Lipophilic Molecules Research Articles

Coenzyme Q10 improves ovarian histology and attenuates the expression of angiogenesis-associated proteins in the ovary of rats with experimental hyperstimulation syndrome.

Objective(s):Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication characterized by many side effects. Coenzyme Q10 (CoQ10) is a protective lipophilic molecule with an extensive range of biological functions, but its possible protective effect on the ovary in OHSS has not as yet been studied. The present study aimed to investigate the potential protective effects of CoQ10 on ovarian histological and molecular alterations in an experimental model of OHSS in rats. Materials and Methods:Thirty female (2 months old) Wistar rats were randomly divided into 6 equal groups: control, OHSS, OHSS+CoQ10 (OHSS+ 200 mg/kg CoQ10 for 10 days), OHSS+ cabergoline (CAB) (OHSS+ 100 µg/kg CAB for 6 days), and CoQ10 and CAB (rats receiving similar doses to treatment groups.( In the end, the effects of treatments were assessed by measuring expressions of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in the ovary via western blotting, ovarian histomorphological alterations assessments, and serum estradiol and progesterone levels via ELISA. Results:There were histological alterations in OHSS groups, including the elevation of diameter and numbers of the corpus luteum and atretic follicles, and decreasing follicular reserve count, hyperemia, and hemorrhage at ovarian stroma. Treatment of OHSS groups with CAB and CoQ10 could decrease histological changes, serum estrogen and progesterone, and overexpression of VEGF and COX-2 proteins.Conclusion:Our results showed that ovarian histological and molecular alterations observed in experimental OHSS can be ameliorated by administration of CoQ10, indicating that CoQ10 can be used as new supportive care for OHSS patients.

Synthesis, Pharmacokinetic Characterization and Antioxidant Capacity of Carotenoid Succinates and Their Melatonin Conjugates.

Carotenoid succinates were synthesized from hydroxy carotenoids and were coupled to a commercially available derivative of melatonin via amide bond for producing more powerful anti-oxidants and yet new hybrid lipophilic bifunctional molecules with additional therapeutic effects. The coupling reactions produced conjugates in acceptable to good yields. Succinylation increased the water solubility of the carotenoids, while the conjugation with melatonin resulted in more lipophilic derivatives. The conjugates showed self-assembly in aqueous medium and yielded relatively stable colloidal solutions in phosphate-buffered saline. Antioxidant behavior was measured with ABTS and the FRAP methods for the carotenoids, the carotenoid succinates, and the conjugates with melatonin. A strong dependence on the quality of the solvent was observed. TEAC values of the new derivatives in phosphate-buffered saline were found to be comparable to or higher than those of parent carotenoids, however, synergism was observed only in FRAP assays.

Enhancing very long chain fatty acids production in Yarrowia lipolytica

BackgroundVery long chain fatty acids (VLCFA) and their derivatives are industrially attractive compounds. The most important are behenic acid (C22:0) and erucic acid (C22:1Δ13), which are used as lubricants, and moisturizers. C22:0 and C22:1Δ13 have also potential for biofuel production. These fatty acids are conventionally obtained from plant oils. Yarrowia lipolytica is an oleaginous yeast with a long history of gene manipulations resulting in the production of industrially interesting compounds, such as organic acids, proteins, and various lipophilic molecules. It has been shown previously that it has potential for the production of VLCFA enriched single cell oils.ResultsThe metabolism of Y. lipolytica was redesigned to achieve increased production of VLCFA. The effect of native diacylglycerol acyltransferases of this yeast YlLro1p, YlDga1p, and YlDga2p on the accumulation of VLCFA was examined. It was found that YlDga1p is the only enzyme with a beneficial effect. Further improvement of accumulation was achieved by overexpression of 3-ketoacyl-CoA synthase (TaFAE1) under 8UAS-pTEF promoter and blockage fatty acid degradation pathway by deletion of YlMFE1. The best-producing strain YL53 (Δmfe, pTEF-YlDGA1, 8UAS-pTEF-TaFAE1) produced 120 µg of very long chain fatty acids per g of produced biomass, which accounted for 34% of total fatty acids in biomass.ConclusionsRecombinant strains of Y. lipolytica have proved to be good producers of VLCFA. Redesign of lipid metabolism pathways had a positive effect on the accumulation of C22:1Δ13 and C22:0, which are technologically attractive compounds.

NANOSTRUCTURED LIPID CARRIERS FOR TRANSDERMAL DRUG DELIVERY

Transdermal drug delivery offers many advantages over oral delivery, such as avoiding first-pass metabolism, enhancing the bioavailability of poorly soluble drugs, and providing better patient compliance. However, only small lipophilic molecules can be delivered across the stratum corneum, the outermost layer of the skin. Unfortunately, the delivery of larger molecules remains a challenge. Nanostructured lipid carriers (NLCs) are second-generation lipid nanocarriers composed of biocompatible solid lipids, liquid lipids, surfactants, and co-surfactants. NLCs can be loaded with various classes of drugs, provide a controlled drug release profile, enhance drug stability, and be scaled up without needing organic solvents. This review article discusses the features, composition, formulation processes, and characterization of NLCs and their potential use in transdermal drug delivery.

Hexagonal liquid crystalline system containing cinnamaldehyde for enhancement of skin permeation of sinomenine hydrochloride

Sinomenine hydrochloride (SH) is usually applied to treat rheumatoid arthritis (RA) with severe side effects due to oral administration. Cinnamaldehyde (CA) as essential oil possesses an anti-RA effect and can facilitate transdermal penetration. Hence, this study developed hexagonal liquid crystalline (HII) gels to deliver two components (SH and CA) across the skins. HII gels were prepared and characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS) and rheology. Moreover, in vitro drug release behavior and ex vivo skin permeation were investigated. Finally, Fourier transforms infrared spectral analysis (FTIR) and confocal laser scanning microscopy (CLSM) were used to explore the skin penetration mechanism. PLM and SAXS showed that the inner structure of the gels was HII phase. The addition of lipophilic or hydrophilic molecules slowed down one another’s release and the release model was dominated by Fickian diffusion (n < 0.43). Furthermore, in vitro permeation studies indicated that appropriate CA could improve the skin permeability of SH. FTIR and CLSM suggested that infiltration occurred due to disruption of the lipid bilayer structure and increased fluidity of the skin. In conclusion, HII gels and CA exhibited a penetration-promoting effect for transdermal applications in SH.

FORMULATION AND EVALUATION OF CYCLOSPORINE LOADED CUBOSOMES FOR THE MANAGEMENT OF PSORIASIS

Cubosomes can be considered as novel lipid-based nanosystems similar to well-known vesicular systems such as liposomes and niosomes. Cubosomes have been widely formulated using certain amphiphilic lipids (e.g. glyceryl monooleate and phytantriol) in the presence of a suitable stabilizer. They can represent a novel drug delivery system which could be loaded with hydrophilic, lipophilic and amphiphilic drug molecules. They are widely used for various drug delivery applications such as oral, ocular, transdermal and chemotherapy drug delivery. In this study, preparation and characterization of cyclosporine loaded cubosomes have done for the management of psoriasis. The preformulation study and formulation of cubosomes was performed. Evaluation parameters of the cubosomes were performed and results were reported.

Improved Performance of Asphalt Concretes using Bottom Ash as an Alternative Aggregate

Road networks are major infrastructures that support the economic development in both developed and developing countries. Bottom ash (BA) is a by-product from coal-fired powerplants, which is composed of a lipophilic molecule with effective reactivity to bituminous binder. BA was adopted in this research, as a green fine aggregate, to improve the mechanistic performance of asphalt concretes in this research. The effect of BA-replacement ratio (0%, 10%, 15%, 20% and 25%, by total weight of natural fine aggregate) on the Marshall stability and flow, indirect tensile strength (ITS), and mechanistic performance of BA-asphalt concrete, were examined. The mechanistic performance tests included the indirect-tensile condition (indirect tensile resilient modulus (IT Mr), indirect tensile fatigue life (ITFL)) and compressive condition (permanent deformation (PD), rut depth, and skid resistance). BA replacement improves the Marshall stability and flow, strength index, and ITS, up to the optimum BA-replacement ratio, of 5%. The change in IT Mr was found to be linearly proportional to the change in ITS, for all BA-replacement ratios. The ITFL is dependent upon the repeated stress level and can be estimated in terms of IT Mr. For the compressive condition, the PD, rutting, and skid resistances were found to be improved by the BA replacement. The lowest PD and rut depth as well as the highest skid resistance, for IT Mr and ITFL, were found at the optimum BA-replacement ratio, of 5%. The outcome of this research will promote the usage of BA as a cleaner additive in asphalt concrete pavement, which is useful in terms of engineering and environmental perspectives.

Comparison Between Franz Diffusion Cell and a novel Micro-physiological System for In Vitro Penetration Assay Using Different Skin Models.

In vitro diffusive models are an important tool to screen the penetration ability of active ingredients in various formulations. A reliable assessment of skin penetration enhancing properties, mechanism of action of carrier systems, and an estimation of a bioavailability are essential for transdermal delivery. Given the importance of testing the penetration kinetics of different compounds across the skin barrier, several in vitro models have been developedThe aim of this study was to compare the Franz Diffusion Cell (FDC) with a novel fluid-dynamic platform (MIVO) by evaluating penetration ability of caffeine, a widely used reference substance, and LIP1, a testing molecule having the same molecular weight but a different lipophilicity in the two diffusion chamber systems. A 0.7% caffeine or LIP1 formulation in either water or propylene glycol (PG) containing oleic acid (OA) was topically applied on the Strat-M® membrane or pig ear skin, according to the infinite-dose experimental condition (780 ul/cm2). The profile of the penetration kinetics was determined by quantify the amount of molecule absorbed at different time-points (1, 2, 4, 6, 8 hours), by means of HPLC analysis. Both diffusive systems show a similar trend for caffeine and LIP1 penetration kinetics. The Strat-M® skin model shows a lower barrier function than the pig skin biopsies, whereby the PGOA vehicle exhibits a higher penetration, enhancing the effect for both diffusive chambers and skin surrogates. Most interestingly, MIVO diffusive system better predicts the lipophilic molecules (i.e. LIP1) permeation through highly physiological fluid flows resembled below the skin models.

Development and Evaluation of Khellin-loaded Microemulgel for Dermatological Applications.

Microemulsions are optically nanosized emulsions, isotropic and thermodynamically stable. They represent versatile drug delivery systems with high potential because they can be administered regardless of route. In the present study, we report on the formulation of a microemulsion made with glycerol (2.25%), Labrasol (20.25%) vitamin E acetate (2.50%), and water (75.00%), which was developed using the pseudo-ternary phase diagram. Globules of the microemulsion had PdI less than 0.25 and size of about 17 nm, evaluated by DLS analysis. These values did not change after loading khellin, a natural lipophilic molecule with interesting biological activities, used as a model of lipophilic drug. Carboxymethyl cellulose was selected as gelling polymer to obtain a microemulgel. Viscosity was 22 100.0 ± 1555.6 mPas·s at 21 ± 2 °C, while it was 8916.5 ± 118.1 mPas·s at 35 ± 2 °C, remaining stable over time. Khellin recovery was 93.16 ± 4.39% and was unchanged after 4 weeks of storage (93.23 ± 2.14%). The pH was 6.59 ± 0.19 and it was found to be 6.42 ± 0.34 at the end of the storage lifetime. The diffusion of khellin from the developed formulation was prolonged over an extended period. Based on overall results and due to the dermatological properties of the ingredients of the formulation, the developed microemulgel loaded with khellin is very promising and suitable for skin care applications.

Development and evaluation of liposomal nanoparticles incorporating dimethoxycurcumin. In vitro toxicity and permeability studies

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.

Development and Characterization of Novel LRH‐1 Antagonist Using Structural and Computational Techniques

Nuclear receptors are transcription factors that respond to external lipophilic signaling molecules by recruiting coactivators that enhance target gene expression. Liver receptor homolog‐1 (LRH‐1) is a nuclear receptor that drives ERα signaling and expression of cell cycle regulatory genes. LRH‐1 antagonists are therefore attractive potential therapeutics for the treatment of ERα positive and negative breast cancer. However, mechanistic studies exploring LRH‐1 antagonism are incredibly limited due to the lack of structural insight on the few existing compounds that decrease receptor activity. Using structure‐guided compound design, we have made modifications to the chemical scaffold of a highly potent LRH‐1 agonist to target and disrupt the region of the receptor responsible for coactivator binding. Our strategy effectively decreases LRH‐1 thermal stability, coactivator association, and transcriptional activity. Interestingly, molecular dynamics simulations reveal that antagonism is achieved through disruption of allosteric paths of communication unique to LRH‐1. Our work therefore characterizes a highly efficacious small molecule LRH‐1 antagonist and provides mechanistic insight into how signaling for this receptor can be effectively disrupted without large structural rearrangements.

Cyclodextrins and Drug Membrane Permeation: Thermodynamic Considerations

Cyclodextrins are hydrophilic oligosaccharides that can increase aqueous solubility of lipophilic drugs through formation of water-soluble drug/cyclodextrin complexes. Although the complexes are hydrophilic, and as such do not permeate biological membranes, the complexes are known to enhance drug permeation through lipophilic membranes and improve drug bioavailability after, for example, oral administration. However, it is not clear how cyclodextrins enhance the permeation. An artificial biomembrane (PermeaPad®) was used to study the effect of donor medium composition on drug permeation. It was observed that in aqueous solutions the hydrophilic cyclodextrins behave not like disperse systems but rather like organic cosolvents such as ethanol, increasing the solubility without having significant effect on the molecular mobility and ability of lipophilic drug molecules to partition into the lipophilic membrane. Also, that partition of dissolved drug molecules from the aqueous exterior into the membrane is at its maximum when their thermodynamic activity is at its maximum. In other words, that drug flux from aqueous cyclodextrin solutions through lipophilic membranes depends on both the concentration and the thermodynamic activity of dissolved drug. Maximum flux is obtained when both the drug concentration and thermodynamic activity of the dissolved drug molecules are at their maximum value.

Evaluation of Brain Targeting Potential of Zolmitriptan Mucoadhesive Nanoparticles for Intranasal Drug Delivery.

Hydrophilic drugs are poor applicants for brain targeting via oral route due to the presence of a blood-brain barrier that allows only small lipophilic molecules to freely access the brain. Due to unique anatomical connections between the nasal cavity and the brain, intranasal administration can be explored for drug delivery to the brain directly that circumvents the blood-brain barrier too. Zolmitriptan is a widely used antimigraine drug, and its brain targeting by nasal route in the form of mucoadhesive nanoparticles is more effective in migraine treatment as it provides fast relief and good bioavailability as compared to its oral drug delivery. In the present study, zolmitriptan mucoadhesive nanoparticles were prepared to improve the bioavailability and brain targeting for the better management of Migraine attacks. The mucoadhesive polymeric nanoparticles of zolmitriptan were formulated by a modified ionic gelation method using thiolated chitosan. The pharmacokinetic parameters were counted in male Wistar rats by intranasal and oral delivery of the anti-migraine drug zolmitriptan and compared statistically. The concentration of zolmitriptan in the blood plasma and brain samples was determined by using the liquid-liquid extraction method followed by a reversed-phase highperformance liquid chromatography (RP-HPLC) analysis. The pharmacodynamic analysis was conducted in adult male Swiss albino mice by behavioral models, a light/dark box model, and acetic acid-induced writhing (abdominal stretching or constriction). These tests were used to reproduce the important associated symptoms of migraine viz. hyperalgesia (nociceptive sensitization) and photophobia to assess the therapeutic potential of intranasal delivery of nanoparticles antimigraine activity. The absolute bioavailability accessed for Zolmitriptan nanoparticles by IN route was found to be very high (193%), suggesting that the sufficient amount of drug transported by nanoparticles and DTE ratio was calculated as 2.8. Moreover, it revealed better nose-to-brain transport by zolmitriptan nanoparticles as compared to oral delivery in male Wistar rats. A significant increase in the tolerance capacity of animals to bright light and a fall in the number of stretching in mice suggested the better management of migraine-associated symptoms by the zolmitriptan nanoparticles. Thus, the present study confers the significance of nasal drug delivery for brain targeting of zolmitriptan nanoparticles for the treatment of migraine.

Isoprene Emission Influences the Proteomic Profile of Arabidopsis Plants under Well-Watered and Drought-Stress Conditions.

Isoprene is a small lipophilic molecule synthesized in plastids and abundantly released into the atmosphere. Isoprene-emitting plants are better protected against abiotic stresses, but the mechanism of action of isoprene is still under debate. In this study, we compared the physiological responses and proteomic profiles of Arabidopsis which express the isoprene synthase (ISPS) gene and emit isoprene with those of non-emitting plants under both drought-stress (DS) and well-watered (WW) conditions. We aimed to investigate whether isoprene-emitting plants displayed a different proteomic profile that is consistent with the metabolic changes already reported. Only ISPS DS plants were able to maintain the same photosynthesis and fresh weight of WW plants. LC–MS/MS-based proteomic analysis revealed changes in protein abundance that were dependent on the capacity for emitting isoprene in addition to those caused by the DS. The majority of the proteins changed in response to the interaction between DS and isoprene emission. These include proteins that are associated with the activation of secondary metabolisms leading to ABA, trehalose, and proline accumulations. Overall, our proteomic data suggest that isoprene exerts its protective mechanism at different levels: under drought stress, isoprene affects the abundance of chloroplast proteins, confirming a strong direct or indirect antioxidant action and also modulates signaling and hormone pathways, especially those controlling ABA synthesis. Unexpectedly, isoprene also alters membrane trafficking.

225Ac-rHDL Nanoparticles: A Potential Agent for Targeted Alpha-Particle Therapy of Tumors Overexpressing SR-BI Proteins.

Actinium-225 and other alpha-particle-emitting radionuclides have shown high potential for cancer treatment. Reconstituted high-density lipoproteins (rHDL) specifically recognize the scavenger receptor B type I (SR-BI) overexpressed in several types of cancer cells. Furthermore, after rHDL-SR-BI recognition, the rHDL content is injected into the cell cytoplasm. This research aimed to prepare a targeted 225Ac-delivering nanosystem by encapsulating the radionuclide into rHDL nanoparticles. The synthesis of rHDL was performed in two steps using the microfluidic synthesis method for the subsequent encapsulation of 225Ac, previously complexed to a lipophilic molecule (225Ac-DOTA-benzene-p-SCN, CLog P = 3.42). The nanosystem (13 nm particle size) showed a radiochemical purity higher than 99% and stability in human serum. In vitro studies in HEP-G2 and PC-3 cancer cells (SR-BI positive) demonstrated that 225Ac was successfully internalized into the cytoplasm of cells, delivering high radiation doses to cell nuclei (107 Gy to PC-3 and 161 Gy to HEP-G2 nuclei at 24 h), resulting in a significant decrease in cell viability down to 3.22 ± 0.72% for the PC-3 and to 1.79 ± 0.23% for HEP-G2 at 192 h after 225Ac-rHDL treatment. After intratumoral 225Ac-rHDL administration in mice bearing HEP-G2 tumors, the biokinetic profile showed significant retention of radioactivity in the tumor masses (90.16 ± 2.52% of the injected activity), which generated ablative radiation doses (649 Gy/MBq). The results demonstrated adequate properties of rHDL as a stable carrier for selective deposition of 225Ac within cancer cells overexpressing SR-BI. The results obtained in this research justify further preclinical studies, designed to evaluate the therapeutic efficacy of the 225Ac-rHDL system for targeted alpha-particle therapy of tumors that overexpress the SR-BI receptor.

Development, Therapeutic Evaluation and Theranostic Applications of Cubosomes on Cancers: An Updated Review.

Cancer is a group of disorders characterized by aberrant gene function and alterations in gene expression patterns. In 2020, it was anticipated that 19 million new cancer cases would be diagnosed globally, with around 10 million cancer deaths. Late diagnosis and interventions are the leading causes of cancer-related mortality. In addition, the absence of comprehensive cancer therapy adds to the burden. Many lyotropic non-lamellar liquid-crystalline-nanoparticle-mediated formulations have been developed in the last few decades, with promising results in drug delivery, therapeutics, and diagnostics. Cubosomes are nano-structured liquid-crystalline particles made of specific amphiphilic lipids in particular proportions. Their ability to encapsulate lipophilic, hydrophilic, and amphiphilic molecules within their structure makes them one of a kind. They are biocompatible, versatile drug carriers that can deliver medications through various routes of administration. Many preclinical studies on the use of cubosomes in cancer treatment and theranostic applications have been conducted. However, before cubosomes may be employed in clinical practice, significant technical advances must be accomplished. This review summarizes the development of cubosomes and their multifunctional role in cancer treatment based on the most recent reports.

Ethosomes: A Novel Vesicular Innovation to Enhance Transdermal Delivery of Drugs

Transdermal route of drug delivery is a promising substitute to oral-systemic delivery of drug substances. It offers several benefits such as avoidance of first pass metabolism, patience compliance, ease of application and so on. But along with these benefits, the major drawback is the barrier function of the skin which hinders the transdermal delivery of the drugs. Hence, ethosomes are useful in such conditions as they surpass the barriers of the skin. Ethosomes are the noninvasive delivery carriers that enable drugs to reach deep into the skin layers or the systemic circulation. They are made up of phospholipids, high concentration of ethanol and water. Ethosomes are able to encapsulate and distribute extremely lipophilic molecules through the skin, as well as cationic drugs, due to their unique structure and deliver them to the deep layers of the skin. Ethosomes have become an area of research interest, because of its enhanced skin permeation, improved drug delivery, increased drug entrapment efficiency etc. This review article provides an insight about the ethosomal systems, their mechanism of penetration into the skin, methods of preparation, evaluation and applications in the field of pharmacy.

Susceptibility of Lung Carcinoma Cells to Nanostructured Lipid Carrier of ARV-825, a BRD4 Degrading Proteolysis Targeting Chimera.

The present work was aimed at developing an optimized and modified nanostructured lipid carrier of BRD4 protein degrading Proteolysis Targeting Chimera (PROTAC) against non-small cell lung carcinoma. PROTACs are an emerging class of anticancer molecules with nanomolar activity but associated with significant solubility challenges. Lipid-based colloidal systems like nanostructured lipid carriers are widely explored for such highly lipophilic molecules. ARV-825, a cereblon-based PROTAC was investigated for its anticancer efficacy in vitro in 2D and 3D lung cancer models. ARV-825 loaded PEGylated nanostructured lipid carriers (AP-NLC) was prepared using melt emulsification technique. ARV-825 was stabilized using Precirol® ATO5 and Captex® 300 EP/NF as the solid and liquid lipid, respectively. However, hydrophobic ion-pairing with medium chain fatty acid was required to improve drug loading and stability. A hydrodynamic diameter and polydispersity index of 56.33 ± 0.42nm and 0.16 respectively with zeta potential of -21 ± 1.24mV was observed. In vitro migration and colony formation assay confirmed the anticancer activity of ARV-825 alone and AP-NLC. Nearly 38% and 50% apoptotic cell population were observed after ARV-825 and AP-NLC treatment. Immunoblotting assay showed complete suppression of BRD4 and c-Myc protein expression for AP-NLC. Most importantly, significant reduction in the growth of multicellular 3D spheroid of A549 cells confirmed the effectiveness of BRD4 PROTAC and its lipid nanoparticle in non-small cell lung cancer (NSCLC). AP-NLC. Higher amount of red fluorescence throughout the spheroid surface further confirmedsuperior efficacy of AP-NLC in tumor penetration and cell killing.

Targeting TLR9 agonists to secondary lymphoid organs induces potent immune responses against HBV infection

Despite the existence of a prophylactic vaccine against hepatitis B virus (HBV), chronic hepatitis B virus (CHB) infection remains the leading cause of cirrhosis and liver cancer in developing countries. Because HBV persistence is associated with insufficient host immune responses to the infection, development of an immunomodulator as a component of therapeutic vaccination may become an important strategy for treatment CHB. In the present study, we aimed to design a novel immunomodulator with the capacity to subvert immune tolerance to HBV. We developed a lymphoid organ-targeting immunomodulator by conjugating a naturally occurring, lipophilic molecule, α-tocopherol, to a potent CpG oligonucleotide adjuvant pharmacophore. This approach resulted in preferential trafficking of the α-tocopherol-conjugated oligonucleotide to lymphoid organs where it was internalized by antigen-presenting cells (APCs). Moreover, we show that conjugation of the oligonucleotides to α-tocopherol results in micelle-like structure formation, which improved cellular internalization and enhanced immunomodulatory properties of the conjugates. In a mouse model of chronic HBV infection, targeting CpG oligonucleotide to lymphoid organs induced strong cellular and humoral immune responses that resulted in sustained control of the virus. Given the potency and tolerability of an α-tocopherol-conjugated CpG oligonucleotide, this modality could potentially be broadly applied for therapeutic vaccine development.

Biocompatible, photo-responsive layer-by-layer polymer nanocapsules with an oil core: in vitro and in vivo study.

In cancer therapy, stimulus-responsive drug delivery systems are of particular interest for reducing side effects in healthy tissues and improving drug selectivity in the tumoral ones. Here, a strategy for the preparation of a photo-responsive cross-linked trilayer deposited onto an oil-in-water nanoemulsion via a layer-by-layer technique is reported. The system is made of completely biocompatible materials such as soybean oil, egg lecithin and glycol chitosan, with heparin as the polymeric shell. The oil core is pre-loaded with curcumin as a model lipophilic active molecule with anti-tumoral properties. The trilayer cross-linkage is performed via a photoinitiator-free thiol-ene 'click' reaction. In particular, the system is implemented with an o-nitrobenzyl group functionalized with a thiol moiety which can perform both the thiol-ene 'click' reaction and the cleavage meant for controlled drug release at two different wavelengths, respectively. So the preparation and characterization of a photo-responsive natural nanocarrier (PNC) that is stable under physiological conditions owing to the thiol-ene cross-linkage are reported. PNC performance has been assessed in vitro on melanoma cells as well as in vivo on xenograft tumour-induced mice.