Phosphatidylserine liposomes containing curcumin inhibit bone loss in osteoporotic rats: A possible synergy through a common signaling pathway.

The present study aimed to investigate the effect of phosphatidylserine liposomes containing curcumin (PSLs-Cur) on the development of osteoporosis induced by glucocorticoids (GCs) in the rat model. PSL-Cur, phosphatidylserine (PSL), curcumin (Cur), and alendronate (AL) drugs as a positive control were administrated orally to evaluate the beneficial effects of 3-week treatments on osteoporotic rats. The biochemical and biomechanical properties of bone parameters as well as gene expression were evaluated in treated rats. Moreover, histomorphometric examinations were performed on the bone tissues of the animals. The results revealed that PSL-Cur oral administration caused a significant improvement in serum markers, mechanical strength, and OPG gene expression rather than PSL or Cur administration in osteoporotic rats. Also, PSL-Cur significantly increased the thickness and volume of cortical and trabecular bone mass in comparison with the untreated osteoporotic group. The results of this study indicated that PSL-Cur had a more inhibitory effect on bone loss induced by GCs compared to AL standard drug. Our findings suggested that PSL-loaded Cur may be an appropriate alternative therapy for glucocorticoid-induced osteoporosis. PRACTICAL APPLICATIONS: Osteoporosis is one of the most serious metabolic chronic diseases that causes fragile bone due to decreased mineral density and microarchitectural deterioration in humans. The osteoprotective effects of curcumin and phosphatidylserine, as a food spice and supplementary diet, respectively, have been shown, previously. However, the low bioavailability of curcumin (Cur) due to its poor absorption, rapid metabolism, and fast systemic elimination, limits its benefits. This deficit can be modified with phosphatidylserine liposome (PSL) formulation that facilitates the gastrointestinal delivery of Cur. Moreover, PSL is known as an osteoprotective agent that may make synergy effect with Cur against GC-induced osteoporosis. In this study, daily oral administration of phosphatidylserine liposomes containing curcumin (PSL-Cur) for 3 weeks, considerably improved biochemical, biomechanical, and gene expression of bone parameters in the treated animals subjected to osteoporosis. PSL-Cur can significantly increase the thickness and volume of cortical and trabecular bone mass as well as the mechanical bone strength in animals. Experimental findings proposed PSL-Cur consumption as a proper and safe supplementary medication in the controlling of bone loss in patients with a high risk of osteoporosis.

Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study.

AIMS: Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics and pharmacodynamics of glutathione-PEGylated liposomes containing MP (2B3-201). METHODS: The first part was a double-blind, three-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pretreatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in six healthy female subjects. MP plasma concentrations, lymphocyte counts, adrenocorticotropic hormone, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and central nervous system tests. RESULTS: The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37 h and caused a prolonged decrease in the lymphocyte count, adrenocorticotropic hormone and osteocalcin, and a rise in fasting glucose. CONCLUSION: 2B3-201 is considered safe, with no clinically relevant changes in central nervous system safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects.

Irinotecan Delivery by Lipid-Coated Mesoporous Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for Pancreatic Cancer.

Urgent intervention is required to improve the 5 year survival rate of pancreatic ductal adenocarcinoma (PDAC). While the four-drug regimen, FOLFIRINOX (comprising irinotecan, 5-fluorouracil, oxaliplatin, and leucovorin), has a better survival outcome than the more frequently used gemcitabine, the former treatment platform is highly toxic and restricted for use in patients with good performance status. Since irinotecan contributes significantly to FOLFIRINOX toxicity (bone marrow and gastrointestinal tract), our aim was to reduce the toxicity of this drug by a custom-designed mesoporous silica nanoparticle (MSNP) platform, which uses a proton gradient for high-dose irinotecan loading across a coated lipid bilayer (LB). The improved stability of the LB-coated MSNP (LB-MSNP) carrier allowed less drug leakage systemically with increased drug concentrations at the tumor sites of an orthotopic Kras-derived PDAC model compared to liposomes. The LB-MSNP nanocarrier was also more efficient for treating tumor metastases. Equally important, the reduced leakage and slower rate of drug release by the LB-MSNP carrier dramatically reduced the rate of bone marrow, gastrointestinal, and liver toxicity compared to the liposomal carrier. We propose that the combination of high efficacy and reduced toxicity by the LB-MSNP carrier could facilitate the use of irinotecan as a first-line therapeutic to improve PDAC survival.

[Effect of phospholipid composition on pharmaceutical properties and anti-tumor activity of stealth liposomes containing brucine].

OBJECTIVE: To compare the pharmaceutical properties and the anti-tumor activities of three kinds of stealth liposomes prepared with different phospholipid composition containing brucine. METHOD: Stealth liposomes with different phospholipids composition, such as soybean phosphatidycholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC) and the complex of SPC and HSPC, were prepared by ammonium sulfate transmembrane gradient method. Pharmaceutical properties such as shape, encapsulation efficiency and size of three stealth liposomes were compared intensively. Anti-tumor activity of SPC, HSPC and novel stealth liposomes composed of both SPC and HSPC were compared by established mouse liver cancer H22 model. Meanwhile, the mice body weight and immune organ weight were also compared. RESULT: The encapsulation efficiency of novel, SPC and HSPC stealth liposomes were 77.7%, 64.8% and 74.8%, respectively. The mean diameters of them were less than 100 nm. The tumor inhibition rate of novel, HSPC and SPC stealth liposomes were 57.88%, 49.15%, 23.37%, respectively. The mice body weight, thymus gland index of three stealth liposomes group and spleen index of novel stealth liposomes group had no significant difference with the negative group while SPC and HSPC stealth liposomes group increased the spleen index. CONCLUSION: Phospholipids composition is the key factor which determines the antitumor activity of brucine-loaded stealth liposomes.

Preparation and pharmaceutical/pharmacodynamic evaluation of topical brucine-loaded liposomal hydrogel.

To reduce the toxicity and enhance the therapeutic efficacy of brucine, a traditional Chinese medicine for relieving arthritic and traumatic pain, in this study, a novel brucine-loaded liposomal hydrogel (BLH) formulation, suitable for topical application, was developed. Spherical liposomes composed of lecithin and cholesterol, with brucine, was prepared by a modified ethanol-dripping method. High percentage (over 80%) of encapsulated brucine in liposomes was obtained. Topical liposomal hydrogel formulations were prepared by further incorporation of the prepared liposomes into structured carbopol 940 hydrogels with the concentration of carbopol 1.0%, the ratio of glycerol to carbopol 8:1 and the brucine content 0.1%. The liposomal hydrogel formulations provided an obvious promotion for skin permeation of bruicne while for the free brucine in hydrogels (BH), there was no detectable drug permeation through the skin. The safety evaluation showed that the prepared BLH were no irritation to both the broken and integrity skin. Pharmacodynamic evaluation revealed that the BLH showed a better therapeutic efficacy than that of the BH. So, it can be concluded that the BLH developed here could represent a safe, effective and promising transdermal formulation for local treatment of analgesic and anti-inflammatory disease.

In vitro and in vivo evaluation of Bola-surfactant containing niosomes for transdermal delivery.

A novel niosome formulation is proposed for topical drug delivery of ammonium glycyrrhizinate, a natural compound with an efficacious anti-inflammatory activity. Niosomes were made up of a new non ionic surfactant, alpha,omega-hexadecyl-bis-(1-aza-18-crown-6) (Bola-surfactant)-Span 80-cholesterol (2:3:1 molar ratio). Niosome vesicles were prepared with the thin layer evaporation method and were physico-chemically characterized. The tolerability of Bola-surfactant both as free molecules or assembled ion niosome vesicles was evaluated in vitro on cultured of human keratinocyte cells (NCTC2544). Human tolerability was evaluated on volunteers. The ability of Bola-niosomes to promote intracellular delivery was evaluated by confocal laser scanning microscopy (CLSM) studies. Human stratum corneum and epidermis (SCE) membranes were used in vitro to investigate the percutaneous permeation. The anti-inflammatory activity of ammonium glycyrrhizinate was evaluated in vivo on human volunteers with a chemically induced erythema. Experimental data show that Bola-niosomes are characterized by a mean size of approximately 400 nm and are able to provide an encapsulation efficiency of 40% with respect to the drug amount used during preparation. CLSM showed that Bola-niosomes were able to promote the intracellular uptake of the delivered substances. Bola-niosomes were also able to significantly improve (p<0.001) the percutaneous permeation of ammonium glycyrrhizinate with respect to both the aqueous drug solution and a physical mixture between unloaded Bola-niosomes and the aqueous drug solution. Bola-niosomes showed a suitable tolerability both in vitro and in vivo. Ammonium glycyrrhizinate-loaded Bola-niosomes determined a significant (p<0.001) and noticeable improvement of the in vivo anti-inflammatory activity of the drug. An effective example of conjugating innovative colloidal carriers, coming from pharmaceutical nanotechnology, and therapeutically effective natural compounds, coming from traditional medicine, was reported.

Severe hyperphosphatemia resulting from high-dose liposomal amphotericin in a child with leukemia.

Children with acute lymphoblastic leukemia (ALL) are at risk for serious electrolyte abnormalities. The authors report their experience in managing a child with ALL who developed severe hyperphosphatemia as a consequence of a large exogenous load of phosphorus from high-dose liposomal amphotericin B. Health care providers need to recognize this potentially life-threatening complication of liposomal amphotericin B, since early detection and intervention can prevent significant morbidity.