brain delivery. Upon aerosolization in a nasal spray device, a suitable spray cone angle (22.5 ± 0.2°) and adequate droplet size distribution (Dv (90) of 317.77 ± 44.12 µm) were observed. Biocompatibility studies have shown that the developed formulation is safe towards RPMI 2650 cells in concentrations up to 100 μg/mL. Deposition studies on a 3D-printed human nasal cavity model revealed that the best nasal deposition profile was obtained upon formulation administration without airflow and at an angle from horizontal plane of 75°, resulting in 47% of administered dose deposited in the olfactory region and 89% recovery. The results of this study suggested that the intranasal administration of the developed in situ hydrogel containing DZP-NLC could be a promising alternative to the conventional treatments for epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Migraine is a disabling neurovascular polygenic disorder affecting life quality with escorted socioeconomic encumbrances. Herein, we investigated the consolidated amalgamation of passive lipomer approach alongside active sonophoresis assisted transdermal delivery of zolmitriptan (ZT) using high frequency ultrasound pre-treatment protocol to mitigate migraine attacks. A modified nanoprecipitation technique was utilized to prepare zolmitriptan loaded lipomers (ZTL) adopting 2 3 factorial design. Three factors were scrutinized namely lipid type, ZT: lipid ratio and ZT: Gantrez® ratio. The prepared systems were characterized regarding particle size, zeta potential, polydispersity index, entrapment efficiency and in-vitro release studies. The best achieved ZTL system was evaluated for ZT- Gantrez® intermolecular interactions, drug crystallinity, morphology, ex-vivo permeation and histopathological examination. Finally, a comparative in-vivo biodistribution study through radiotracking technique using Technetium-99 m was adopted. L2 was the best-achieved ZTL system with respect to spherical particle size (390.7 nm), zeta-potential (-30.8 mV), PDI (0.2), entrapment efficiency (86.2%), controlled release profile, flux (147.13 μg/cm 2 /hr) and enhancement ratio (5.67). Histopathological studies proved the safety of L2 system upon application on skin. L2 revealed higher brain C max (12.21 %ID/g), prolonged brain MRT (8.67 hr), prolonged brain 0.23 hr), significantly high relative bioavailability (2929.36%) and similar brain T max (0.5 hr) compared to I.V. route with higher brain/blood ratio. Thus, sonophoresis assisted transdermal delivery of ZTL offers a propitious alterative to alleviate migraine symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This work aimed at evaluating the potential of amphiphilic polyoxazolines bearing lipid chain called lipopolyoxazolines to reach efficient intracellular delivery. Four lipid chains: linear saturated, linear unsaturated and two branched one of various length were associated to poly(2-methyl-2-oxazoline) block. The evaluation of their physicochemical features and their impact on cell viability and internalization capacity indicated that the linear saturated gathered the highest cell internalization with a good cell viability. Its intracellular delivery capacity was compared to the PEG reference (DSPE-PEG) after being formulated in liposomes and loaded with fluorescent probe. Both POxylated and PEGylated liposomes showed similar characteristics regarding size distribution, drug loading and cell viability. However, their intracellular delivery was dramatically different, with an improved delivery by 30 folds for the POxylated ones. This significantly better performance highlighted the difficulty of PEGylated liposomes to enter the cells by endocytosis, contrary to POxylated liposomes. This study promotes the value of lipopoly(oxazoline) as a lipopoly(ethylene glycol) alternative for effective intracellular delivery and holds great promises for development of nanoformulations for intravenous administration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LAPINTE Vincent reports financial support was provided by SATT AxLR. LAPINTE Vincent reports a relationship with SATT AxLR that includes: funding grants. LAPINTE Vincent has patent pending to ROS-peau-POx. Nothing to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Exemestane (EXE), an irreversible aromatase inhibitor, is primarily used as a first-line therapy for estrogen receptor-positive breast cancer patients. However, complex physicochemical characteristics of EXE limit its oral bioavailability (<10%) and anti-breast cancer efficacy. The present study aimed to develop a novel nanocarrier system to improve the oral bioavailability and anti-breast cancer efficacy of EXE. In this perspective, EXE-loaded TPGS-based polymer lipid hybrid nanoparticles (EXE-TPGS-PLHNPs) were prepared by the nanoprecipitation method and evaluated for their potential in improving oral bioavailability, safety, and therapeutic efficacy in the animal model. EXE-TPGS-PLHNPs showed significantly higher intestinal permeation in comparison to EXE-PLHNPs (without TPGS) and free EXE. After oral administration, EXE-TPGS-PLHNPs and EXE-PLHNPs revealed 3.58 and 4.69 times higher oral bioavailability in Wistar rats compared to the conventional EXE suspension. The results of the acute toxicity experiment suggested that the developed nanocarrier was safe for oral administration. Furthermore, EXE-TPGS-PLHNPs and EXE-PLHNPs represented much better anti-breast cancer activity in Balb/c mice bearing MCF-7 tumor xenograft with tumor inhibition rate of 72.72% and 61.94% respectively in comparison with the conventional EXE suspension (30.79%) after 21 days of oral chemotherapy. In addition, insignificant changes in the histopathological examination of vital organs and hematological analysis further confirm the safety of the developed PLHNPs. Therefore, the findings of the present investigation advocated that the encapsulation of EXE in PLHNPs can be a promising approach for oral chemotherapy of breast cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pulmonary delivery of antibiotics for the treatment of tuberculosis provides several benefits compared to conventional oral and parenteral administration. API-loaded particles delivered directly to alveolar macrophages, where Mycobacterium tuberculosis resides, can reduce the required dose and decrease the severe side effects of conventional treatment. In this work, lipid-microparticles loaded with rifampicin were engineered via spray-drying to be administered as a carrier-free dry powder for inhalation. Although, it is well-known that spray-drying of lipid-based excipients is strongly limited, a completely lipid-based formulation using diglycerol full ester of behenic acid was produced. The solid state of the lipid, providing high melting temperature, absence of polymorphism and monophasic crystallization, led to high yield of spray-dried particles (83%). Inhalable particles of mass median aerodynamic diameter of 2.36 µm, median geometric size of 2.05 µm, and negative surface (-50.03 mV) were engineered. Such attributes were defined for deep lung deposition and targeted delivery of antibiotics to alveolar macrophages. Superior aerodynamic performance as carrier-free DPI was associated to a high fine particle fraction of 79.5 %. No in vitro cytotoxic effects were found after exposing epithelial cell lines and alveolar macrophages. In vitro uptake of particles into alveolar macrophages indicated the efficiency of their targeted delivery. The use of highly processable and safe lipid-based excipients for particle engineering via spray-drying can extend the availability of materials for functionalized applications for pulmonary delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Because of their poor water-soluble properties and non-specific distribution, most hydrophobic therapeutics had limited benefit for patients with ulcerative colitis. Herein, an in-situ oil-based gel has been developed as a rectal delivery vehicle for these therapeutics. In situ gel-forming oil (BBLG) was composed of soybean phosphatidyl choline (40%, w/w), glyceryl dioleate (50%, w/w), and ethanol (10%, w/w). The hydrophobic laquinimod (LAQ) as a model drug was easily dissolved in gel-forming oil and its solubility was reaching to 7 ± 0.1 mg/mL. Importantly, upon contact with the colonic fluids, the gel-forming oil was quickly transited to a semi-solid gel, adhering to the inflamed colon mucosa and forming a protective barrier. Transmission Electron Microscopy showed that the gel network was arranged by the connected lipid spheres and LAQ was non-crystally encapsulated into the lipid spheres. Moreover, the universal adhesive test showed that the adhesive force and the adhesive energy of BBLG toward fresh colon tissues were 711 ± 12 mN and 25 ± 2 J/m 2 , which was 2.14-fold and 5-fold higher than that of the marketed Poloxamer 407 gel, respectively. Meanwhile, in vivo imaging confirmed that the retention time of BBLG in the colon lumen was more than 8 h after rectal administration. In vivo animal studies showed that BBLG also greatly enhanced the therapeutic impact of LAQ on TNBS-treated rats with ulcerative colitis, as evidenced by reduced disease activity index (DAI) scores and weight loss. Moreover, the colonic inflammation was significantly alleviated and the goblet cells were obliviously restored after treatment. Importantly, the gut mucosa barrier was largely repaired without any formation of fibrosis remodeling. Conclusively, in situ liquid gel may be a potential delivery system of hydrophobic medicines for ulcerative colitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)