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Background: Natural and living systems are dynamical systems that demonstrate complex behavior, which appears to be deterministic chaotic, characterized and governed by entropy increase and loss of information throughout their entire lifespan. Lipidic nanoparticles, such as liposomes, as artificial biomembranes, have long been considered appropriate models for studying various membrane phenomena that cell systems exhibit. By utilizing these models, we can better comprehend cellular functions, stability, as well as factors that might alter the cell physiology, leading to severe disease states. In addition, liposomes are well-established drug and vaccine delivery nanosystems, which are present in the market, playing a significant role; therefore, due to their importance, issues concerning their effectiveness and stability are research topics that are constantly investigated and updated. Methods: In this study, the emergent deterministic chaotic behavior of liposomes is described, while evaluation in accordance to their colloidal physical stability, by utilizing established nonlinear dynamics tools, is presented. Two liposomes of different composition and physical stability were de-veloped and a chaotic evaluation on the time series of their size and polydispersity was conducted. Results: The utilized models revealed instability, loss of information and order loss for both lipo-somes in due time, with important differentiations. An initial interpretation of the results is apposed, whereas the foundations for further investigating possible exploitation of the demonstrated nonlinear-ity and adaptability of artificial biomembranes is laid, with projection on biosystems. Conclusion: The present approach is expected to impact the application of lipidic nanoparticles and liposomes in various crucial fields, such as drug and vaccine delivery, providing useful information for both the academia and industry. © 2022 Bentham Science Publishers.

Liposomes belong to the class of drug delivery nanosystems and are widely used for the incorporation and delivery of lipophilic drug molecules. The present work deals with the physicochemical characterization of different liposomal nanocarriers, loaded with dimethoxycurcumin (DMC), an analog of curcumin with antioxidant and anticancer activity. The in vitro toxicity and intestinal permeability of drug-free liposomes were evaluated using a Caco-2/TC7 and HT29-MTX co-culture. The results revealed that all liposomal nanosystems were of size lower than 180 nm upon preparation, while their ζ-potential depended on the type of utilized biomaterials. The incorporation efficiency of DMC inside the nanocarriers was dependent on their composition and affected their properties. In addition, the systems did not induce cytotoxic effects on epithelial cells, as MTT assay indicated. Permeability studies of rhodamine-loaded nanoparticles demonstrated 2–2.5-fold intestinal permeability enhancement of the chromophore when using liposomes compared to the free molecule. Among these systems, the liposomes containing cationic lipids exhibited the highest percentage of transport across the epithelial monolayer. Conclusively, the composition and resultant properties of the liposomes are determinant for DMC incorporation and their in vitro toxicity and permeability. The herein developed nanosystems are promising for further application, due to their biocompatibility and permeability. © 2022

The aim of the present study is the development and evaluation of the physicochemical properties of chimeric hydrogenated soya phosphatidylcholine (HSPC) and egg phosphatidylcholine (EggPC) liposomes with incorporated triblock copolymer Poloxamer P407 (P407). The physicochemical assay was held in water HPLC-grade and Foetal Bovine Serum (FBS), in order to determine whether these systems can be used as drug or antigen delivery nanosystems. Dynamic and electrophoretic light scattering (DLS/ELS) techniques were used for the measurement of the hydrodynamic diameter, the polydispersity index, and the ζ-potential of the prepared nanosystems. The incorporation of the P407 resulted in a size reduction of all systems. A decrease in the hydrodynamic diameter and polydispersity index were also found as a result of increasing the storage temperature from 4 °C to 25 °C, attributed to P407. The experiments that were carried out in FBS, showed that the addition of P407 improved systems stealth properties. Concluding, we propose P407 as a promising alternative to PEG in the development of lipid nanoparticles with optimized bio- and shelf-stability. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Transdermal administration has gained much attention due to the remarkable advantages such as patient compliance, drug escape from first-pass elimination, favorable pharmacokinetic profile and prolonged release properties. However, the major limitation of these systems is the limited skin penetration of the stratum corneum, the skin's most important barrier, which protects the body from the insertion of substances from the environment. Transdermal drug delivery systems are aiming to the disruption of the stratum corneum in order for the active pharmaceutical ingredients to enter successfully the circulation. Therefore, nanoparticles are holding a great promise because they can act as effective penetration enhancers due to their small size and other physicochemical properties that will be analyzed thoroughly in this report. Apart from the investigation of the physicochemical parameters, a comparison between the different types of nanoparticles will be performed. The complexity of skin anatomy and the unclear mechanisms of penetration should be taken into consideration to reach some realistic conclusions regarding the way that the described parameters affect the skin permeability. To the best of the authors knowledge, this is among the few reports on the literature describing the technology of transdermal delivery systems and how this technology affects the biological activity. © 2021 Elsevier B.V.

In this study, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-3-dimethylammonium-propane (DAP) and amphiphilic block copolymer poly(2-(dimethylamino)ethyl methacrylate)-b-poly(lauryl methacrylate) (PLMA-b-PDMAEMA) in the weight ratios: 1:0:0.03, 1:0.1:0.03, 1:0.3:0.03, 1:0.5:0.03, 1:0.7:0.03, and1:1:0.03, were used for the design and development of hybrid polymer-lipid nanostructures. The polymer-lipid nanostructures were prepared using the aqueous heat method. The pure lipid systems were used as reference systems. Differential Scanning Calorimetry (DSC) was utilized to investigate the interactions between the components. The presence of the polymeric guest caused different orientation of the polar groups of phospholipids, as the DSC thermotropic values revealed. The changes of the physicochemical characteristics of the systems with the increase of the weight ratio of DAP are more intense in comparison to those without this lipid due to the presence of the block copolymer, which contributes significantly to the repulsive interactions between the vesicles as a result of its positive charge. The only exception is the DSPC:DAP:PLMA-b-PDMAEMA nanosystem at 1:0.5:0.03 wt ratio, where the size of the polymer/lipid structures (Dh≈320 nm) increased and the ζ-potential decreased in absolute values in comparison with the systems with lower weight ratio of the DAP lipid. Cryogenic Transmission Electron Microscopy (cryo-TEM) images showed different structures which strongly depend on the composition of the system, ranging from lamella structures, disc forms, and “spaghetti” morphologies. Based on toxicity studies, it was found all samples are biocompatible and show a dose-dependent cytotoxicity on HEK293 (Human Embryonic Kidney 293 cell line). In conclusion, we developed polymer/lipid nanostructures with knowledge of their structural and physicochemical characteristics, useful as drug or antigen delivery platforms. © 2021

We study the structures of micelleplexes formed by quaternized poly(2-(dimethylamino) ethyl methacrylate)-b-poly(lauryl methacrylate) (QPDMAEMA-b-PLMA) amphiphilic cationic copolymer micelles interacting electrostatically with linear DNA of different lengths (113 and 2000 base pairs). QPDMAEMA-b-PLMA copolymers form micelles in aqueous milieu, with PLMA hydrophobic cores and QPDMAEMA cationic coronas. Nanosized micelleplexes were formed after mixing QPDMAEMA-b-PLMA micelles with DNAs, in a wide range of N/P ratios (nitrogen (N) of amine group of QPDMAEMA over phosphate (P) groups of DNA), as shown by Ultraviolet–Visible (UV–Vis) and fluorescence spectroscopy. Light scattering techniques demonstrated the formation of well-defined micelleplexes with monomodal and narrow size distributions, whose size and surface charge vary according to the N/P ratio. Micelleplexes presented stability under certain salt concentration. Spherical and worm-like micelleplexes were visualized by cryogenic transmission electron microscopy (Cryo-TEM). Overall, QPMDAEMA-b-PLMA micelles can efficiently interact with DNA. The stability, morphology and complexation of the micelleplexes were found to depend on copolymer molecular mass, the hydrophilic/hydrophobic ratio, the micellar structure, the length of DNA, the N/P ratio and the ionic strength. The findings demonstrate that QPDMAEMA-b-PLMA polyelectrolyte copolymer micelles have prospects for their application as non-viral vectors for nucleic acids delivery and gene therapy. © 2022 Elsevier Ltd

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Lyotropic liquid crystals result from the self-assembly process of amphiphilic molecules, such as lipids, into water, being organized in different mesophases. The non-lamellar formed mesophases, such as bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes), attract great scientific interest in the field of pharmaceutical nanotechnology. In the present review, an overview of the engineering and characterization of non-lamellar lyotropic liquid crystalline nanosystems (LLCN) is provided, focusing on their advantages as drug delivery nanocarriers and innovative vaccine platforms. It is described that non-lamellar LLCN can be utilized as drug delivery nanosystems, as well as for protein, peptide, and nucleic acid delivery. They exhibit major advantages, including stimuli-responsive properties for the “on demand” drug release delivery and the ability for controlled release by manipulating their internal conformation properties and their administration by different routes. Moreover, non-lamellar LLCN exhibit unique adjuvant properties to activate the immune system, being ideal for the development of novel vaccines. This review outlines the recent advances in lipid-based liquid crystalline technology and highlights the unique features of such systems, with a hopeful scope to contribute to the rational design of future nanosystems. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Research on the improvement and fabrication of polymeric systems as non-viral gene delivery carriers is required for their implementation in gene therapy. Random copolymers have not been extensively utilized for these purposes. In this regard, double hydrophilic poly[(2-(dimethylamino) ethyl methacrylate)-co-(oligo(ethylene glycol) methyl ether methacrylate] [P(DMAEMA-co-OEGMA)] random copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The copolymers were further modified by quaternization of DMAEMA tertiary amine, producing the cationic P(QDMAEMA-co-OEGMA) derivatives. Fluorescence and ultraviolet– visible (UV–vis) spectroscopy revealed the efficient interaction of copolymers aggregates with linear DNAs of different lengths, forming polyplexes, with the quaternized copolymer aggregates exhibiting stronger binding affinity. Light scattering techniques evidenced the formation of polyplexes whose size, molar mass, and surface charge strongly depend on the N/P ratio (nitrogen (N) of the amine group of DMAEMA/QDMAEMA over phosphate (P) groups of DNA), DNA length, and length of the OEGMA chain. Polyplexes presented colloidal stability under physiological ionic strength as shown by dynamic light scattering. In vitro cytotoxicity of the empty nanocarriers was evaluated on HEK293 as a control cell line. P(DMAEMA-co-OEGMA) copolymer aggregates were further assessed for their biocompatibility on 4T1, MDA-MB-231, MCF-7, and T47D breast cancer cell lines presenting high cell viability rates. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Oleocanthal, oleacein, oleuropein and hydroxytyrosol comprise characteristic polyphenols of olive with high biological value. However, stability problems hinder their further investigation. Thus, in the present study they were incorporated in nanoliposomes by thin film hydration method. The particles sizes, PDI, zeta-potential and physicochemical stabilities of nanoliposomes were evaluated by light scattering methods while FTIR, XRD, TGA and DSC methods were carried out for further physicochemical characterization. Their micromorphology was illustrated by negative-staining TEM and Cryo-TEM, revealing well-dispersed round-shaped vesicles. According to in vitro release studies, oleocanthal and oleacein were rapidly released in a higher percentage than oleuropein and hydroxytyrosol and compatible with the Ritger-Peppas model release mechanism while only oleuropein liposomes were governed by anomalous diffusion of non-Fickian diffusion. Antioxidant assays showed that nanoliposomes presented comparable activity with pure compounds enabling them as suitable carriers for the delivery of olive active biophenols in the human organism. © 2022 Elsevier Ltd

Differential scanning calorimetry (DSC) is a widely utilized method for the interactions of drug molecules with drug delivery systems (DDSs). Herein is described a protocol for studying the interactions and entrapment efficiency of the prototype sartan losartan and the polydynamic, structurally similar irbesartan inside the nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The thermal scan properties of both sartan molecules have been studied when physically mixed or complexed with the cyclodextrin. The thermograms indeed showed significant differences between the mixtures and complexes, establishing DSC as a valuable method to characterize the state of the drugs in these pharmaceutical formulations. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

The investigation of properties of amphiphilic block copolymers as stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles represents a fundamental issue for the formation, stability and upgraded functionality of these nanosystems. The aim of this work is to use am-phiphilic block copolymers, not studied before, as stabilizers of glyceryl monooleate 1-(cis-9-octa-decenoyl)-rac-glycerol (GMO) colloidal dispersions. Nanosystems were prepared with the use of poly(ethylene oxide)-b-poly(lactic acid) (PEO-b-PLA) and poly(ethylene oxide)-b-poly(5-methyl-5-ethyloxycarbonyl-1,3-dioxan-2-one) (PEO-b-PMEC) block copolymers. Different GMO:polymer molar ratios lead to formulation of nanoparticles with different size and internal organization, de-pending on the type of hydrophobic block. Resveratrol was loaded into the nanosystems as a model hydrophobic drug. The physicochemical and morphological characteristics of the prepared nanosystems were investigated by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), fast Fourier transform (FFT) analysis and X-ray diffraction (XRD). The studies allowed the description of the lyotropic liquid crystalline nanoparticles and evaluation of impact of copolymer composition on these nanosystems. The structures formed in GMO:block copolymer colloidal dispersions were compared with those discussed previously. The investigations broaden the toolbox of polymeric stabilizers for the development of this type of hybrid polymer/li-pid nanostructures. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

The fields of medicine and therapeutics have lately turned towards more modern approaches for the therapy of diseases. These approaches have been classified as new health technologies and various issues that regard their development, application in therapy, regulatory framework, approval and post-approval monitoring have emerged. In the European environment, the law and legislation distinguish new health technologies in certain subcategories, namely, medicinal products, medical devices, biotechnological products, advanced therapy medicinal products and nanomedicinal products. Among these strategies, nanomedicine utilizes entities at the nanoscale that exhibit therapeutic effect in various diseases, such as neurodegenerative disorders, through chemical, physical or biological action. Several nanotechnology-based therapies have been authorized until today; however, there is still no marketed nanomedicine for neurodegenerative diseases. Advanced nanotechnological platforms, including the prominent example of stimuli-responsive chimeric/mixed nanocarriers, promise high therapeutic efficacy and safety, through their functional properties and biocompatibility, which come from their composing molecules, self-assembled properties and supramolecular structures. The integration of certain important analytical tools for the study of nanocarriers is also of great importance and may provide knowledge for further development of advanced nanomedicines as well as for their follow-on products, known as “nanosimilars”. © 2021, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Chimeric or mixed nanosystems belong to the class of advanced therapeutics. Their distinctive characteristic compared with other types of nanoparticles is that they combine two or more different classes of biomaterials. These platforms have created a promising and versatile field of nanomedicine, incorporating materials that are biocompatible, such as lipids, but also functional, such as stimuli-responsive polymers. In the present work, thermoresponsive chimeric nanocarriers composed of L-α-phosphatidylcholine (Egg, Chicken) (EPC) phospholipids and poly(N-isopropylacrylamide)-b-poly(lauryl acrylate) (PNIPAM-b-PLA) block copolymers were designed and developed. Initially, model lipid bilayers with incorporated polymers and drug molecule TRAM-34 were built and studied for their thermodynamics, in order to assess the stability and functionality of the systems. Chimeric nanoparticles of EPC and PNIPAM-b-PLA were then developed and evaluated for their physicochemical properties in different medium conditions, as well as for their morphology. Polymer incorporation led to alterations in the properties and morphology of the nanoparticles, while interactions with serum proteins were absent. TRAM-34 was also incorporated inside the developed nanocarriers, followed by incorporation and release studies, which revealed the functionality of the system in elevated temperature conditions. Finally, in vitro studies on normal cells suggest the biocompatibility of these nanosystems. The proposed platforms are promising for further studies and applications in vitro and in vivo. © 2021 Elsevier B.V.

The ability of mixtures of 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the amphiphilic diblock copolymers poly (ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) to stabilize uni-lamellar nano-vesicles is reported. Small angle neutron scattering (SANS) is used to define their size distribution and bilayer structure and resolve the copresence of aggregates and clusters in solution. The vesicles have a broad size distribution which is compatible with bilayer membranes of relatively low bending stiffness. Their mean diameter increases moderately with temperature and their number density and mass is higher in the case of the diblock copolymer with the larger hydrophobic block. Bayesian analysis is performed in order to justify the use of the partic-ular SANS fitting model and confirm the reliability of the extracted parameters. This study shows that amphiphilic block copolymers can be effectively used to prepare mixed lipid-block copolymer vesicles with controlled lamellarity and a significant potential as nanocarriers for drug delivery. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Nanocarriers are delivery platforms of drugs, peptides, nucleic acids and other therapeutic molecules that are indicated for severe human diseases. Gliomas are the most frequent type of brain tumor, with glioblastoma being the most common and malignant type. The current state of glioma treatment requires innovative approaches that will lead to efficient and safe therapies. Advanced nanosystems and stimuli-responsive materials are available and well-studied technologies that may contribute to this effort. The present study deals with the development of functional chimeric nanocarriers composed of a phospholipid and a diblock copolymer, for the incorporation, delivery and pH-responsive release of the antiglioma agent TRAM-34 inside glioblastoma cells. Nanocarrier analysis included light scattering, protein incubation and electron microscopy, and flu-orescence anisotropy and thermal analysis techniques were also applied. Biological assays were carried out in order to evaluate the nanocarrier nanotoxicity in vitro and in vivo, as well as to evaluate antiglioma activity. The nanosystems were able to successfully manifest functional properties under pH conditions, and their biocompatibility and cellular internalization were also evident. The chimeric nanoplatforms presented herein have shown promise for biomedical applications so far and should be further studied in terms of their ability to deliver TRAM-34 and other therapeutic molecules to glioblastoma cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Amphiphilic polymers represent one of the main class of stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles, being essential for their formation and stability. In the present study, poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymers were incorporated as stabilizers in liquid crystalline nanoparticles prepared from glyceryl monooleate. The polymers were chosen according to their high biocompatibility and promising stealth properties, in order to develop safe and efficient drug delivery nanosystems. The physicochemical characteristics and fractal dimension of the resultant nanosystems were obtained from light scattering techniques, while their micropolarity and microfluidity from fluorescence spectroscopy. The effect of temperature, serum proteins and ionic strength on the physicochemical behavior was monitored. Their morphology was assessed by cryo-TEM, while their thermal behavior by microcalorimetry and high-resolution ultrasound spectroscopy. Their properties were dependent on the stabilizer chemistry and topology (block/gradient copolymer) and its concentration. Subsequently, resveratrol, as model hydrophobic drug, was loaded into the nanosystems, the entrapment efficiency was calculated and in vitro release studies were carried out, highlighting how the different stabilizer can differentiate the drug release profile. In conclusion, the proposed copolymers broaden the toolbox of polymeric stabilizers for the development of liquid crystalline nanoparticles intended for drug delivery applications. © 2020

The purpose of this study is to prepare stimuli-responsive chimeric liposomes (i.e. hybrid polymer-lipid liposomes) containing functional copolymers and conduct aqueous solution studies in order to determine their properties and potential as drug-delivery nanocarriers. Two random copolymers, composed of the hydrophilic, pH and thermo-responsive 2-(dimethyl amino) ethyl methacrylate (DMAEMA) monomer and the hydrophobic stearyl methacrylate (SMA) monomer, were synthesized via free-radical polymerization and molecularly characterized using SEC, FTIR, and 1H-NMR. The synthesis was followed by aqueous solution studies, utilising dynamic light scattering (DLS) in order to determine their stimuli responsive self-assembly properties. The preparation of chimeric liposomes was mediated by thin film deposition and hydration, followed by aqueous solution studies via DLS, ζ-potential and fluorescence spectroscopy. The drug-loading studies include curcumin loading via a thin film deposition and hydration technique, while aqueous solution properties of the drug-loaded chimeric liposomes were determined utilizing DLS, and UV–Vis spectroscopy. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

While classic vaccines have proved greatly efficacious in eliminating serious infectious diseases, innovative vaccine platforms open a new pathway to overcome dangerous pandemics via the development of safe and effective formulations. Such platforms play a key role either as antigen delivery systems or as immune-stimulators that induce both innate and adaptive immune responses. Liposomes or lipid nanoparticles, virus-like particles, nanoemulsions, polymeric or inorganic nanoparticles, as well as viral vectors, all belong to the nanoscale and are the main categories of innovative vaccines that are currently on the market or in clinical and preclinical phases. In this paper, we review the above formulations used in vaccinology and we discuss their connection with the development of safe and effective prophylactic vaccines against SARS-CoV-2. © 2021 Elsevier B.V.

Stimuli-responsive nanosystems are an emerging technology in the field of therapy and are very promising for various applications, including targeted drug delivery. In this chapter, our scope is to integrate two different methodologies, namely differential scanning calorimetry (DSC) and dynamic light scattering (DLS), in order to rationally approach the functional behavior of thermoresponsive chimeric/mixed liposomes and interpret their thermoresponsiveness on a thermodynamic basis. In particular, chimeric bilayers comprised of the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and two different-in-composition thermoresponsive amphiphilic block copolymers poly(N-isopropylacrylamide)-b-poly(lauryl acrylate) (PNIPAM-b-PLA) 1 or 2 were built by a conventional evaporation technique, followed by DSC, and chimeric liposomes of DPPC and PNIPAM-b-PLA 1 were developed and studied by DLS, after preparation and after a simple heating protocol. The results from both methodologies indicate the composition- and concentration-dependent lyotropic effect of the foreign copolymer molecule on the properties and functionality of the lipidic membrane. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Elastic liposomes consist of phospholipids and of surfactants, could be considered as promising nanotechnological platforms for skin drug delivery. The aim of the present study was the formation of elastic liposomes by thin film hydration method, using different phospholipids and surfactants, in order to determine the effect of the components on their physical characteristics and on their physical stability. Physical properties of elastic liposomes were evaluated using dynamic light scattering (DLS)method. The particle size at the day of their preparation, was ranged between small and large unilamellar vesicles (SUVs and LUVs), dependent on the hydrophilicity of the surfactant used, while their PDI (Poly Dispersity Index) value was close to zero, indicating monodispersed systems. Physical stability study involved the measure of particle size, as a quantifiable physical property, at selected times over a 30-days period, at storage conditions: (i) 4 °C, (ii) 25 °C, iii) 45 °C, suggested that refrigerated conditions promote physical stability, while high temperatures induce aggregation. According to the physical stability study elastic liposomes composed ofTween80 were found to bemore stable than those composed of Span80, at ambient conditions. The goal of our investigation was centred to the development and evaluation of a well know liposomal category i.e. elastic liposomes, by modified their composition with common surfactants (i.e. Span and/or Tween), creating, a new liposomal class namely, elastic lipo-niosomes. To the best of knowledge this the first time that these hybrid vesicles appeared in the literature exhibiting the aforementioned category lipid/surfactants and molar ratios. © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Mixed liposomes of dipalmitoylphosphatidylcholine (DPPC) and gradient (pseudodiblock) poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) copolymers are investigated by small angle neutron scattering (SANS). All experimental data, from different phospholipid-copolymer compositions, concentrations and temperatures are fitted with one model. This model allows the determination of the separate contributions from vesicular populations of different lamellarity and size. MPOx copolymers are proved to modify both the size and lamellarity of DPPC liposomes. The gradient copolymer with higher hydrophilic content induces shrinkage of the uni- and bi-lamellar DPPC vesicles. The copolymer with lower hydrophilic content causes dramatic changes on the lamellarity of DPPC vesicles by the formation of hexa-lamellar vesicles. The tendency of multi-lamellar vesicles to transform into uni-lamellar ones as temperature increases is more pronounced in the presence of the copolymers. These findings may have direct implications on the drug loading and release properties of liposomes and their interactions with cells. © 2020 Elsevier B.V.

Differential scanning calorimetry (DSC) is a well-established technique, suitable to monitor the interactions that may take place among the drug delivery systems of liposomes and the potential bioactive molecules that are incorporated inside them. Moreover, the DSC technique is considered to be a useful tool to characterize the thermal behavior of lipidic bilayers in the absence and presence of drugs and to highlight parameters, such as the cooperativity between the lipids and the guest molecules (i.e. drugs, polymers, dendrimers), providing also a prediction of the behavior of potential future drug delivery liposomal platforms. In this study, a protocol for DSC measurements on liposomal systems with incorporated guest molecules is described. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Liposomes and lipidic vehicles are nanotechnological platforms that are present in the clinic and industry, with extensive application and much potential in the field of therapeutics. Currently, the obstacles associated with the pathology and physiology of Alzheimer’s disease (AD) and neurodegenerative disorders (NDDs) in general have rendered it impossible to find an effective therapy for these conditions. The only achievement of the available drugs and treatments is that they have succeeded in temporarily alleviating the symptoms and assisting patients in carrying on with their activities of daily living, but they do not delay, let alone halt, the progression of the diseases. So far, numerous small drug molecules and biological molecules have failed in clinical trials. Liposomes represent a promising option for drug delivery that have yet to be tested in clinical trials. They are manufactured by many different and versatile techniques. Their contribution in AD regards mainly the delivery of bioactive agents in a targeted and controlled manner through the blood-brain barrier and into the brain, with the ultimate goal to block the β-amyloid (Aβ) and/or tau aggregation. Their flexibility and biocompatibility as platforms, combined with their ability to protect the encapsulated/incorporated molecules, are advantages that are expected to assist this endeavor. © 2021, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Thermoresponsive nanomaterials have led to a plethora of new applications in the fields of Nanobiotechnology, Biomedicine and Therapeutics. Since liposomal membranes are lyotropic liquid crystals, the development of thermoresponsive liposomes for drug delivery has been recognized as an attractive scientific field. Additionally, plenty of studies utilizing the temperature-dependent response of certain synthetic polymers are conducted, alone or in combination with liposomes. In the present study, we combined the liposomal and thermoresponsive polymer technologies, in order to create functional chimeric/mixed liposomal nanosystems with innovative properties. Initially, differential scanning calorimetry was applied on chimeric/mixed bilayers to evaluate the effect of polymeric guests on the thermotropic behavior of lipidic membranes. Thereafter, chimeric/mixed liposomes were built and their physicochemical properties, as well as their colloidal stability were measured and evaluated. The nature of the self-assembled structures and the lipidic membrane morphology were investigated through cryo-transmission electron microscopy, while their thermoresponsiveness and its consequences on the lipidic membrane properties were assessed, through a simple heating protocol. The presence of a new thermodynamic phase on the lipidic membrane acts as an agglomeration and aggregation inducer, affecting the whole colloidal chimeric/mixed nanosystem. This mechanism might be characterized as “phase functionality” and may be utilized for drug delivery purposes and also in other applications. Biophysics and thermodynamics are very important tools to study the self-assembly process, as well as the stability and bio-functionality of drug delivery systems. © 2019, Akadémiai Kiadó, Budapest, Hungary.

Background: The use of functionalized iron oxide nanoparticles of various chemical properties and architectures offers a new promising direction in theranostic applications. The increasing applications of nanoparticles in medicine require that these engineered nanomaterials will contact human cells without damaging essential tissues. Thus, efficient delivery must be achieved, while minimizing cytotoxicity during passage through cell membranes to reach intracellular target compartments. Methods: Differential Scanning Calorimetry (DSC), molecular modeling, and atomistic Molecular Dynamics (MD) simulations were performed for two magnetite nanoparticles coated with polyvinyl alcohol (PVA) and polyarabic acid (ARA) in order to assess their interactions with model DPPC membranes. Results: DSC experiments showed that both nanoparticles interact strongly with DPPC lipid head groups, albeit to a different degree, which was further confirmed and quantified by MD simulations. The two systems were simulated, and dynamical and structural properties were monitored. A bimodal diffusion was observed for both nanoparticles, representing the diffusion in the water phase and in the proximity of the lipid bilayer. Nanoparticles did not enter the bilayer, but caused ordering of the head groups and reduced the area per lipid compared to the pure bilayer, with MAG-PVA interacting more strongly and being closer to the lipid bilayer. Conclusions: Results of DSC experiments and MD simulations were in excellent agreement. Our findings demonstrate that the external coating is a key factor that affects nanoparticle-membrane interactions. Magnetite nanoparticles coated with PVA and ARA did not destabilize the model membrane and can be considered promising platforms for biomedical applications. General significance: Understanding the physico-chemical interactions of different nanoparticle coatings in contact with model cell membranes is the first step for assessing toxic response and could lead to predictive models for estimating toxicity. DSC in combination with MD simulations is an effective strategy to assess physico-chemical interactions of coated nanoparticles with lipid bilayers. © 2020

The application of the nanotechnology in medicine and pharmaceutics opens new horizons in therapeutics. Several nanomedicines are in the market and an increasing number is in clinical trials. But which is the advantage of the medicines in nanoscale? The scientists and the regulatory authorities agree that the size and consequently the physiochemical/biological properties of nanomaterials play a key role in their safety and effectiveness. Additionally, all of them agree that a new scientific-based regulatory landscape is required for the establishment of nanomedicines in the market. The aim of this review is to investigate the parameters that the scientists and the regulatory authorities should take into account in order to build up a dynamic regulatory landscape for nanomedicines. For this reason, we propose an “astrolabe-like system” as the guide for establishing the regulatory approval process. Its function is based on the different physicochemical/biological properties in comparison to low molecular weight drugs. © 2020, American Association of Pharmaceutical Scientists.

The utilization of liposomes in biomedical applications has greatly benefited the diagnosis and treatment of various diseases. These biomimetic nano-entities have been very useful in the clinical practice as drug delivery systems in their conventional form, comprising lipids as structural components. However, the scientific efforts have recently shifted towards the development of more sophisticated nanotechnological platforms, which apply functional biomaterials, such as stimuli-responsive polymers, in order to aid the drug molecule targeting concept. These nanosystems are defined as chimeric/mixed, because they combine more than one different in nature biomaterials and their development requires intensive study through biophysical and thermodynamic approaches before they may reach in vivo application. Herein, we designed and developed chimeric liposomes, composed of a phospholipid and pH-responsive amphiphilic diblock copolymers and studied their morphology and behavior based on crucial formulation parameters, including biomaterial concentration, dispersion medium pH and polymer composition. Additionally, their interactions with biological components, pH-responsiveness and membrane thermodynamics were assessed. Finally, preliminary in vivo toxicity experiments of the developed nanosystems were carried out, in order to establish a future protocol for full in vivo evaluation. The results have been correlated with the properties of the chimeric nanosystems and highlight the importance of such approaches for designing and developing effective nanocarriers for biomedical applications. © 2019 Elsevier B.V.

Non-lamellar liquid crystalline nanoparticles are promising drug delivery lipidic nanosystems, stabilized by amphiphilic block copolymers. In the present investigation, the widely used Poloxamer P407 is compared with the innovative stimuli-responsive polycationic block copolymer poly(2-(dimethylamino)ethyl methacrylate)-b-poly(lauryl methacrylate) (PDMAEMA-b-PLMA) as stabilizer for glyceryl monooleate (GMO) or phytantriol (PHYT)-based colloidal dispersions of liquid crystalline nanoparticles. As such, a variety of techniques was combined in order to comprehensively characterize these nanosystems in terms of physicochemical, morphological and thermal properties. Particle size, size distribution, ζ-potential and the fractal dimension parameter (df), calculated from light scattering data, as well as the morphology (from cryo-TEM analysis) of nanoparticles were markedly affected by the different lipid and type of polymeric stabilizer, indicating different kind of interfacial lipid-polymer interactions. Notably, PDMAEMA-b-PLMA block copolymer was effective as well as P407 in stabilizing the GMO-based, but not PHYT-based nanosystems. Furthermore, microcalorimetry, high-resolution ultrasound spectroscopy and rheology were applied to characterize the thermal behavior of these nanosystems, highlighting their transition temperatures. In conclusion, a detailed evaluation was carried out on liquid crystalline nanoparticles, providing significant information, useful for the development of innovative non-lamellar therapeutic nanosystems with advanced properties that can be successfully applied in the pharmaceutical nanotechnology field. © 2020

Lipidic vehicles are novel industrial products, utilized as components for pharmaceutical, cosmeceutical and nutraceutical formulations. The present study concerns a newly invented method to produce lipidic vehicles in the nanoscale that is simple, nontoxic, versatile, time-efficient, low-cost and easy to scale up. The process is a modification of the heating method (MHM) and comprises (i) providing a mixture of an amphiphilic lipid and a charged lipid and/or a fluidity regulator in a liquid medium composed of water and a liquid polyol, (ii) stirring and heating the mixture in two heating steps, wherein the temperature of the second step is higher than the temperature of the first step and (iii) allowing the mixture to cool down to room temperature. The process leads to the self-assembly of nanoparticles of small size and good homogeneity, compared with conventional approaches that require additional size reduction steps. In addition, the incorporation of bioactive molecules, such as drugs, inside the nanoparticles is possible, while lyophilization of the products provides long-term stability. Most importantly, the absence of toxic solvents and the simplicity guarantee the safety and scalability of the process, distinguishing it from most prior art processes to produce lipidic vehicles. © MDPI AG. All rights reserved.

Multiple sclerosis (MS) is a chronic, autoimmune, neurodegenerative disease of the central nervous system (CNS) that yields to neuronal axon damage, demyelization, and paralysis. Although several drugs were designed for the treatment of MS, with some of them being approved in the last few decades, the complete remission and the treatment of progressive forms still remain a matter of debate and a medical challenge. Nanotechnology provides a variety of promising therapeutic tools that can be applied for the treatment of MS, overcoming the barriers and the limitations of the already existing immunosuppressive and biological therapies. In the present review, we explore literature case studies on the development of drug delivery nanosystems for the targeted delivery of MS drugs in the pathological tissues of the CNS, providing high bioavailability and enhanced therapeutic efficiency, as well as nanosystems for the delivery of agents to facilitate efficient remyelination. Moreover, we present examples of tolerance-inducing nanocarriers, being used as promising vaccines for antigen-specific immunotherapy of MS. We emphasize on liposomes, as well as lipid- and polymer-based nanoparticles. Finally, we highlight the future perspectives given by the nanotechnology field toward the improvement of the current treatment of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Liposomes have been on the market as drug delivery systems for over 25 years. Their success comes from the ability to carry toxic drug molecules to the appropriate site of action through passive accumulation, thus reducing their severe side effects. However, the need for enhanced circulation time and site and time-specific drug delivery turned research focus on other systems, such as polymers. In this context, novel composites that combine the flexibility of polymeric nanosystems with the properties of liposomes gained a lot of interest. In the present work a mixed/chimeric liposomal system, composed of phospholipids and block copolymers, was developed and evaluated in regards with its feasibility as a drug delivery system. These innovative nano-platforms combine advantages from both classes of biomaterials. Thermal analysis was performed in order to offers an insight into the interactions between these materials and consequently into their physicochemical characteristics. In addition, colloidal stability was assessed by monitoring z-potential and size distribution over time. Finally, their suitability as carriers for biomedical applications was evaluated by carrying out in vitro toxicity studies. © 2019 Informa UK Limited, trading as Taylor & Francis Group.

The investigation and observations made for the M2TM, excess aminoadamantane ligands in DMPC were made using the simpler version of biophysical methods including SDC, SAXS and WAXS, MD simulations and ssNMR. 1H, 31P ssNMR and MD simulations, showed that M2TM in apo form or drug-bound form span the membrane interacting strongly with lipid acyl chain tails and the phosphate groups of the polar head surface. The MD simulations showed that the drugs anchor through their ammonium group with the lipid phosphate and occasionally with M2TM asparagine-44 carboxylate groups. The 13C ssNMR experiments allow the inspection of excess drug molecules and the assessment of its impact on the lipid head-group region. At low peptide concentrations of influenza A M2TM tetramer in DPMC bilayer, two lipid domains were observed that likely correspond to the M2TM boundary lipids and the bulk-like lipids. At high peptide concentrations, one domain was identified which constitute essentially all of the lipids which behave as boundary. This effect is likely due, according to the MD simulations, to the preference of AK13 to locate in closer vicinity to M2TM compared to Amt as well as the stronger ionic interactions of Amt primary ammonium group with phosphate groups, compared with the secondary buried ammonium group in AK13.

Niosomes belong to drug delivery systems and consist mainly of non-ionic surfactants and cholesterol. In this study, we designed and developed systems composed of non-ionic surfactants i.e. Tween 80, Span 80 and cholesterol with and without poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) block copolymer, using different molar ratios of the above components. The nanosystems were formed by the thin-film hydration method with purified water as dispersion medium. Several physicochemical techniques were utilized in order to study the physicochemical and morphological characteristics of the prepared assemblies. The results showed that the presence of the block copolymer alters significantly the size and morphology of neat surfactant/cholesterol niosomes. The ageing studies also revealed that the stability is strongly dependent on the nature and the molar ratios of the components. Moreover, neither of the studied nanosystems exhibited elevated signs of cellular toxicity in vitro nor acute systemic toxicity in vivo short-term experiments. This investigation covers a new field of drug delivery platforms those of niosomes composed by different biomaterials i.e. surfactants and block copolymers. © 2019 Elsevier B.V.

The aim of the present study is to investigate the interactions between liposomes and proteins and to evaluate the role of liposomal lipid composition and concentration in the formation of protein corona. Liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or hydrogenated soybean phosphatidylcholine (HSPC) with 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt) (DPPG), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (DPPE-PEG 3000), cholesterol (CH) or mixtures of these lipids, were prepared at different concentrations by the thin-film hydration method. After liposomes were dispersed in HPLC-grade water and foetal bovine serum (FBS), their physicochemical characteristics, such as size, size distribution, and ζ-potential, were determined using dynamic and electrophoretic light scattering. Aggregation of DPPC, HSPC, DPPC:CH (9:1 molar ratio), and HSPC:CH (9:1 molar ratio) in FBS was observed. On the contrary, liposomes incorporating DPPG lipids and CH both in a molar ratio of 11% were found to be stable over time, while their size did not alter dramatically in biological medium. Liposomes containing CH and PEGylated lipids retain their size in the presence of serum as well as their physical stability. In addition, our results indicate that the protein binding depends on the presence of polyethylene glycol (PEG), CH, concentration and surface charge. In this paper, we introduce a new parameter, fraction of stealthiness (Fs), for investigating the extent of protein binding to liposomes. This parameter depends on the changes in size of liposomes after serum incubation, while liposomes have stealth properties when Fs is close to 1. Thus, we conclude that lipid composition and concentration affect the adsorption of proteins and the liposomal stabilization. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

There is an emerging need to evolve the conventional lyotropic liquid crystalline nanoparticles to advanced stimuli-responsive, therapeutic nanosystems with upgraded functionality. Towards this effort, typically used stabilizers, such as Pluronics®, can be combined or replaced by smart, stimuli-responsive block copolymers. The aim of this study is to incorporate the stimuli-responsive amphiphilic block copolymer poly(2-(dimethylamino)ethyl methacrylate)-b-poly(lauryl methacrylate) (PDMAEMA-b-PLMA) as a stabilizer in lipidic liquid crystalline nanoparticles, in order to provide steric stabilization and simultaneous stimuli-responsiveness. The physicochemical and morphological characteristics of the prepared nanosystems were investigated by light scattering techniques, cryogenic-transmission electron microscopy (cryo-TEM), X-ray diffraction (XRD) and fluorescence spectroscopy. The PDMAEMA-b-PLMA, either individually or combined with Poloxamer 407, exhibited different modes of stabilization depending on the lipid used. Due to the protonation ability of PDMAEMA blocks in acidic pH, the nanoparticles exhibited high positive charge, as well as pH-responsive charge conversion, which can be exploited towards pharmaceutical applications. The ionic strength, temperature and serum proteins influenced the physicochemical behavior of the nanoparticles, while the polymer concentration differentiated their morphology; their micropolarity and microfluidity were also evaluated. The proposed liquid crystalline nanosystems can be considered as novel and attractive pH-responsive drug and gene delivery nanocarriers due to their polycationic content. © 2019 by the authors.

In the present work, the convergence of two different drug delivery systems is investigated, namely the combination of carbon nanohorns (CNHs) and liposomes. Our effort initially included the synthesis of two conversely charged carbon nanohorns and their subsequent analysis through various methods. The study of their effect on the thermotropic behavior of artificial membranes provided an essential assistance for the upcoming liposome preparation, which were estimated for their physicochemical properties. The presence of CNHs alters the calorimetric parameters of the lipids. We also prepared CNHs:liposome systems. The characteristic morphology and secondary spherical superstructure of CNHs is retained in the chimeric materials, suggesting that the interactions with the liposomes do not alter the dahlia-flower-like aggregation of CNHs. Both CNHs-liposome systems exhibit a relatively small cellular cytotoxicity in vitro, tested in mouse embryonic fibroblasts. To summarize, we developed CNHs:liposome platforms with a complete knowledge of their thermotropic, physicochemical, morphological and nanotoxicological characteristics. © 2019 Elsevier B.V.

The investigation of colloidal properties of nanosystems represents a fundamental issue for the development of nanotechnology-based medicines. The aim of this study is to combine various techniques in order to characterize more comprehensively chimeric nanovesicles composed of block or gradient block copolymers with different architectures and compositions. Several chimeric systems were prepared and the impact of the block [poly(ε-caprolactone)−poly(ethylene oxide); PEO-b-PCL] and gradient block [poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline); MPOx] copolymers on the physicochemical and morphological characteristics of conventional 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes was examined. Light scattering techniques and cryo-TEM were used for the physicochemical and morphological characterization of the prepared systems. The size and the morphology were strongly related to the architecture and the composition of the polymeric compounds. Micro differential scanning calorimetry and high-resolution ultrasound spectroscopy were used for investigating the interactions between the DPPC lipids and the polymeric guest. An increase in the main transition temperature was observed for the prepared chimeric systems in comparison to DPPC liposomes. In conclusion, a detailed characterization of the colloidal behavior of chimeric liposomes can benefit from the combination of the aforementioned techniques that operate synergistically, giving information on their physicochemical and morphological characteristics as well as on their thermotropic behavior. © 2018 Elsevier B.V.

Liposomes are considered to be one of the most extensively investigated drug delivery nanosystems. Each drug can be loaded either in the liposomal hydrophilic core or within the lipidic bilayer and delivered eventually to the proper site into the organism. There are already many marketed approved liposomal products. The development of a liposomal product is a quite complicated process, while many critical parameters have to be investigated during the preparation process. The present study deals with the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation. D/L ratio is affected by the composition, the different biomaterials and the loading method being used, so the improvement of D/L ratio can optimize the liposomal formulation. D/L ratio can be used as an index of the effectiveness of the preparation method too. Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated. There is a variety of analytical methods, quantifying the drug and the lipids and estimating eventually the D/L ratio. According to the regulatory framework of nanomedicine, about the development of nanosimilars, D/L ratio is a necessary element for the nanosimilar product description and the statement of product comparability. © 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group.