Modulating liposomal nanoparticles to enhance uptake and targeting of methicillin-resistant Staphylococcus aureus.

Aims: To explore the role of modifying the phospholipid composition of liposomal nanoparticles (LNPs) on their uptake. Methods: Different LNPs were labeled with a fluorescent marker and their uptake by human lung fibroblast (WI-38) cells was evaluated using flow cytometry and confocal microscopy. Linezolid was loaded in LNPs showing enhanced uptake, and their ability to reduce intracellular methicillin-resistant Staphylococcus aureus (MRSA) was investigated by in vitro infection. Results: Liposomes with disaturated dipalmitoylphosphatidylcholine-phosphatidylglycerol-phosphatidylethanolamine at a molar ratio of 60:10:10, mimicking that of WI-38 cells, were more effectively uptaken. Linezolid-loaded LNPs significantly reduced intracellular MRSA viable count. Conclusion: Modified LNPs could be promising antibiotic nanocarriers for targeting intracellular MRSA, which are usually resistant to conventional antibiotics.

Liposomal nanoparticles (LNPs) are considered effective drug-delivery nanocarriers. We investigated the effect of altering the phospholipid composition of LNPs on their uptake into lung cells. Intracellular uptake of LNPs with different phospholipids was evaluated. LNPs showing enhanced uptake were loaded with linezolid antibiotic and their potential to kill the intracellular bacteria was explored as the difficulty for an antibiotic to reach the intracellular bacteria results in treatment failure. LNPs with phospholipid composition similar to that of the lung cells were effectively uptaken and were also able to deliver linezolid into lung cells and kill the intracellular bacteria. This approach could be successfully applied to reduce the antibiotic dose and subsequently overcome antibiotic resistance.

Nose-to-brain delivery of galantamine loaded nanospray dried polyacrylic acid/taurodeoxycholate mixed matrix as a protective therapy in lipopolysaccharide-induced Alzheimer's in mice model.

One of the promising drug delivery approaches is performed by nanosizing the administered drug product using the nanospray drying technique. In this study, a combination of several formulation factors was integrated and exploited to augment the bioavailability of galantamine hydrobromide (GAL) via the intranasal route. Nanosized polymeric particles were fabricated using the mucoadhesive polymer, polyacrylic acid (PAA), and the permeability booster, sodium taurodeoxycholate (TDC). First, a preliminary study was conducted to adjust the nanospray drying conditions. Then, formulations were prepared on the basis of a mixed factorial experimental design and further analyzed using Design Expert® software. Different responses were investigated: particle size, polydispersity index, spray rate, drying efficiency, and percent yield. The optimized formulation was further assessed for physical morphology using the scanning electron microscope, flowability, in vitro drug release, and in vivo brain cell uptake using confocal laser scanning microscopy. The promising formulation (F6), composed of equal ratio of PAA and TDC and 20 mg GAL, exhibited a particle size of 185.55 ± 4.3 nm, polydispersity index of 0.413 ± 0.02, and yield-value of 69.58 ± 5.82 %. It also displayed good flowability, complete drug release within 2 h, and enhanced in vivo fluorescent dye uptake and penetration in brain cells. The efficacy of the optimized formulation was examined using lipopolysaccharide-induced Alzheimer's in mice. Results revealed the advantageous influence of the optimized formulation (F6) through downregulation of NF-κß, IL-1ß and GFAP as well as upregulating TGF-1ß in adult mice.

Towards more efficient inhalable chemotherapy: Fabrication of nanodiamonds-releasing microspheres.

Nanodiamonds (NDs) are among the most promising chemotherapy vectors, however, they tend to aggregate upon storage, or when exposed to mild changes in pH or ionic strength. Therefore, fabrication of dried NDs with minimal change in particle size is highly desirable. In this study, we have developed a dried powder form of NDs with controlled particle size to be eligible for pulmonary delivery, after screening different drying protectants for their effect on NDs particle size and surface charge. Results showed that the nanospray-drying process in the presence of mannitol prevented the aggregation of NDs. Nanospray-dried NDs microparticles exhibited an optimal aerodynamic size for pulmonary delivery, and the in vitro aerosol deposition testing showed that NDs-embedded mannitol microspheres could deliver more than half of the emitted fraction to the lower stage of the Twin impinger device; indicating high pulmonary delivery potential. Upon loading NDs with doxorubicin (NDX) prior to spray dryng, they were able to deliver 2.6 times more drug to A549 lung cancer cell line compared to the free drug. Pharmacokinetics study in rats showed that inhaled NDX microparticles could efficiently limit the biodistribution of the drug to the lungs, and minimize the drug fraction reaching the systemic circulation. To conclude, nanospray-dried NDs microparticles present a promising vehicle for the pulmonary delivery of chemotherapeutic agents for treatment of lung cancer.

Single step nanospray drying preparation technique of gabapentin-loaded nanoparticles-mediated brain delivery for effective treatment of PTZ-induced seizures.

In the present study, gabapentin (GBP)-loaded chitosan nanosized particles were fabricated applying the nanospray drying technique. Different preparation parameters (spray mesh diameter, chitosan concentration and presence of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) were studied while fixing other parameters (spraying rate, inlet temperature and gas flow rate). An optimized formulation with a particle size 107 ± 13 nm was obtained upon spraying 0.1% (w/v) chitosan solution containing 0.05% (w/v) of TPGS utilizing the small nozzle (4 µm spray mesh hole size). Drug entrapment efficiency and yield were as high as 95% and 83%, respectively. A 98.1 ± 6.1% (w/w) cumulative drug release was recorded after 2 h. Confocal laser scanning microscopy showed higher fluorescent dye penetration into brain tissue following intranasal administration of Rhodamine B labeled spray dried chitosan nanoparticles (NPs) as compared to Rhodamine B solution. Pentylenetetrazole (PTZ) was used to induce convulsions in rats through elevating seizure stages, releasing neuroinflammatory mediators and reducing excitatory amino acid transporter 2 (EAAT 2) and γ-aminobutyric acid (GABA) brain contents. Nanospray dried GBP-loaded chitosan NPs reduced seizure score, neuroinflammation; TNF-α and TGF-ß, elevated EAAT 2 and GABA as well as decreased degeneration in pyramidal neurons compared to marketed product Conventin® capsules. Thus, it can be concluded from the aforementioned data that nanospray dried GBP-loaded chitosan NPs could comprise an appropriate treatment of epilepsy.

Topical delivery of l-ascorbic acid spanlastics for stability enhancement and treatment of UVB induced damaged skin.

l-Ascorbic acid (LAA) is considered a powerful antioxidant that protects skin from premature aging. Maintaining the stability of vitamin C remains the biggest challenge in cosmeceuticals. Our main aim is the entrapment of high dose of vitamin C in spanlastic vesicles to provide maximum stability and efficacy. LAA-loaded spanlastics were prepared by ethanol injection method and were characterized for entrapment efficiency (EE%), particles size (PS), polydispersity index (PDI), zeta potential, deformability index (DI) and in vivo skin permeation. Selected spanlastics formula composed of span 60 and tween 60 (5:1) showed highest EE% of 89.77 ± 3.61% (w/w), high deformability of 11.13 ± 1.145 as well as good physical and chemical stability for 6 months. Improved drug penetration into stratum corneum (SC) was obtained from spanlastics compared to topical LAA solution. Quantitative real time PCR revealed that MMP2 and MMP9 levels were significantly suppressed in response to LAA spanlastics treated rats by 30.4% and 65.3%, respectively, when compared to the control group after exposure to UV irradiation. Results were confirmed by western blot analysis. Histopathological study of rat skin after UV irradiation revealed that application of LAA-loaded spanlastics provided the highest skin protection compared to UVB and LAA solution treated group which was evident by the normal thick epidermal morphology and the densely arranged dermal collagen fibers. LAA-loaded spanlastics successfully improved LAA stability, skin permeation and antioxidant protection against skin photodamage.

Near IR responsive targeted integrated lipid polymer nanoconstruct for enhanced magnolol cytotoxicity in breast cancer.

Advances in cancer nanotechnology aim at improving specificity and effectiveness for tumor treatment. Amalgamation of different treatment modalities is expected to provide better cancer combating. Herein, We developed a long circulating nanocarrier comprising trastuzumab (TZB) surface modified polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) co-encapsulating magnolol (Mag) and gold nanoparticles (GNPs). A modified single step nanoprecipitation method was adopted ensuring particle coating with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) while co-encapsulating GNPs. TZB was then anchored on NPs surface using a carbodiimide chemistry. The cytotoxicity of the developed system was evaluated with and without photothermal irradiation. NPs cellular uptake was then followed using confocal microscopical imaging. A hybrid matrix composed of PLGA/TPGS and surface decorated with TZB with a conjugation efficiency of ˃65%, was confirmed via FTIR, 1HNMR. GNPs could only be included in the NPs, when placed in the organic phase as evidenced by the shifted GNPs surface plasmonic resonance and confirmed via imaging coupled with energy dispersive X-ray analysis. Optimized NPs (136.1 ± 1.3 nm, -8.2 ± 1 mV and Mag encapsulation efficiency of 81.4 ± 1.8%) were able to boost Mag cytotoxicity on breast cancer cells while providing a selective multifunctional therapy with an added photothermal effect.