Lipid-based Drug Delivery Research Articles

An overview of lipid based vesicular systems: stability and regulatory considerations

Lipid based drug delivery systems are used to encapsulate the active substance within or interior space of the lipid bilayer. The lipid-based drug products are designed to improve the stability in-vivo and pharmacokinetics behavior of active substances. However, understanding of the factors that affect the stability is critical for rationale development of lipid based drug delivery systems with desired pharmacokinetics and bio-distribution. Lyophilization is one primary approach to improve the stability of lipid based systems. The article presents an overview of the characteristics of the lipid based drug delivery systems as drug carriers, particularly in relation to stability, regulatory considerations. Further, the present review emphasizes the formulation problems and marketed formulation of lipid-based systems.

Tailoring Lipid-Based Drug Delivery Nanosystems by Synchrotron Small Angle X-ray Scattering.

Thanks to specific physico-chemical properties, drug delivery systems based on nanoparticles have proven to effectively transport delicate molecules for therapeutic purposes, protecting them from degradation, increasing their stability in the blood circulation and allowing to convey and release the transported substances in specific areas of the body. Nanoparticles obtained from biopolymers for applications in medicine and pharmaceutics have become particularly popular in recent years due to the enormous research effort in the field of vaccines to respond to the pandemic emergency. Among the various types of biopolymers used to produce nanoparticles for therapeutics, lipids have characteristics that make them biocompatible, with low toxicity and ease of clearance. They can be synthesized by designing their characteristics according to the foreseen administration path, or to the target of the transported drug. The analytical methods mostly used to evaluate the characteristics of lipid nanosytems for drug delivery involve studying their effects on cells, in vitro and in vivo. Although it is often considered a "niche technique" for research in the bio-related sciences, Small Angle X-ray Scattering (SAXS) is a versatile tool to study the structure of nanosystems based on lipids, both ex situ and in situ. Therefore, it allows to evaluate both the effect of the different synthesis parameters and of the exposure of lipid nanoparticles to physiological conditions, which is of fundamental importance to design efficient drug delivery systems. In this mini-review, we will report some recent examples of characterization and design of nanoparticles based on lipids, where SAXS has been a fundamental step both to guide the synthesis of nanomaterials with tailored characteristics, and to understand the interaction between nanomaterials and cells.

Preparation and evaluation of a lipid-based drug delivery system to ımprove valsartan oral bioavailability: pharmacokinetic and pharmacodynamic analysis

Antihypertensive treatment reduces the risk of cardiovascular complications in patients with high mortality with hypertension. Valsartan is highly selective antihypertensive that is rapidly absorbed after oral administration, but its oral bioavailability is only 25%. It is absorbed from the upper part of the gastrointestinal tract but is less soluble in this acidic environment. We aimed to develop a lipid-based formulation to produce a self-emulsifying drug delivery system (SEDDS) for valsartan. Solubility studies were performed to identify the components of the SEDDS that provided the best dissolution of valsartan. Ternary phase diagrams were drawn using the titration method with oil, surfactants and co-surfactants in which valsartan was highly soluble, and microemulsion formulations with the highest area were determined. Characterization and in vitro release studies were performed to optimize the formulation. In vitro release profiles of commercial and SEDDS formulations showed the F2 formulation release rate increased at pH 1.2 fasted state simulated gastric fluid. After oral administration, plasma drug concentrations in rats indicate that the F2 formulation provided a 4.2-fold greater AUC for valsartan than the commercial formulaiton, resulting in an 8.5-fold greater Cmax. These findings suggest the F2 formulation increases valsartan solubility, resulting in an improved oral pharmacokinetic profile. According to the pharmacodynamic study, the F2 formulation is more effective than the commercial formulation in restoring systolic and diastolic blood pressure within a few hours.

Lipid-Based Drug Delivery System (LBDDS): An Emerging Paradigm to Enhance Oral Bioavailability of Poorly Soluble Drugs

Low-oral bioavailability as a consequence of low-water solubility of drugs is challenging for formulation scientists in the development of new pharmaceutical products. This review aims to highlight relevant considerations when implementing a rational strategy for the development of lipid-based oral drug delivery systems and to discuss shortcomings and challenges to the current classification of these delivery systems such as nanoemulsion, Solid lipid nanoparticle (SLN), Nanostructured lipid carriers (NLC), Self-emulsifying drug delivery system (SEDDS). Lipid-based drug delivery systems consist of a diverse group of formulations, each consisting of varying functional and structural properties that are amenable to modifications achieved by varying the composition of lipid excipients and other additives thereby facilitating the bioavailability of poorly water-soluble drugs. In addition, lipid nanoparticles may also protect the loaded drugs from chemical and enzymatic degradation and gradually release drug molecules from the lipid matrix into the blood, resulting in improved therapeutic profiles compared to free drugs. Therefore, due to their physiological and biodegradable properties, lipid molecules may decrease adverse side effects and chronic toxicity of the drug-delivery systems when compared to others of polymeric nature. Accordingly, the present review is mainly centred on the various lipid-based drug delivery system and excipients used in lipid-based drug delivery systems (LBDDS).

Nanostructured lipid carriers of alkannins and shikonins: Experimental design, characterization and bioactivity studies

The chiral pair alkannin and shikonin and their ester derivatives (A/S), are lipophilic secondary metabolites possessing a wide spectrum of pharmacological activities. Their incorporation in lipid-based drug delivery systems can enhance their therapeutic efficacy, especially for dermal or transdermal applications. In this work, A/S in the form of oily extracts and isolated mixture of pigments from Alkanna tinctoria roots were entrapped in lipid based nanocarriers for dermal applications. In both cases, Experimental Design was carried out to evaluate the effect of process parameters on mean particle size, ζ-potential and entrapment efficiency, aiming to identify the optimum process conditions. The optimum oily extract loaded liposomes showed a mean particle size of 106 nm, ζ-potential value of −45.1 mV and entrapment efficiency (EE%) up to 72%. On the other hand, the optimum nanocarriers for the incorporation of A/S mixture showed a mean particle size of 138 nm, ζ-potential value of −15.6 mV and EE% up to 56%. The in vitro release profiles for both drug delivery systems were satisfactory and revealed that, in both cases, the release of the active pharmaceutical ingredients from the nanocarriers is controlled by diffusion. Moreover, we evaluated the effect of the optimum formulations on the viability of human dermal fibroblasts and we found that, A/S mixture loaded nanocarriers enhance cell viability. In order to assess the effect of A/S derivatives loaded nanocarriers on human fibroblasts we targeted genes related to the antioxidant cellular response, cell aging and extracellular matrix organization. The findings showed that nanocarriers induced the antioxidant response, presented a positive impact on cells’ longevity and promoted extracellular matrix organization. Based on these findings, formulated nanocarriers can be used as a potential drug delivery system for dermal applications in cosmetic products.

Exploring the potential of anti-inflammatory activity of berberine chloride-loaded mesoporous silica nanoparticles in carrageenan-induced rat paw edema model

Berberine is a traditional Chinese medicine that has excellent potential for anti-inflammatory activity. However, due to its poor penetration into the skin, its applicability via topical administration is restricted. Also, due to the high hydrophilicity of BCS class III drugs such as Berberine chloride (BBR), loading such drugs into lipid-based drug delivery systems is challenging. It is also difficult to achieve a sustained drug release for such drugs. Mobil Crystalline Materials (MCM-41) is an extensively employed mesoporous silica nanoparticle (MSNs) due to their high surface area, tuneability, and exceptional stability. In this study, berberine chloride was loaded into the synthesized MSNs having high surface area and pore volume to understand the drug loading and drug release kinetics from MSNs. Further, the anti-inflammatory efficacy of BBR-MSNs was evaluated on animal models. The MSNs fabricated using the sol-gel method exhibited characteristic type IV adsorption-desorption isotherm, confirming the material's mesoporous nature and having spherical morphological characteristics. The hemolysis study proved that the MCM 41 MSNs were safe and hemocompatible. Finally, the in vivo anti-inflammatory study of carrageenan-induced rat paw edema proved the superiority of BBR-MSN over plain BBR in terms of maximum inhibition (%) of rat paw edema.

Dynamic drug release state and PEG length in PEGylated liposomal formulations define the distribution and pharmacological performance of drug

To optimize the therapeutic efficacy of active pharmaceutical ingredients, various lipid-based drug delivery systems have been developed. In particular, due to the various advantages, most of the lipid-based nanoformulation products on the market contain the poly(ethylene glycol) (PEG) block on the carrier. However, the effect of PEG length on pharmacokinetic (PK) profile, nanoparticle distribution, and pharmacological efficacy of the encapsulated drug have not been explored fully. Here, we assessed the effects of PEG length on the distribution and pharmacological efficacy of doxorubicin (Dox)-loaded liposomal formulations. Compared to PEG-Lipo 2 K, PEG-Lipo 10 K increased the drug concentration in blood at 24 and 48 h and the extent of particle accumulation at the tumor site due to the enhanced blood circulation time of the nanoparticles having higher PEG length. However, as the drugs begin to be released from the carrier at the point of administration, the drug concentration at that later time point drops to 4% or less compared to that of the initial time points. Thus, the pharmacological efficacy among the PEG-Lipo formulations did not differ significantly, which could be attributed to their dynamic drug-releasing characteristics during circulation in the blood. These findings suggest that although PEG length plays a critical role in the particle and drug distribution of the formulations, it does not affect the therapeutic efficacy of the incorporated drug because of the dynamic character of drug-loaded PEG-Lipo structures.

Polyphenol-Functionalized Cubosomes as Thrombolytic Drug Carriers.

The safeadministration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase-type plasminogen activator (uPA) and coated with a low-fouling peptide that is incorporated within a metal-phenolic network (MPN). The peptide-containing MPN (pep-MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep-MPN-coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane-dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA-loaded pep-MPN-coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half-life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane-dependent release of uPA within pep-MPN-coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.

Formulation optimization and characterization of Pistacia atlantica Desf. essential oil-loaded nanostructured lipid carriers on the proliferation of human breast cancer cell line SKBR3 (in vitro studies)

IntroductionBreast cancer is among the most prevalent type of cancer in women across the world. The essential oils of Pistacia atlantica Desf. have been utilized as a medicine owing to their antibacterial, antioxidant, anti-inflammatory, and anticancer effects. The current research aims to enhance the anticancer effect of the essential oil of Pistacia atlantica Desf. by incorporating it in a nanostructured lipid carrier (NLC), a lipid-based drug delivery system. MethodsNLCs-containing Pistacia atlantica Desf. essential oil was prepared by probe ultrasonication method to obtain Pistacia atlantica Desf. EO-loaded NLCs (PAEO-NLCs) and its anticancer effect against SKBR3 breast cancer cells was investigated. Dynamic light scattering (DLS) method was used to determine the particle size, as well as polydispersity index (PDI) and zeta potential (ZP) of formulations. Transmission electron microscopy (TEM) was also used to determine the size and morphology of optimized formulation (PAEO-NLC4). In vitro cellular assays (MTT, apoptosis, and cell cycle) were employed to assess the anticancer effect of PAEO-NLC4 against SKBR3 cells. ResultsTEM results revealed that PAEO-NLC4 have a well-defined spherical shape, with a size of 151 ± 1 nm, with a negative surface charge of − 29.1 ± 1.4 mV, and a PDI of 0.16 ± 0.03. Cellular data revealed that the PAEO-NLC4 can decline the viability of SKBR3 cells through cell cycle arrest and apoptosis, compared to cells treated with placebo and free PAEO. ConclusionsBased on our findings, PAEO-NLC4 could serve as a potential and effective treatment for breast cancer therapy.

Thiolation of non-ionic surfactants for the development of lipid-based mucoadhesive drug delivery systems

The aim of this study was to develop thiolated self-emulsifying drug delivery systems (SEDDS) and nanostructured lipid carriers (NLCs) with improved mucoadhesive properties. Two non-ionic surfactants bearing a short and long PEG chain, namely polyoxyethylene (10) stearyl ether (PSE10) and polyoxyethylene (100) stearyl ether (PSE100), were thiolated for the first time by substituting the terminal hydroxyl group with a thiol group. The synthesis was confirmed by FT-IR, NMR and Ellman’s test. SEDDS and NLCs containing these thiolated compounds were investigated for size, polydispersity index (PDI) and ζ potential. Subsequently, mucus diffusion studies, rheological evaluations after mixing the nanocarriers with mucus and mucoadhesion studies on porcine intestinal mucosa were performed. All nanocarriers had a size less than 250 nm, a maximum PDI of 0.3 and a ζ potential < −9.0 mV. Mucus diffusion studies resulted in the rank order of increasing diffusivity: PSE10-SH < PSE100-SH < PSE10-OH < PSE100-OH for NLCs and PSE10-OH < PSE100-OH < PSE100-SH < PSE10-SH for SEDDS. The mucoadhesive properties and increase in viscosity of SEDDS and NLCs ranked: PSE100-OH < PSE10-OH < PSE100-SH < PSE10-SH. In addition, the short chain PSE10-SH showed higher mucus interactions than the long chain PSE100-SH for both SEDDS and NLCs. The thiolated PSE surfactants appeared to be promising excipients for the design of highly mucoadhesive drug delivery systems.

Tailoring the multi-functional properties of phospholipids for simple to complex self-assemblies.

The unique interfacial properties, huge diversity, and biocompatible nature of phospholipids make them an attractive pharmaceutical excipient. The amphiphilic nature of these molecules offers them the property to self-assemble into distinct structures. The solubility, chemical and structural properties, surface charge, and critical packing parameters of phospholipids play an essential role during formulation design. This review focuses on the relationship between the structural features of a phospholipid molecule and the formation of different lipid-based nanocarrier drug delivery systems. This provides a rationale and guideline for the selection of appropriate phospholipids while designing a drug delivery system. Finally, we refer to relevant recent case studies covering different types of phospholipid-based systems including simple to complex assemblies. Different carriers in the size range of 50nm to a few microns can be prepared using phospholipids. The carriers can be delivered through oral, intravenous, nasal, dermal, transmucosal, and subcutaneous routes. A wide range of applicability can be achieved by incorporating various hydrophilic and lipophilic additives in the phospholipid bilayer. Advanced research has led to the discovery of phospholipid complexes and cell membrane mimicking lipids. Overall, phospholipids remain a versatile pharmaceutical excipient for drug delivery. They play multiple roles as solubilizer, emulsifier, surfactant, permeation enhancer, coating agent, release modifier, and liposome former.

Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug.

Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (Seq) in the SNEDDS (superSNEDDS, 250% of Seq). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of Seq), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% Seq in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48h to 1month under ambient conditions. The PK study in rats displayed significantly higher Cmax and AUC0-7h (3-fold increase) and faster Tmax for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.

PEGylation of Nanoemulsion Using Spontaneous Emulsification Method.

Nanoemulsion (NE), a lipid-based drug delivery system, plays an important role in delivering drugs and enhancing bioavailability. They are mainly taken up by the reticuloendothelial system, because of which their bioavailability is diminished, leading to poor therapeutic activity. It is important to protect this delivery system using a coating agent. Thus, we have coated o/w type NE using polyethylene glycol (PEG). The novelty in our study is use of dicarboxylic acid-linked PEG. Furthermore, the spontaneous emulsification method was used in preparation and peg coating, not mentioned previously. After the preparation of NE, various characterization and stability studies were carried out. We have also optimized the ratios for NE and PEG NE by using various concentrations of Smix, PEG, and water. Also, the same has also been plotted in a pseudoternary-phase diagram. As a conclusion, the PEGylation of NE was carried out successfully and may also be used for linking with other ligands because of the presence of COOH group.

Lipid-Based Drug Delivery Systems for Diseases Managements.

Liposomes are tiny lipid-based vesicles composed of one or more lipid bilayers, which facilitate the encapsulation of hydrophilic, lipophilic, and amphiphilic biological active agents. The description of the physicochemical properties, formulation methods, characteristics, mechanisms of action, and large-scale manufacturing of liposomes as delivery systems are deeply discussed. The benefits, toxicity, and limitations of the use of liposomes in pharmacotherapeutics including in diagnostics, brain targeting, eye and cancer diseases, and in infections are provided. The experimental approaches that may reduce, or even bypass, the use of liposomal drug drawbacks is described. The application of liposomes in the treatment of numerous diseases is discussed.

Formulation, characterization and in-vitro evaluation of self-nanoemulsifying drug delivery system containing rhamnolipid biosurfactant

Self-nanoemulsifying drug delivery systems (SNEDDS) are most commonly used lipid-based drug delivery systems for bioavailability enhancement. Mostly SNEDDS contains high concentrations of synthetic surfactants which may result in gastric irritation and cause toxicity. In this study, Rhamnolipid, a biosurfactant, is utilized as a cosurfactant to minimize the quantity of synthetic surfactant in SNEDDS formulation. Two sets of SNEDDS formulations comprising of medium-chain (MC) or long-chain (LC) glycerides, Kolliphor ® RH40 (KOL) and Rhamnolipid (RL) were produced using a D-optimal design in MODDE software. The monodispersed SNEDDS preconcentrates were further characterized by utilizing dynamic light scattering (at pH 2.5 & 6.5), cryogenic transmission electron microscopy, thermodynamic stability, in-vitro lipid digestion, and viscosity measurements. All MC-SNEDDS preconcentrates were not homogenous and considered unstable, while LC-SNEDDS were homogenous and produced nanoemulsions with droplet sizes ranging from 21 to 336 nm. LC-SNEDDS formulations containing RL produced smaller droplet sizes when dispersed in simulated intestinal media while droplet size slightly increased in the simulated gastric fluid which suggested that RL reduces droplet size more efficiently at higher pH. The zeta potential of nanoemulsion produced by dispersion of LC-SNEDDS containing RL was decreased at low pH. Thermodynamic stability studies have shown that all selected preconcentrates were stable. During in vitro lipolysis, only 24–34% of formulations were enzymatically digested, and at higher concentrations of RL, low number of fatty acids was released. Based on the results of dynamic viscosity studies, all the formulations showed non-Newtonian properties and were suitable for the capsule filling process. During cytotoxicity studies, LC-SNEDDS formulation and RL cosurfactant were well-tolerable at doses normally administered to human. In conclusion, this study demonstrated that LC-SNEDDS comprising RL as cosurfactant are favorable formulations when reduction in the amount of synthetic surfactant is desirable and RL also possibly helps to alter the digestion rate.

Permeability of Olmesartan Medoxomil from Lipid Based and Suspension Formulations using an Optimized HDM-PAMPA Model

Hexadecane membrane-parallel artificial membrane permeability assay (HDM-PAMPA) is based on an artificial hexadecane membrane that separates the two compartments (donor and acceptor compartment). This model is used to predict the permeability of drugs in gastrointestinal tract and to simulate the passive absorption. In vivo behaviour of the drugs can be estimated with these systems in drug development studies. In our study we optimized HDM-PAMPA model to determine permeability of olmesartan medoxomil (OM) lipid based drug delivery system (OM-LBDDS). In order to prove that LBDDS formulation facilitates the weak permeability of OM, permeation rates were compared with the OM suspension formula (containing 0.25% v/w CMC). The experiment was performed on a 96-well MultiScreen® PAMPA filter plate (MAIPN4510). The permeability of olmesartan formulations from the donor to acceptor compartment separated by a HDM membrane were determined by the previous validated HPLC method. We created positive control series without coating hexadecane membrane to present the LBDDS and suspension formulation permeability from uncoated plates. The effective permeability constant (Pe) was calculated by the formula and improvement of permeability of OM-LBDDS formulation from hexadecane membrane was confirmed. On the contrary there was no permeation of OM-Suspension in the hexadecane coated plates. As a result, the intestinal permeability of OM-LBDDS was calculated to be at least 100 times more than the suspension. OM-Suspension permeation was only observed in the hexadecane uncoated positive control plates. This was also manifestation of HDM-PAMPA mimicking permeability of intestines because of its lipidic construction.

Structural and dynamical properties of Palmitoyl-Oleoyl phosphatidylserine lipid nanotubes containing cholesterols and PEGylated dioleoyl Phosphatidylethanolamine: A Coarse-Grained molecular dynamics simulation

Lipid nanotubes (LNTs) are a class of lipid-based drug delivery systems (LBDDSs). Reports indicate that LBDDSs are effective systems in drug delivery to deal with COVID-19. The rational design of LNTs requires a deeper understanding of their structural properties in various influential factors such as lipid composition and PEGylation. This work uses coarse-grained molecular dynamics simulation to study the structural/dynamical properties of palmitoyl-Oleoyl phosphatidylserine (POPS) LNTs. To this end, the density distribution profiles are examined to evaluate of diameters and thicknesses of LNTs. The results show that adding cholesterol to LNT leads to lipid tail regularity, increasing the bilayer thickness and LNT diameter. PEGylation tends to increase irregularities of lipid chains, reduce the molecular packing and increase lipids dynamics. Our calculations predicted that manipulating LNT composition can be used to obtain favorable structural/dynamical properties and desired dimensions.

Engineered Nanoscale Lipid-Based Formulation as Potential Enhancer of Gefitinib Lymphatic Delivery: Cytotoxicity and Apoptotic Studies Against the A549 Cell Line.

The present study aimed to engineer a nanoscale lipid-based lymphatic drug delivery system with D-α-Tocopherol polyethylene glycol 1000 succinate to combat the lymphatic metastasis of lung cancer. The nanoscale lipid-based systems including GEF-SLN, GEF-NLC, and GEF-LE were prepared and pharmaceutically characterized. In addition, the most stable formulation (GEF-NLC) was subjected to an in vitro release study. Afterward, the optimized GEF-NLC was engineered with TPGS (GEF-TPGS-NLC) and subjected to in vitro cytotoxicity, and apoptotic studies using the A549 cells line as a surrogate model for lung cancer. The present results revealed that particle size and polydispersity index of freshly prepared formulations were ranging from 198 to 280 nm and 0.106 to 0.240, respectively, with negative zeta potential ranging from − 14 to − 27.6.mV. An in vitro release study showed that sustained drug release was attained from GEF-NLC containing a high concentration of lipid. In addition, GEF-NLC and GEF-TPGS-NLC showed remarkable entrapment efficiency above 89% and exhibited sustained release profiles. Cytotoxicity showed that IC50 of pure GEF was 11.15 μg/ml which decreased to 7.05 μg/ml for GEF-TPGS-NLC. The apoptotic study revealed that GEF-TPGS-NLC significantly decreased the number of living cells from 67 to 58% when compared with pure GEF. The present results revealed that the nanoscale and lipid composition of the fabricated SLN, NLC, and LE could mediate the lymphatic uptake of GEF to combat the lymphatic tumor metastasis. Particularly, GEF-TPGS-NLC is a promising LDDS to increase the therapeutic outcomes of GEF during the treatment of metastatic lung cancer.Graphical abstract

Computational Insights into the Role of Cholesterol in Inverted Hexagonal Phase Stabilization and Endosomal Drug Release.

Cholesterol is a major component of many lipid-based drug delivery systems, including cationic lipid nanoparticles. Despite its critical role in the drug release stage, the underlying molecular mechanism by which cholesterol assists in endosomal escape remains unclear. An efficient drug release from the endosome requires endosomal disruption. This disruption is believed to involve a lamellar-to-inverted hexagonal (Lα-HII) phase transition upon fusion of the lipid nanoparticle with the endosomal membrane. We used molecular dynamics simulations to study the structural properties of HII systems composed of an anionic lipid distearoyl phosphatidylserine (DSPS), an ionizable cationic lipid (KC2H), and cholesterol for several hydration levels and molar ratios. This system corresponds to the lipid mixtures in the hypothesized HII structure formed upon fusion and is of interest for the rational design of ionizable cationic lipids, including KC2, for an optimal drug release. Simulations suggest a geometry- and symmetry-driven lipid sorting and cholesterol-DSPS co-location around the water cores. Cholesterol preferentially co-locates with negatively charged saturated DSPS lipids at interstitial angles. The observed cholesterol-DSPS co-location results in an overall increase in the DSPS acyl chains' order parameters, which we propose to assist in stabilizing the HII phase by stretching the DSPS acyl chains for filling the voids formed by three adjacent lipid tubules. Furthermore, a systematic increase in the cholesterol concentration increased the lattice plane spacing and the water core radius but decreased the undulations along the lipid tubule axis. We propose that cholesterol and the degree of saturation/polyunsaturation of the lipid acyl chains, and not the lipid charge, are the main contributors in facilitating the Lα-HII phase transition and stabilizing/destabilizing the formed HII phase, whereas the positive charge of the ionizable cationic lipid promotes the LNP-endosomal membrane adhesion and assists in initiating the fusion process at the local contact area. We also propose that the effect of cholesterol on the HII structure and curvature is the main underlying reason for the well-documented HII stabilization and destabilization at low and high molar concentrations of cholesterol, respectively.

Novel microfluidic swirl mixers for scalable formulation of curcumin loaded liposomes for cancer therapy

Liposomes have been widely used in nanomedicine for the delivery of hydrophobic and hydrophilic anticancer agents. The most common applications of these formulations are vaccines and anticancer formulations (e.g., mRNA, small molecule drugs). However, large-scale production with precise control of size and size distribution of the lipid-based drug delivery systems (DDSs) is one of the major challenges in the pharmaceutical industry. In this study, we used newly designed microfluidic swirl mixers with simple 3D mixing chamber structures to prepare liposomes at a larger scale (up to 320 mL/min or 20 L/h) than the commercially available devices. This design demonstrated high productivity and better control of liposome size and polydispersity index (PDI) than conventional liposome preparation methods. The microfluidic swirl mixer devices were used to produce curcumin-loaded liposomes under different processing conditions which were later characterized and studied in vitro to evaluate their efficiency as DDSs. The obtained results demonstrated that the liposomes can effectively deliver curcumin into cancer cells. Therefore, the microfluidic swirl mixers are promising devices for reproducible and scalable manufacturing of DDSs.