Solid Lipid Nanoparticles Containing Dopamine and Grape Seed Extract: Freeze-Drying with Cryoprotection as a Formulation Strategy to Achieve Nasal Powders.

(1) Background: DA-Gelucire® 50/13-based solid lipid nanoparticles (SLNs) administering the neurotransmitter dopamine (DA) and the antioxidant grape-seed-derived proanthocyanidins (grape seed extract, GSE) have been prepared by us in view of a possible application for Parkinson's disease (PD) treatment. To develop powders constituted by such SLNs for nasal administration, herein, two different agents, namely sucrose and methyl-ß-cyclodextrin (Me-ß-CD), were evaluated as cryoprotectants. (2) Methods: SLNs were prepared following the melt homogenization method, and their physicochemical features were investigated by Raman spectroscopy, Scanning Electron Microscopy (SEM), atomic force microscopy (AFM) and X-ray Photoelectron Spectroscopy (XPS). (3) Results: SLN size and zeta potential values changed according to the type of cryoprotectant and the morphological features investigated by SEM showed that the SLN samples after lyophilization appear as folded sheets with rough surfaces. On the other hand, the AFM visualization of the SLNs showed that their morphology consists of round-shaped particles before and after freeze-drying. XPS showed that when sucrose or Me-ß-CD were not detected on the surface (because they were not allocated on the surface or completely absent in the formulation), then a DA surfacing was observed. In vitro release studies in Simulated Nasal Fluid evidenced that DA release, but not the GSE one, occurred from all the cryoprotected formulations. Finally, sucrose increased the physical stability of SLNs better than Me-ß-CD, whereas RPMI 2650 cell viability was unaffected by SLN-sucrose and slightly reduced by SLN-Me-ß-CD. (4) Conclusions: Sucrose can be considered a promising excipient, eliciting cryoprotection of the investigated SLNs, leading to a powder nasal pharmaceutical dosage form suitable to be handled by PD patients.

Modern Photodynamic Glioblastoma Therapy Using Curcumin- or Parietin-Loaded Lipid Nanoparticles in a CAM Model Study.

Natural photosensitizers, such as curcumin or parietin, play a vital role in photodynamic therapy (PDT), causing a light-mediated reaction that kills cancer cells. PDT is a promising treatment option for glioblastoma, especially when combined with nanoscale drug delivery systems. The curcumin- or parietin-loaded lipid nanoparticles were prepared via dual asymmetric centrifugation and subsequently characterized through physicochemical analyses including dynamic light scattering, laser Doppler velocimetry, and atomic force microscopy. The combination of PDT and lipid nanoparticles has been evaluated in vitro regarding uptake, safety, and efficacy. The extensive and well-vascularized chorioallantois membrane (CAM) of fertilized hen's eggs offers an optimal platform for three-dimensional cell culture, which has been used in this study to evaluate the photodynamic efficacy of lipid nanoparticles against glioblastoma cells. In contrast to other animal models, the CAM model lacks a mature immune system in an early stage, facilitating the growth of xenografts without rejection. Treatment of xenografted U87 glioblastoma cells on CAM was performed to assess the effects on tumor viability, growth, and angiogenesis. The xenografts and the surrounding blood vessels were targeted through topical application, and the effects of photodynamic therapy have been confirmed microscopically and via positron emission tomography and X-ray computed tomography. Finally, the excised xenografts embedded in the CAM were analyzed histologically by hematoxylin and eosin and KI67 staining.

Lipid-Coated Polymeric Nanoparticles for the Photodynamic Therapy of Head and Neck Squamous Cell Carcinomas.

Next to alcohol and tobacco abuse, infection with human papillomaviruses (HPVs) is a major risk factor for developing head and neck squamous cell carcinomas (HNSCCs), leading to 350,000 casualties worldwide each year. Limited therapy options and drug resistance raise the urge for alternative methods such as photodynamic therapy (PDT), a minimally invasive procedure used to treat HNSCC and other cancers. We prepared lipid-coated polymeric nanoparticles encapsulating curcumin as the photosensitizer (CUR-LCNPs). The prepared CUR-LCNPs were in the nanometer range (153.37 ± 1.58 nm) and showed an encapsulation efficiency of 92.69 ± 0.03%. Proper lipid coating was visualized using atomic force microscopy (AFM). The CUR-LCNPs were tested in three HPVpos and three HPVneg HNSCC lines regarding their uptake capabilities and in vitro cell killing capacity, revealing a variable but highly significant tumor cell inhibiting effect in all tested HNSCC cell lines. No significant differences were detected between the HPVpos and HPVneg HNSCC groups (mean IC50: (9.34 ± 4.73 µmol/L vs. 6.88 ± 1.03 µmol/L), suggesting CUR-LCNPs/PDT to be a promising therapeutic option for HNSCC patients independent of their HPV status.

Co-Delivery of Ylang Ylang Oil of Cananga odorata and Oxaliplatin Using Intelligent pH-Sensitive Lipid-Based Nanovesicles for the Effective Treatment of Triple-Negative Breast Cancer.

Smart pH-responsive niosomes loaded with either Oxaliplatin (Ox), Ylang ylang essential oil (Y-oil), or co-loaded with both compounds (Ox-Y) (Ox@NSs, Y@NSs, and Ox-Y@NSs, respectively) were formulated utilizing the thin film method. The developed nanocontainers had a spherical morphology with mean particle sizes lower than 170 nm and showed negative surface charges, high entrapment efficiencies, and a pH-dependent release over 24 h. The prepared pH-responsive niosomes' cytotoxicity was tested against the invasive triple-negative breast cancer (MDA-MB-231) cells, compared to free OX and Y-oil. All niosomal formulations loaded with Ox and/or Y-oil significantly improved cytotoxic activity relative to their free counterparts. The Ox-Y@NSs demonstrated the lowest IC50 (0.0002 µg/mL) when compared to Ox@NSs (0.006 µg/mL) and Y@NSs (18.39 µg/mL) or unloaded Ox (0.05 µg/mL) and Y-oil (29.01 µg/mL). In addition, the percentages of the MDA-MB-231 cell population in the late apoptotic and necrotic quartiles were profoundly higher in cells treated with the smart Ox-Y@NSs (8.38% and 5.06%) than those exposed to free Ox (7.33% and 1.93%) or Y-oil (2.3% and 2.13%) treatments. Gene expression analysis and protein assays were performed to provide extra elucidation regarding the molecular mechanism by which the prepared pH-sensitive niosomes induce apoptosis. Ox-Y@NSs significantly induced the gene expression of the apoptotic markers Tp53, Bax, and Caspase-7, while downregulating the antiapoptotic Bcl2. As such, Ox-Y@NSs are shown to activate the intrinsic pathway of apoptosis. Moreover, the protein assay ascertained the apoptotic effects of Ox-Y@NSs, generating a 4-fold increase in the relative protein quantity of the late apoptotic marker Caspase-7. Our findings suggest that combining natural essential oil with synthetic platinum-based drugs in pH-responsive nanovesicles is a promising approach to breast cancer therapy.

Photothermally Controlled Drug Release of Poly(d,l-lactide) Nanofibers Loaded with Indocyanine Green and Curcumin for Efficient Antimicrobial Photodynamic Therapy.

Chronic wound infections with antibiotic-resistant bacteria have become a significant problem for modern healthcare systems since they are often associated with high costs and require profound topical wound management. Successful wound healing is achieved by reducing the bacterial load of the wound and providing an environment that enhances cell growth. In this context, nanofibers show remarkable success because their structure offers a promising drug delivery platform that can mimic the native extracellular matrix and accelerate cell proliferation. In our study, single-needle electrospinning, a versatile and cost-efficient technique, was used to shape polymers into an applicable and homogeneous fleece capable of a photothermally triggered drug release. It was combined with antimicrobial photodynamic therapy, a promising procedure against resistant bacteria. Therefore, poly(d,l-lactide) nanofibers loaded with curcumin and indocyanine green (ICG) were produced for local antimicrobial treatment. The mesh had a homogeneous structure, and the nanofibers showed a smooth surface. Recordings with a thermal camera showed that near-infrared light irradiation of ICG increased the temperature (>44 °C) in the surrounding medium. Release studies confirmed more than 29% enhanced curcumin release triggered by elevated temperature. The antimicrobial activity was tested against the gram-positive strain Staphylococcus saprophyticus subsp. bovis and the gram-negative strain Escherichia coli DH5 alpha. The nanofibers loaded with both photosensitizers and irradiated with both wavelengths reduced the bacterial viability (~4.4 log10, 99.996%) significantly more than the nanofibers loaded with only one photosensitizer (<1.7 log10, 97.828%) or irradiated with only one wavelength (<2.0 log10, 98.952%). In addition, our formulation efficiently eradicated persistent adhered bacteria by >4.3 log10 (99.995%), which was also confirmed visually. Finally, the produced nanofibers showed good biocompatibility, proven by the cellular viability of mouse fibroblasts (L929). The data demonstrate that we have developed a new economic nanofiber formulation, which offers a triggered drug release, excellent antimicrobial properties, and good biocompatibility.

Editorial on the "Special Issue in Honor of Dr. Michael Weber's 70th Birthday: Photodynamic Therapy: Rising Star in Pharmaceutical Applications".

Thousands of years ago, phototherapy or heliotherapy was performed by ancient Egyptians, Greeks, and Romans [...].

Thermosensitive liposomes encapsulating hypericin: Characterization and photodynamic efficiency.

The potent photodynamic properties of Hypericin (Hyp) elicit a range of light-dose-dependent anti-tumor activities. However, its low water solubility hampers its broad application. Therefore, the administration of Hyp into biological systems requires drug carriers that would enable sufficient bioavailability. Stimuli-triggered nanocarriers, which are sensitive to endogenous or exogenous stimuli, have become an attractive replacement for conventional therapeutic regimens. Herein, we produced optimized Hyp thermosensitive liposomes (Hyp-TSL), self-assembled from DPPC, DSPC, DSPE-PEG2000. Hyp-TSL displayed a hydrodynamic diameter below 100 nm with an adequate encapsulation efficiency of 94.5 % and good colloidal stability. Hyp-TSL exhibited thermal sensitivity over a narrow range with a phase transition temperature of 41.1 °C, in which liposomal destruction was evident in AFM images after elevated temperature above the phase transition temperature. The uptake of TSL-Hyp into MDA-MB-231 cells was significantly increased with hyperthermic treatment of 42 °C when compared to the uptake at a average physiological temperature of 37 °C. Consequent enhancement of cellular reactive oxygen species was observed after hyperthermic treatment at 42 °C. The half-maximal inhibitory concentration of Hyp TSL was reduced by 3.8 fold after hyperthermic treatment at 42 °C in comparison to treatment at 37 °C. Hyp-TSL were considered safe for intravenous applications as compared by hemocompatibility studies, where coagulation time was <50 s and hemolytic potential was <10%. Conclusively, the enhancement in tumor drug availability correlated with improved therapeutic outcomes.

Improvement of Pulmonary Photodynamic Therapy: Nebulisation of Curcumin-Loaded Tetraether Liposomes.

Lung cancer is one of the most common causes for a high number of cancer related mortalities worldwide. Therefore, it is important to improve the therapy by finding new targets and developing convenient therapies. One of these novel non-invasive strategies is the combination of pulmonary delivered tetraether liposomes and photodynamic therapy. In this study, liposomal model formulations containing the photosensitiser curcumin were nebulised via two different technologies, vibrating-mesh nebulisation and air-jet nebulisation, and compared with each other. Particle size and ζ-potential of the liposomes were investigated using dynamic light scattering and laser Doppler anemometry, respectively. Furthermore, atomic force microscopy and transmission electron microscopy were used to determine the morphological characteristics. Using a twin glass impinger, suitable aerodynamic properties were observed, with the fine particle fraction of the aerosols being ≤62.7 ± 1.6%. In vitro irradiation experiments on lung carcinoma cells (A549) revealed an excellent cytotoxic response of the nebulised liposomes in which the stabilisation of the lipid bilayer was the determining factor. Internalisation of nebulised curcumin-loaded liposomes was visualised utilising confocal laser scanning microscopy. Based on these results, the pulmonary application of curcumin-loaded tetraether liposomes can be considered as a promising approach for the photodynamic therapy against lung cancer.

Potent Cytotoxicity of Four Cameroonian Plant Extracts on Different Cancer Cell Lines.

In this study, the potential cytotoxicity of four plant extracts originated from Cameroon: Xylopia aethiopica (XA), Imperata cylindrica (IC), Echinops giganteus (EG) and Dorstenia psilurus (DP) were examined in vitro. We tested the anti-proliferative activity of the methanolic extracts of these compounds using MTT assay on seven different human cancer cell lines: HeLa, MDA-MB-231, A549, HepG2, U-87, SK-OV-3 and HL60. Induction of cell death was assessed by cell cycle analysis, apoptosis was determined by Annexin V-FITC binding and caspase 3/7 activity. As well, changes in mitochondrial membrane potential (MMP) and cell migration were tested. The genetic toxicity, using the alkaline comet assay, was evaluated. The studied extracts inhibited the cell proliferation of all tested cancer cell lines with concentration dependent effect over time. All of these extracts mainly induced apoptosis of HeLa cells by the accumulation of hypodiploid cells in the sub-G0/G1 phase and increasing the activity of caspase 3/7, as well they showed potential MMP disturbance and expressed a marked inhibitory effect on cell migration. Assessment of probable genetic toxicity by these extracts revealed no or minimum incidence of genetic toxicity. Therefore, the studied plant extracts are exhibiting potent anticancer activity based upon marked induction of tumor-cell death.

Sensitivity of Papilloma Virus-Associated Cell Lines to Photodynamic Therapy with Curcumin-Loaded Liposomes.

Photodynamic therapy (PDT) is a minimally invasive therapeutic approach used in the treatment of various medical conditions and cancerous diseases, involving light, a photosensitizing substance, and oxygen. Curcumin, a naturally occurring compound, carries antitumor activities and potentially could be exploited as a photosensitizer in PDT. Only little is known about liposomal-encapsulated curcumin that could help in increasing the efficacy, stability, and bioavailability of this compound. This study investigates the in vitro effects of curcumin-loaded liposomes in combination with PDT. Three papilloma virus-associated cell lines were treated with curcumin-loaded liposomes corresponding to a curcumin concentration of 0-100 µmol/L for 4 h followed by illumination at 457 nm (blue) for 45, 136, and 227 s at a fluence of 220.2 W/m2 (100 mA) corresponding to 1, 3 and 5 J·cm-2. After 24 h, the biological outcome of the treatment was assessed with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), SYTO9/PI (propidium iodide), Annexin V-FITC (fluorescein isothiocyanate)/PI, clonogenic survival, and scratch (wound closure) assays. Photoactivation of curcumin-loaded liposomes led to a significant reduction in colony formation and migratory abilities, as well as to an increase in tumor cell death. The results point to the combination of curcumin-loaded liposomes with PDT as a potentially useful tool for the treatment of papillomavirus-associated malignancies.

Platinum Nanoparticles: Green Synthesis and Biomedical Applications.

Platinum nanoparticles (PtNPs) have superior physicochemical properties and great potential in biomedical applications. Eco-friendly and economic approaches for the synthesis of PtNPs have been developed to overcome the shortcomings of the traditional physical and chemical methods. Various biogenic entities have been utilized in the green synthesis of PtNPs, including mainly plant extracts, algae, fungi bacteria, and their biomedical effects were assessed. Other biological derivatives have been used in the synthesis of PtNPs such as egg yolk, sheep milk, honey, and bovine serum albumin protein. The green approaches for the synthesis of PtNPs have reduced the reaction time, the energy required, and offered ambient conditions of fabrication. This review highlights the state-of-the-art methods used for green synthesis of PtNPs, synthesis parameters, and their reported biomedical applications.

Palladium Nanoparticles Fabricated by Green Chemistry: Promising Chemotherapeutic, Antioxidant and Antimicrobial Agents.

Palladium nanoparticles (Pd NPs) showed great potential in biomedical applications because of their unique physicochemical properties. Various conventional physical and chemical methods have been used for the synthesis of Pd NPs. However, these methods include the use of hazardous reagents and reaction conditions, which may be toxic to health and to the environment. Thus, eco-friendly, rapid, and economic approaches for the synthesis of Pd NPs have been developed. Bacteria, fungi, yeast, seaweeds, plants, and plant extracts were used to prepare Pd NPs. This review highlights the most recent studies for the biosynthesis of Pd NPs, factors controlling their synthesis, and their potential biomedical applications.

Magnetic resonance activatable thermosensitive liposomes for controlled doxorubicin delivery.

To limit the massive cytotoxicity of chemotherapeutic agents, it is desirable to establish an appropriate subtle blend of formulation design based on a dual-responsive strategy. In this study, a combined therapeutic platform based on magnetic thermosensitive liposomes (LipTS-GD) was developed. The incorporation of chelated-gadolinium imparted magnetic properties to thermosensitive liposomes (LipTS). The application of an ultra high field magnetic resonance imaging (UHF-MRI) induced hyperthermia, thus provided an improved chemotherapeutic effect of Doxorubicin (DOX). The paramagnetic platform demonstrated thermal sensitivity over a narrow temperature range starting at 37.8 °C, hence the release of DOX from LipTS-GD can be well triggered by inducing hyperthermia using UHF-MRI application. The prepared LipTS-GD were below 200 nm in diameter and an adequate release of DOX reaching 68% was obtained after 1 h UHF-MRI exposure. Profoundly, triple-negative breast cancer (TNBC) cells that were treated with LipTS-GD and subjected thereafter to UHF-MRI exposure for 60 min showed 36% viability. Hemocompatibility studies of LipTS-GD showed a physiological coagulation time and minimal hemolytic potential. Conclusively, LipTS-GD guided local delivery of DOX to solid tumors will potentially raise the therapeutic index, thus reducing the required dose and frequency of DOX administered systemically without influencing the adjacent tissues.

Targeted ErbB3 cancer therapy: A synergistic approach to effectively combat cancer.

Surface modification of nanoparticles with aptamer is gaining popularity lately due to its selective targeting and low immunogenicity. In this study, sorafenib tosylate (SFB) was loaded in biodegradable PLGA nanoparticles prepared by solvent evaporation method. The surfaces of drug deprived and drug-loaded particles (PN and PNS, respectively) were coupled with aptamer to target ErbB3 using EDC/NHS chemical modification. Nanoparticles were characterized with regard to their size, shape and chemical composition by dynamic light scattering, atomic force microscopy, FTIR and elemental analysis respectively. To evaluate the particles in vitro cell culture studies were performed. Cell viability assay, pathway analysis and apoptosis assay showed cellular toxicity in the presence of aptamer in PNS-Apt (p < 0.001). Metastatic progression assay showed decreased cell migration in the presence of aptamer and SFB. Confocal laser scanning microscopy was used to visualize the receptor-mediated time-dependent intracellular uptake and distribution of the nanoparticles throughout the cytoplasm. The findings of the current study demonstrated the potential efficacy of the surface modified SFB-loaded particles against ErbB3.

Spray dried curcumin loaded nanoparticles for antimicrobial photodynamic therapy.

Antimicrobial resistance is one of the most serious problems that researchers of multiple disciplines are working on. The number of new antibiotics and their targeted structures have continuously decreased emphasizing the demand of alternative therapy for bacterial infections. Photodynamic therapy is such a promising strategy that has been proven to be effective against a wide range of bacterial strains. In this study, an inhalable nanoformulation for photodynamic therapy against respiratory infections was developed in the form of nano-in-microparticles consisting of curcumin nanoparticles embedded in a mannitol matrix. The produced nano-in-microparticles exhibited suitable aerodynamic properties with a mass median aerodynamic diameter of 2.88 ±â€¯0.13 µm and a high fine particle fraction of 60.99 ±â€¯9.50%. They could be readily redispersed in an aqueous medium producing the original nanoparticles without any substantial changes in their properties. This was confirmed using dynamic light scattering and electron microscopy. Furthermore, the redispersed nanoparticles showed an efficient antibacterial photoactivity causing 99.99992% (6.1log10) and 97.75% (1.6log10) reduction in the viability of Staphylococcus saprophyticus subsp. bovis and Escherichia coli DH5 alpha respectively. Based on these findings, it can be concluded that nano-in-microparticles represent promising drug delivery systems for antimicrobial photodynamic therapy.

Photodynamic Therapy of Ovarian Carcinoma Cells with Curcumin-Loaded Biodegradable Polymeric Nanoparticles.

Accumulation of photosensitisers in photodynamic therapy in healthy tissues is often the cause of unwanted side effects. Using nanoparticles, improved bioavailability and site-specific drug uptake can be achieved. In this study, curcumin, a natural product with anticancer properties, albeit with poor aqueous solubility, was encapsulated in biodegradable polymeric poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CUR-NP). Dynamic light scattering, laser Doppler anemometry and atomic force microscopy were used to characterise the formulations. Using haemolysis, serum stability and activated partial thromboplastin time tests, the biocompatibility of CUR-NP was assessed. Particle uptake and accumulation were determined by confocal laser scanning microscopy. Therapeutic efficacy of the formulation was tested in SK-OV-3 human ovarian adenocarcinoma cells post low level LED irradiation by determining the generation of reactive oxygen species and cytotoxicity. Pharmacologic inhibitors of cellular uptake pathways were used to identify the particle uptake mechanism. CUR-NP exhibited better physicochemical properties such as stability in the presence of light and improved serum stability compared to free curcumin. In addition, the novel nanoformulation facilitated the use of higher amounts of curcumin and showed strong apoptotic effects on tumour cells.

Development of inhalable curcumin loaded Nano-in-Microparticles for bronchoscopic photodynamic therapy.

Photodynamic therapy is amongst the most rapidly developing therapeutic strategies against cancer. However, most photosensitizers are administered intravenously with very few reports about pulmonary applications. To address this issue, an inhalable formulation consisting of nanoparticles loaded with photosensitizer (i.e. curcumin) was developed. The nanoparticles were prepared using nanoprecipitation method. Dynamic light scattering measurements of the curcumin loaded nanoparticles revealed a hydrodynamic diameter of 181.20 ±â€¯11.52 nm. In vitro irradiation experiments with human lung epithelial carcinoma cells (A549) showed a selective cellular toxicity of the nanoparticles upon activation using LED irradiating device. Moreover, curcumin nanoparticles exhibited a dose-dependent photocytotoxicity and the IC50 values of curcumin were directly dependent on the radiation fluence used. The nanoparticles were subsequently spray dried using mannitol as a stabilizer to produce Nano-in-Microparticles with appropriate aerodynamic properties for a sufficient deposition in the lungs. This was confirmed using the next generation impactor, which revealed a large fine particle fraction (64.94 ±â€¯3.47%) and a mass median aerodynamic diameter of 3.02 ±â€¯0.07 µm. Nano-in-Microparticles exhibited a good redispersibility and disintegrated into the original nanoparticles upon redispersion in aqueous medium. The Langmuir monolayer experiments revealed an excellent compatibility of the nanoparticles with the lung surfactant. Results from this study showed that the Nano-in-Microparticles are promising drug carriers for the photodynamic therapy of lung cancer.

Low level LED photodynamic therapy using curcumin loaded tetraether liposomes.

Oncological use of photodynamic therapy is an evolving field in cancer therapeutics. Photosensitisers are prone to accumulation inside healthy tissues causing undesirable effects. To avoid this, we have developed tetraether lipid liposomal formulations containing curcumin which is a naturally occurring anti-cancer substance and deemed to be safe towards healthy cells. Upon excitation with light at a specific wavelength, curcumin produces reactive oxygen species (ROS) in presence of oxygen, thereby exhibiting a cytotoxic effect towards the surrounding tissues, giving a total control on the onset of therapy. In our study, we examined two different liposomal formulations wherein curcumin is encapsulated within the hydrophobic milieu with the intent to increase its bioavailability. Hydrodynamic diameter, surface charge, stability, morphology and haemocompatibility of the liposomes were studied. The results confirmed the formation of stable nanometre range liposomal vesicles (200-220 nm) containing curcumin which were haemocompatible with coagulation time less than 50 s and a haemolytic potential below 40%. Increased ROS generation post irradiation (>50% compared to un-irradiated samples) was confirmed using fluorescence spectroscopy. The efficiency and selectivity of the PDT was demonstrated by assessing their viability post irradiation and by qualitative analysis using confocal microscopy showing nuclear perforation induced by PDT. Photo-destructive effects of PDT on the microvasculature were studied in vivo using chick chorioallantoic membrane model (CAM). Considerable phototoxicity could be observed in the irradiated area of the CAM 30 min post irradiation. Phototoxic effects in vitro (in SK-OV-3 and PCS-100-020™) and in vivo (in chorioallantoic membrane model) in combination with a novel custom manufactured LED irradiating device showed a formulation dependant selective photodynamic effect of the curcumin liposomes.

Photo-responsive tetraether lipids based vesicles for prophyrin mediated vascular targeting and direct phototherapy.

Tetraether lipids (TELs) derived from the thermoacidophilic archaeon Sulfolobus acidocaldarius are dominated by polyisoprenoid skeleton. The unique molecular stability of TELs is attributed to the presence of cyclopentane rings, methyl side groups and sugar residues that create extensive hydrogen bond network. In addition, the presence of ether linkages and the lacking of double bonds make them an epitome candidate for photodynamic therapy (PDT). A subtle blend of formulation design to trigger efficient photo responses of protoporphyrin IX (PpIX) exploiting TELs was developed. The platform has demonstrated in principle a practical potential in PDT in terms of prompt Vascular Targeting Photodynamic therapy (VTP) in-ovo chick chorioallantoic membrane (CAM) model. Short PpIX-light interval was associated with thrombosis and massive vascular occlusion in and out the irradiated area after TEL9mol% liposomes have been intravenously injected. Profoundly, TEL62mol% liposomes have proved to be the most effective liposomes that demonstrated localized suppression of angiogenesis in the irradiated area without quiescent vasculature damage. The massive thrombotic effect was no longer observed and eventually the chick has survived. After long PpIX-light interval, TEL62mol% has deliberately gained metronomic PDT at low rate of PpIX dosimetry and the radiant exposure doses in human ovarian carcinoma (SKOV-3) cells as determined by PpIXIC50. These findings could be explained by the fact that TELs impart a remarkable stability to the liposomal bilayer that makes them a potential platform for photodynamic applications.

Model membrane approaches to determine the role of calcium for the antimicrobial activity of friulimicin.

Friulimicin is a cyclic lipopeptide antibiotic, currently in clinical development, that possesses excellent activity against Gram-positive bacteria, including multiresistant strains. A recent study on the mode of action of friulimicin reported on the interference with bacterial cell wall biosynthesis via a calcium-dependent complexing of the bactoprenol phosphate carrier C55-P. The calcium dependency of this non-common targeted activity remains to be elucidated. In the present model membrane approach, the role of calcium for friulimicin targeting to C55-P was investigated by biosensor-based detection of binding affinities. The findings were supplemented by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy. Comparing the calcium salt of friulimicin with the calcium-free peptide, calcium appeared to be essential for friulimicin interaction with DOPC model membranes. The binding affinity was even higher in the presence of 0.1 mol% C55-P (0.21 µM vs. 1.22 µM), confirming the targeted mode of action. Binding experiments with supplemented calcium salts suggest (i) the phosphate group as the essential moiety of C55-P, referring to a bridging function of calcium between the negatively charged friulimicin and C55-P, and (ii) a structural effect of calcium shifting the peptide into a suitable binding conformation (CD spectra). AFM images confirmed that calcium has no, or only a minor, effect on the aggregate formation of friulimicin. These data shed new light on the mechanisms of antibacterial activity of friulimicin.