Multifunctional magneto-plasmonic lipogel based on peptide hydrogel for application in combined cancer therapy.

Supramolecular hydrogels, particularly low-molecular-weight peptide hydrogels, are promising drug delivery systems due to their ability to change the solubility, targeting, metabolism and toxicity of drugs. Magneto-plasmonic liposomes, in addition to being remotely controllable with the application of an external magnetic field, also increase the efficiency of encapsulated drug release through thermal stimulation, for example, with magnetic and optical hyperthermia. Thus, the combination of those two materials-giving magneto-plasmonic lipogels-brings together several functionalities, among which are hyperthermia and spatiotemporally controlled drug delivery. In this work, a novel dehydrodipeptide hydrogelator was synthesised, and the respective hydrogel was functionalized with magneto-plasmonic liposomes. After individually characterising the components with regard to their rheological, spectroscopic and magnetic properties, the magneto-plasmonic lipogel was equally characterised and evaluated concerning its ability to deliver drugs in a controlled fashion. To this end, the response of the 5(6)-carboxyfluorescein-loaded magneto-plasmonic lipogel to near-infrared light was assessed. The results showed that the system is a proper carrier of hydrophilic drugs and allows to envisage photo-responsive drug delivery. These facts, together with the magnetic guidance and hyperthermia capabilities of the developed composite gel, may pave the way to a new era in the treatment of cancer and other diseases.

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

Reversing inflammatory microenvironment by a single intra-articular injection of multi-stimulus responsive lipogel to relieve rheumatoid arthritis and promote joint repair.

Rheumatoid arthritis (RA) is a common chronic disease dominated by inflammatory synovitis, which is characterized with hyperplastic synovium, up-regulated matrix metalloproteinase (MMP) expression, hypoxic joint cavity and excessive reactive oxygen species (ROS) accumulation. Such local adverse microenvironment in RA joints further exacerbates the infiltration of synovial inflammatory cells, especially M1-type macrophages. Regulating intra-articular pathological conditions, eliminating excess M1 macrophages or converting them to an anti-inflammatory M2 phenotype may break the vicious progression circle. Herein, we develop a multi-stimulus responsive lipogel as effective platform to relieve RA symptoms and promote articular cartilage recovery via reversing its inflammatory microenvironment. The injectable lipogel is fabricated by loading polydopamine nanoparticles and methotrexate into a thermosensitive gel, and intra-articularly injected to form the therapeutic depot (PDA/MTX@TSG) in situ. The gel degrades slowly under esterase hydrolysis, and maintains sustained drug release in physiological conditions. Meanwhile, it can 1) induce a reversible gel-sol phase transition upon mild photothermal treatment (external NIR light control), and 2) specifically respond to MMP-rich RA microenvironment (internal enzymatic hydrolysis effect). Such stimulus-responsive system can deliver therapeutic components in a controllable manner, and significantly reverse adverse inflammatory microenvironment of RA joints through ROS eliminating, hypoxia alleviating, and M1-M2 macrophage polarization effects. Animal experiments indicate that observable RA relief and joint repair are realized after a single lipogel injection combined with NIR irradiation. Our study highlights the importance of altering local RA microenvironment via anti-inflammatory macrophage polarization, and therefore presents a potent therapeutic strategy for RA treatment in clinical intervention.

Nanolipogel Loaded with Tea Tree Oil for the Management of Burn: GC-MS Analysis, In Vitro and In Vivo Evaluation.

The GC-MS analysis of tea tree oil (TTO) revealed 38 volatile components with sesquiterpene hydrocarbons (43.56%) and alcohols (41.03%) as major detected classes. TTO efficacy is masked by its hydrophobicity; nanoencapsulation can address this drawback. The results showed that TTO-loaded solid lipid nanoparticles (SLN1), composed of glyceryl monostearate (2% w/w) and Poloxamer188 (5% w/w), was spherical in shape with a core-shell microstructure. TTO-SLN1 showed a high entrapment efficiency (96.26 ± 2.3%), small particle size (235.0 ± 20.4 nm), low polydispersity index (0.31 ± 0.01), and high negative Zeta potential (-32 mV). Moreover, it exhibited a faster active agent release (almost complete within 4 h) compared to other formulated TTO-SLNs as well as the plain oil. TTO-SLN1 was then incorporated into cellulose nanofibers gel, isolated from sugarcane bagasse, to form the 'TTO-loaded nanolipogel' which had a shear-thinning behavior. Second-degree thermal injuries were induced in Wistar rats, then the burned skin areas were treated daily for 7 days with the TTO-loaded nanolipogel compared to the unmedicated nanolipogel, the TTO-loaded conventional gel, and the normal saline (control). The measurement of burn contraction proved that TTO-loaded nanolipogel exhibited a significantly accelerated skin healing, this was confirmed by histopathological examination as well as quantitative assessment of inflammatory infiltrate. This study highlighted the success of the proposed nanotechnology approach in improving the efficacy of TTO used for the repair of skin damage induced by burns.

Production of lipophilic nanogels by spontaneous emulsification.

Nanosized gel particles, so-called nanogels, have attracted substantial interest in different application fields, thanks to their controllable and three-dimensional physical structure, good mechanical properties and potential biocompatibility. Literature reports many technologies for their preparation and design, however a recurrent limitation remains in their broad size distributions as well as in the poor size control. Therefore, the monodisperse and size-controlled nanogels preparation by simple process -like emulsification- is a real challenge still in abeyance to date. In this study we propose an original low energy emulsification approach for the production of monodisperse nanogels, for which the size can be finely controlled in the range 30 to 200 nm. The principle lies in the fabrication of a direct nano-emulsion containing both oil (medium chain triglycerides) and a bi-functional acrylate monomer. The nanogels are thus formed in situ upon UV irradiation of the droplet suspension. Advantage of such modification of the oil nano-carriers are the potential modulation of the release of encapsulated drugs, as a function of the density and/or properties of the polymer chain network entrapped in the oil nano-droplets. This hypothesis was confirmed using a model of hydrophobic drug -ketoprofen- entrapped into the nanogels particles, along with the study of the release profile, carried out in function of the nature of the monomers, density of polymer chains, and different formulation parameters.

Luliconazole vesicular based gel formulations for its enhanced topical delivery.

Luliconazole is a new drug candidate for treatment of topical fungal infections. Its present therapy is associated with limitations of very poor and slow skin permeation, leading to required long term repeated administration for complete cure of disease. Lipid nanocarriers based elastic lipogel and ethogel formulations were developed in strength of 1% w/w and extensively characterized in vitro, ex-vivo, and in vivo and compared for their results to the marketed formulation. The prepared formulations were found to have ideal pH, nanometric vesicle size, encapsulation efficiency (92.7% and 91.2%), zeta potential (-17.0 and -32.8 mV), and viscosity (6.6 and 7.8 Pa.s) with no signs of instability on storage. In vitro activity against Candida albicans and dermatophytes demonstrated the prepared formulations to be 3 and 2.5 times more potent than marketed formulation, respectively. Ex vivo skin permeation and deposition studies, performed on various biological membranes and a synthetic membrane, manifest that Strat-M membrane resembles closest to the human skin followed by porcine ear skin, rat, and mice skin. Enhanced skin deposition of elastic lipogel and ethogel as compared to conventional marketed cream is also confirmed by SEM and CLSM analysis of the treated skin. In vivo antifungal activity on albino rats demonstrated vesicle based gel formulations to be safe, non irritant and more effective in topical treatment of fungal infections, with no drug reaching to systemic circulation. Thus, findings of the study demonstrate elastic liposomes and ethosomes, as a carrier are an attractive approach for enhanced topical delivery of Luliconazole.

Lecithin Microemulsion Lipogels Versus Conventional Gels for Skin Targeting of Terconazole: In Vitro, Ex Vivo, and In Vivo Investigation.

Topical treatment of fungal infections has several superiorities over oral treatment. However, the greatest challenge for dermal delivery is the stratum corneum which is considered an effective barrier for penetration of most antifungal drugs into deeper skin layers. Terconazole (Tr), which is the first marketed triazole antifungal, was reported to be one of the most active azoles against vaginal candidiasis. Nevertheless, our work group is the first to investigate the potential of Tr in the treatment of skin mycosis via integration into lecithin microemulsion-based lipogels (LMBGs). The microemulsion regions of the investigated systems were detected through ternary phase diagrams. The in vitro characterization studies revealed promising physicochemical merits for the selected LMBGs as well as satisfactory in vitro antifungal activity. The current research work was endeavored to investigate the potential of such novel Tr-loaded LMBGs in comparison with conventional gels. Ex vivo permeation and retention studies in addition to in vivo deposition study showed a significant improvement in the permeability of Tr through animal skin from LMBGs compared to other conventional gels. Furthermore, the optimized microemulsion lipogel proved to be safe and a nonirritant to experimental animals through the acute sensitivity study and histological skin examination. Overall, lecithin-based microemulsion lipogels of different composition confirmed their potential as interesting nanocarriers for skin delivery of terconazole compared to current therapy.

Vaginal Delivery of Benzydamine Hydrochloride through Liposomes Dispersed in Mucoadhesive Gels.

Liposomal vaginal drug delivery systems are important strategy in the treatment of both topical and systemic diseases. The aim of this study was to develop a vaginal delivery system for benzydamine hydrochloride (BNZ) loaded liposomes dispersed into mucoadhesive gels. The delivery system was also designed for a once a day dosage and to obtain controlled release of the BNZ. For this purpose BNZ containing gel formulations using hydroxypropyl methylcellulose (HPMC) K100M and Carbopol® 974P, which are composed of polymers that show promising potential as mucoadhesive vaginal delivery systems, were developed. In addition, a BNZ containing liposome formulation was developed for vaginal administration. To improve the vaginal retention time, liposome was incorporated in HPMC K100M and Carbopol® 974P gel formulations. This system is called lipogel. The developed BNZ liposomes have a slightly negative zeta potential (-1.50±0.16 mV), a 2.25±0.009 µm particle size and a 34% entrapment efficiency. These gels and lipogels have appropriate pH, viscosity, textural properties and mucoadhesive value for vaginal administration. Lipogels were found to be the best formulations for in vitro diffusion and ex vivo mucoadhesion. The work of mucoadhesion obtained from liposomes was in the range of 0.027±0.045 and 0.030±0.017 mJ/cm2, while the value obtained from lipogels was between 0.176±0.037 and 0.243±0.53 mJ/cm2. N1 and N2 lipogel formulations diffused 57 and 67% of BNZ respectively at the end of 24 h. Moreover, a higher mucoadhesion, which increases drug residence time in comparison to liposomes, could improve BNZ efficacy. In conclusion, BNZ mucoadhesive vaginal lipogel formulations can be promising alternatives to traditional dosage forms for vaginal topical therapy.

Convergent in situ assembly of injectable lipogel for enzymatically controlled and targeted delivery of hydrophilic molecules.

Applications of liposomes are limited due to their rapid blood clearance and non-specific biodistribution. Surface modification of liposomes could overcome these disadvantages. However, direct coating of liposome surface may cause disruption of liposomes. Herein we present a "top-down" method to coat liposomes in situ with tumor (CD44 receptor) targeting polymer, hyaluronan (HA), by taking advantages of "click" type chemistries and enzymatic degradation. Liposomes entrapped within HA gel were stable without leaking of small cargo molecules from the interior of the liposomes. This injectable liposome-in-hydrogel (lipogel) drug delivery system can achieve sequential two-step release: (1) liposomes release from lipogel after HA degradation; (2) small molecules release from liposomes after the liposomes disruption (either before or after cellular uptake). Similarly to HA coating, this strategy could be used for in situ "top-down" modification of liposomes with other targeting biopolymers. Additionally, it provides the possibility to deliver different types of molecules from two compartments of the lipogel, i.e. large biomacromolecules from the exterior of liposomes and small hydrophilic molecules from the interior of liposomes, locally and systemically.