On the Structure, Stability, and Cell Uptake of Nanostructured Lipid Carriers for Drug Delivery.

The efficacy of nanostructured lipid carriers (NLC) for drug delivery strongly depends on their stability and cell uptake. Both properties are governed by their compositions and internal structure. To test the effect of the lipid composition of NLC on cell uptake and stability, three kinds of liquid lipids with different degrees of unsaturation are employed. After ensuring homogeneous size distributions, the thermodynamic characteristics, stability, and mixing properties of NLC are characterized. Then the rates and predominant pathways of cell uptake are determined. Although the same surfactant is used in all cases, different uptake rates are observed. This finding contradicts the view that the surface properties of NLC are dominated by the surfactant. Instead, the uptake rates are explained by the structure of the nanocarrier. Depending on the mixing properties, some liquid lipids remain inside the nanocarrier, while other liquid lipids are present on the surface. Nanocarriers with liquid lipids on the surface are taken up more readily by the cells. This shows that the engineering of efficient lipid nanocarriers requires a delicate balance of interactions between all components of the nanocarrier on the molecular level.

Facile adipocyte uptake and liver/adipose tissue delivery of conjugated linoleic acid-loaded tocol nanocarriers for a synergistic anti-adipogenesis effect.

Obesity is a major risk to human health. Adipogenesis is blocked by α-tocopherol and conjugated linoleic acid (CLA). However, their effect at preventing obesity is uncertain. The effectiveness of the bioactive agents is associated with their delivery method. Herein, we designed CLA-loaded tocol nanostructured lipid carriers (NLCs) for enhancing the anti-adipogenic activity of α-tocopherol and CLA. Adipogenesis inhibition by the nanocarriers was examined using an in vitro adipocyte model and an in vivo rat model fed a high fat diet (HFD). The targeting of the tocol NLCs into adipocytes and adipose tissues were also investigated. A synergistic anti-adipogenesis effect was observed for the combination of free α-tocopherol and CLA. Nanoparticles with different amounts of solid lipid were developed with an average size of 121‒151 nm. The NLCs with the smallest size (121 nm) showed greater adipocyte internalization and differentiation prevention than the larger size. The small-sized NLCs promoted CLA delivery into adipocytes by 5.5-fold as compared to free control. The nanocarriers reduced fat accumulation in adipocytes by counteracting the expression of the adipogenic transcription factors peroxisome proliferator activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP)α, and lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Localized administration of CLA-loaded tocol NLCs significantly reduced body weight, total cholesterol, and liver damage indicators in obese rats. The biodistribution study demonstrated that the nanoparticles mainly accumulated in liver and adipose tissues. The NLCs decreased adipocyte hypertrophy and cytokine overexpression in the groin and epididymis to a greater degree than the combination of free α-tocopherol and CLA. In conclusion, the lipid-based nanocarriers were verified to inhibit adipogenesis in an efficient and safe way.

Agomelatine-loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2/HO-1 signalling pathway.

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1ß and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.

A comprehensive review on lipid nanocarrier systems for cancer treatment: fabrication, future prospects and clinical trials.

Over the last few decades, cancer has been considered a clinical challenge, being among the leading causes of mortality all over the world. Although many treatment approaches have been developed for cancer, chemotherapy is still the most utilized in the clinical setting. However, the available chemotherapeutics-based treatments have several caveats including their lack of specificity, adverse effects as well as cancer relapse and metastasis which mainly explains the low survival rate of patients. Lipid nanoparticles (LNPs) have been utilized as promising nanocarrier systems for chemotherapeutics to overcome the challenges of the currently applied therapeutic strategies for cancer treatment. Loading chemotherapeutic agent(s) into LNPs improves drug delivery at different aspects including specific targeting of tumours, and enhancing the bioavailability of drugs at the tumour site through selective release of their payload, thus reducing their undesired side effects on healthy cells. This review article delineates an overview of the clinical challenges in many cancer treatments as well as depicts the role of LNPs in achieving optimal therapeutic outcomes. Moreover, the review contains a comprehensive description of the many LNPs categories used as nanocarriers in cancer treatment to date, as well as the potential of LNPs for future applications in other areas of medicine and research.

Quality by design endorsed atorvastatin-loaded nanostructured lipid carriers embedded in pH-responsive gel for melanoma.

AIM: Our aim was to repurpose atorvastatin for melanoma by encapsulating in a nanostructured lipid carrier matrix to promote tumour cell internalisation and skin permeation. pH-responsive chitosan gel was employed to restrict At-NLCs in upper dermal layers. METHODS: We utilised a quality by design approach for encapsulating At within the NLC matrix. Further, cellular uptake and cytotoxicity was evaluated along with pH-responsive release and ex vivo skin permeation. RESULTS: Cytotoxicity assay showed 3.13-fold enhanced cytotoxicity on melanoma cells compared to plain drug with nuclear staining showing apoptotic markers. In vitro, release studies showed 5.9-fold rapid release in chitosan gel matrix at pH 5.5 compared to neutral pH. CONCLUSIONS: At-NLCs prevented precipitation, promoted skin permeation, and SK-MEL 28 cell internalisation. The localisation of NLCs on the upper dermal layer due to electrostatic interactions of skin with chitosan gel diminished the incidence of untoward systemic effects.

Natural-Origin Betaine Surfactants as Promising Components for the Stabilization of Lipid Carriers.

In the present work, we demonstrate studies involving the influence of the formulation composition on the physicochemical properties of nanocarriers: solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Novel lipid-origin platforms were prepared using two "green" betaine-based surfactants, cocamidopropyl betaine (ROKAmina K30) and coco betaine (ROKAmina K30B), in combination with three different solid lipids, cetyl palmitate (CRODAMOL CP), trimyristin (Dynasan 114), and tristearin (Dynasan 118). Extensive optimization studies included the selection of the most appropriate lipid and surfactant concentration for effective SLN and NLC stabilization. The control parameters involving the hydrodynamic diameters of the obtained nanocarriers along with the size distribution (polydispersity index) were determined by dynamic light scattering (DLS), while shape and morphology were evaluated by atomic force microscopy (AFM) and transmission electron microscopy (TEM). Electrophoretic light scattering (ELS) and turbidimetric method (backscattering profiles) were used to assess colloidal stability. The studied results revealed that both betaine-stabilized SLN and NLC formulations containing CRODAMOL CP as lipid matrix are the most monodisperse and colloidally stable regardless of the other components and their concentrations used, indicating them as the most promising candidates for drug delivery nanosystems with a diverse range of potential uses.

Transferrin-Conjugated Nanostructured Lipid Carriers for Targeting Artemisone to Melanoma Cells.

We report a successful formulation of Artemisone (ATM) in transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs), achieving nearly a five-times increase in cell toxicity. The escalating cost of new drug discoveries led to the repurposing of approved drugs for new indications. This study incorporated Artemisone, an antimalarial drug, into a nanostructured lipid carrier (NLC) and tested for possible anticancer effects. The aim was to develop NLCs, and transferrin-conjugated NLCs (NLC-Tf) encapsulating Artemisone to enhance its delivery and anticancer activity. NLC formulations were prepared using high-pressure homogenization followed by ultrasonication and were characterized by particle size, zeta potential, and PDI. The conjugation of (Tf) to (NLC) was confirmed using IR, and the anticancer activity was tested using MTS assay. All formulations were in the nanometer size range (140-167 nm) with different zeta potential values. IR spectroscopy confirmed the successful conjugation of transferrin to NLC. Upon testing the formulations on melanoma cell lines using MTS assay, there was a significant decrease in viability and an increase in the encapsulated ATM-Tf toxicity compared to positive control ATM. The NLCs presented a promising potential carrier for delivering ATM to melanoma cells, and further conjugation with Tf significantly improved the ATM cytotoxicity.

Preparation and characterisation of esculetin-loaded nanostructured lipid carriers gels for topical treatment of UV-induced psoriasis.

SIGNIFICANCE: As an inflammatory and autoimmune skin condition, psoriasis affects 2-3% of people worldwide. Psoriasis requires prolonged treatments with immunosuppressive medications which have severe adverse effects. Esculetin (Esc) is a natural medication that has been utilised to treat psoriasis. OBJECTIVE: The goal of this work is to improve Esc's solubility by developing novel Esc nanostructured lipid carriers (NLCs) for treating psoriasis and increasing the residence time on the skin which infers better skin absorption. METHODS: The particle size, zeta potential and entrapment efficiency (EE) of Esc NLCs were assessed. Incorporating NLCs into gum Arabic gel preparation enhances their industrial applicability, absorption and residence time on the skin. Esc NLC gels were evaluated by in vitro release and in vivo effectiveness on a rat model of UV-induced psoriasis. RESULTS: Esc NLCs showed high EE reaching more than 95% and reasonable particle size ranging between (53.86 ± 0.38 to 236.3 ± 0.11 nm) and were spherical. The release study of Esc NLCs gel demonstrated a fast release of Esc denoting enhanced bioavailability. Compared to free Esc, Esc NLCs gel (F2) could considerably lower the level of CD34 and TNF-α in the skin. The results were validated through histopathological analysis. CONCLUSION: As Esc NLCs gel (F2) has strong anti-inflammatory properties, our results showed that it presented a significant potential for healing psoriasis.

Intranasal delivery of doxepin: enhancing brain targeting efficiency utilizing nanostructured lipid carriers for a biopharmaceutics drug disposition classification system class-I drug.

Doxepin, a Class-I Biopharmaceutics Drug Disposition Classification System (BDDCS) drug, exhibits poor bioavailability due to extensive first-pass metabolism. This research focuses on enhancing the delivery of doxepin by formulating nanostructured lipid carriers (NLCs) through the utilization of the Box-Behnken Design methodology. These optimized NLCs are intended for intranasal administration, with the ultimate goal of improving nose-to-brain drug delivery. NLCs were formulated using a high-speed homogenization technique. The optimized batch had a small particle size (75.80 ± 5.48 nm, PDI = 0.286), high entrapment efficiency (94.10 ± 0.16%), and sustained ex vivo release (82.25 ± 4.61% at 24 h). Characterization studies confirmed the conversion of doxepin from a crystalline to an amorphous state with uniform distribution in the lipid matrix. In vivo pharmacokinetic studies in rats showed significantly higher doxepin concentration in the brain tissue (Cmax = 16.77 µg/g, tmax = 30 min) after intranasal administration compared to intravenous administration (Cmax = 2.53 µg/g, tmax = 6 h). High-drug targeting efficiency (DTE = 284.3%) and direct transport percentage (DTP = 64.8%) suggested direct penetration of NLCs in the brain via olfactory and trigeminal pathways. In conclusion, the study highlights the potential of NLCs to improve the bioavailability of doxepin through nose-to-brain delivery and thereby potentially enable the treatment of neurological disorders.

Development of Betulin-Loaded Nanostructured Lipid Carriers for the Management of Imiquimod-Induced Psoriasis.

Psoriasis is a complex and persistent autoimmune skin disease. The present research focused on the therapeutic evaluation of betulin-loaded nanostructured lipid carriers (BE-NLCs) towards managing psoriasis. The BE-NLCs were synthesized using the emulsification cum solidification method, exhibiting a spherical shape with a particle size of 183.5±1.82nm and a narrow size distribution window (PDI: 0.142±0.05). A high zeta potential -38.64±0.05mV signifies the relative stability of the nano-dispersion system. BE-NLCs show a drug loading and entrapment efficiency of 47.35±3.25% and 87.8±7.86%, respectively. In vitro release study, BE NLCs show a cumulative percentage release of 90.667±5.507% over BE-sol (57.334±5.03%) and BD-oint (42±4.58%) for 720min. In an ex vivo 24-h permeation study, % cumulative amount permeated per cm2 was found to be 55.667±3.33% from BE-NLCs and 32.012±3.26% from BE-sol, demonstrating a better permeability of 21.66% when compared to the standard formulation BD-oint. The in vivo anti-psoriatic activity in the IMQ-induced model shows topical application of BE-sol, BE-NLCs, and BD-oint resulted in recovery rates of 56%, 82%, and 65%, respectively, based on PASI (Psoriasis Area and Severity Index) score. Notably, BE-NLCs demonstrated a more significant reduction in spleen mass, indicating attenuation of the local innate immune system in psoriatic mice. Reductions in TNF-α, IL-6, and IL-17 levels were observed in both BE-sol and BE-NLCs groups compared to the disease control (DC) group, with BE-NLCs exhibiting superior outcomes (74.05%, 44.76%, and 49.26% reduction, respectively). Soy lecithin and squalene-based NLCs could be better carrier system for the improvement of the therapeutic potential of BE towards management of psoriasis.