Sorafenib and triptolide loaded cancer cell-platelet hybrid membrane-camouflaged liquid crystalline lipid nanoparticles for the treatment of hepatocellular carcinoma.

In addition to early detection, early diagnosis, and early surgery, it is of great significance to use new strategies for the treatment of hepatocellular carcinoma (HCC). Studies showed that the combination of sorafenib (SFN) and triptolide (TPL) could reduce the clinical dose of SFN and maintain good anti-HCC effect. But the solubility of SFN and TPL in water is low and both drugs have certain toxicity. Therefore, we constructed a biomimetic nanosystem based on cancer cell-platelet (PLT) hybrid membrane camouflage to co-deliver SFN and TPL taking advantage of PLT membrane with long circulation functions and tumor cell membrane with homologous targeting. The biomimetic nanosystem, SFN and TPL loaded cancer cell-PLT hybrid membrane-camouflaged liquid crystalline lipid nanoparticles ((SFN + TPL)@CPLCNPs), could simultaneously load SFN and TPL at the molar ratio of SFN to TPL close to 10:1. (SFN + TPL)@CPLCNPs achieved long circulation function and tumor targeting at the same time, promoting tumor cell apoptosis, inhibiting tumor growth, and achieving a better "synergy and attenuation effect", which provided new ideas for the treatment of HCC.

Pre-clinical evaluation of an innovative oral nano-formulation of baicalein for modulation of radiation responses.

There is an unmet medical need for non-toxic and effective radiation countermeasures for prevention of radiation toxicity during planned exposures. We have earlier shown that intraperitoneal administration of baicalein (BCL) offers significant survival benefit in animal model. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of baicalein has been reported in pre-clinical model systems and also in healthy human volunteers. However, clinical translation of baicalein is hindered owing to poor bioavailability due to lipophilicity. In view of this, we fabricated and characterized in-situ solid lipid nanoparticles of baicalein (SLNB) with effective drug entrapment and release kinetics. SLNB offered significant protection to murine splenic lymphocytes against 4 Gy ionizing radiation (IR) induced apoptosis. Oral administration of SLNB exhibited ~70% protection to mice against whole body irradiation (WBI 7.5 Gy) induced mortality. Oral relative bioavailability of BCL was enhanced by over ~300% after entrapment in the SLNB as compared to BCL. Oral dosing of SLNB resulted in transient increase in neutrophil abundance in peripheral blood. Interestingly, we observed that treatment of human lung cancer cells (A549) with radioprotective dose of SLNB exhibited radio-sensitization as evinced by decrease in survival and clonogenic potential. Contrary to antioxidant nature of baicalein in normal cells, SLNB treatment induced significant increase in cellular ROS levels in A549 cells probably due to higher uptake and inhibition of TrxR. Thus, a pharmaceutically acceptable SLNB exhibited improved bioavailability, better radioprotection to normal cells and sensitized cancer cells to radiation induced killing as compared to BCL suggesting its possible utility as an adjuvant during cancer radiotherapy.

Stability and release performance of curcumin-loaded liposomes with varying content of hydrogenated phospholipids.

The aim of this study was to substitute part of soybean phospholipid (SPC) with hydrogenated soybean phospholipid (HSPC) in curcumin-loaded liposomes (Cur-LP), in order to further enhance stability and release performances of curcumin. When the SPC/HSPC mass ratio changed from 10:0 to 5:5, vesicle size, encapsulation efficiency and alkali resistance of curcumin increased, although a small decrease in centrifugal stability was observed. Salt stability became worse as more HSPC was used (3:7 and 0:10). Owing storage at 4 °C and 25 °C, Cur-LP at a SPC/HSPC mass ratio of 5:5 performed well considering vesicle size, lipid oxidation and curcumin retention. These vesicles displayed also the best sustained-release performance in simulated digestion, attributed to the tighter lipid packing in membranes as indicated by fluorescence probes, DSC and FTIR. This study can guide the development of a Cur-LP product with improved shelf-life stability by using HSPC.

Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

Rationale: The dual-targeted drug delivery system was designed for enhancing permeation of the blood-brain barrier (BBB) and providing an anti-glioma effect. As transferrin receptor (TfR) is over-expressed by the brain capillary endothelial (hCMEC/D3) and glioma cells, a mouse monoclonal antibody, RI7217, with high affinity and selectivity for TfR, was used to study the brain targeted drug delivery system. Muscone, an ingredient of traditional Chinese medicine (TCM) musk, was used as the "guide" drug to probe the permeability of the BBB for drug delivery into the cerebrospinal fluid. This study investigated the combined effects of TCM aromatic resuscitation and modern receptor-targeted technology by the use of muscone/RI7217 co-modified docetaxel (DTX) liposomes for enhanced drug delivery to the brain for anti-glioma effect. Methods: Cellular drug uptake from the formulations was determined using fluorescence microscopy and flow cytometry. The drug penetrating ability into tumor spheroids were visualized using confocal laser scanning microscopy (CLSM). In vivo glioma-targeting ability of formulations was evaluated using whole-body fluorescent imaging system. The survival curve study was performed to evaluate the anti-glioma effect of the formulations. Results: The results showed that muscone and RI7217 co-modified DTX liposomes enhanced uptake into both hCMEC/D3 and U87-MG cells, increased penetration to the deep region of U87-MG tumor spheroids, improved brain targeting in vivo and prolonged survival time of nude mice bearing tumor. Conclusion: Muscone and RI7217 co-modified DTX liposomes were found to show improved brain targeting and enhanced the efficacy of anti-glioma drug treatment in vivo.

Optimization, characterization and evaluation of liposomes from Malus hupehensis (Pamp.) Rehd. extracts.

The Malus hupehensis (Pamp.) Rehd. is a traditional medicine and edible plant. The previous study found that the extracts of M. hupehensis (Pamp.) Rehd. had a good antioxidant activity in vivo and in vitro. But its clinical application was limited by its poor solubility, rapidly metabolized and poor bioavailability. Hence, this article aimed at developing liposomes as a novel transdermal system for delivering M. hupehensis extracts efficiently. The prepared liposomes were characterized regarding their entrapment efficiency percentage (EE%), vesicle size (VS), polydispersity index (PDI), zeta potential (ZP) and drug loading (DL). Box-Behnken design response surface methodology and factorial design were used to optimize formulation and preparation process, respectively. The optimized liposomes had an EE of 77.29 ± 0.99%, VS of 102.74 ± 1.61 nm, ZP of -21.79 ± 1.43 mV, PDI of 0.291 ± 0.005 and DL was 6.68 ± 0.49%. Transmission electron microscopy showed liposomes had a regular spherical surface. In addition, liposomes exhibited superior skin permeation potential and retention capacity compared with solution. Histopathological study ensured the safety of liposome application. Meanwhile, the optimized liposome has a good stability. Hence, M. hupehensis extracts liposomes could be considered a promising vehicle for transdermal delivery.

Proliposomes for oral delivery of total biflavonoids extract from Selaginella doederleinii: formulation development, optimization, and in vitro-in vivo characterization.

PURPOSE: Amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone are five major active ingredients in the total biflavonoids extract from Selaginella doederleinii (TBESD) with favorable anticancer properties. However, the natural-derived potent antitumor agent of TBESD is undesirable due to its poor solubility. The present study was to develop and optimize a proliposomal formulation of TBESD (P-TBESD) to improve its solubility, oral bioavailability and efficacy. MATERIALS AND METHODS: P-TBESD containing a bile salt, a protective hydrophilic isomalto-oligosaccharides (IMOs) coating, were successfully prepared by thin film dispersion-sonication method. The physicochemical and pharmacokinetic properties of P-TBESD were characterized, and the antitumor effect was evaluated using the HT-29 xenograft-bearing mice models in rats. RESULTS: Compared with TBESD, the relative bioavailability of amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone from P-TBESD were 669%, 523%, 761%, 955% and 191%, respectively. The results of pharmacodynamics demonstrated that both TBESD and P-TBESD groups afforded antitumor effect without systemic toxicity, and the antitumor effect of P-TBESD was significantly superior to that of raw TBESD, based on the tumor growth inhibition and histopathological examination. CONCLUSION: Hence, IMOs-modified proliposomes have promising potential for TBESD solving the problem of its poor solubility and oral bioavailability, which can serve as a practical oral preparation for TBESD in the future cancer therapy.

Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies.

The study highlights the significance of co-application of bioactive components into liposomal gel formulations and their comparison to azithromycin for treatment of Acne. A Design of Experiments (DoE) approach was utilized to obtain optimized liposomal formulation encapsulating curcumin, with size and zeta potential of ∼100 nm and ∼14 mV, respectively, characterized by DLS, HR-TEM, FESEM, and AFM. The curcumin liposomal dispersion depicted excellent stability over the period of 60 days, which was further converted in gel form using Carbopol. Pharmacokinetics of curcumin-loaded liposomal gel showed that Tmax for curcumin was achieved within 1 h of post application in both stratum corneum and skin, indicating quick penetration of nano-sized liposomes. Stratum corneum depicted Cmax of 688.3 ng/mL and AUC0-t of 5857.5 h × ng/mL, while the skin samples displayed Cmax of 203.3 ng/gm and AUC0-t of 2938.1 h × ng/gm. Lauric acid and azithromycin liposomal gel formulations were prepared as per the optimum parameters obtained by DoE. In antibacterial activity using agar diffusion assay, lauric acid gel formulation revealed ∼1.5 fold improved antibacterial effect than curcumin gel formulation. Interestingly, their co-application (1:1) exhibited significantly enhanced antibacterial effect against both macrolide-sensitive (1.81 versus 1.25 folds) and resistant strains of P. acnes (2.93 versus 1.22 folds) than their individual counterparts. The in vivo studies in rat ear model displayed a ∼2 fold reduction in comedones count and cytokines (TNF-α and IL-1ß) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.

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.

A comparison study between lycobetaine-loaded nanoemulsion and liposome using nRGD as therapeutic adjuvant for lung cancer therapy.

To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.

Multifunctional Liposomes for Image-Guided Intratumoral Chemo-Phototherapy.

Intratumoral (IT) drug injections reduce systemic toxicity, but delivered volumes and distribution can be inconsistent. To improve IT delivery paradigms, porphyrin-phospholipid (PoP) liposomes are passively loaded with three hydrophilic cargos: sulforhodamine B, a fluorophore; gadolinium-gadopentetic acid, a magnetic resonance (MR) agent; and oxaliplatin, a colorectal cancer chemotherapeutic. Liposome composition is optimized so that cargo is retained in serum and storage, but is released in less than 1 min with exposure to near infrared light. Light-triggered release occurs with PoP-induced photooxidation of unsaturated lipids and all cargos release concurrently. In subcutaneous murine colorectal tumors, drainage of released cargo is delayed when laser treatment occurs 24 h after IT injection, at doses orders of magnitude lower than systemic ones. Delayed light-triggering results in substantial tumor shrinkage relative to controls a week following treatment, although regrowth occurs subsequently. MR imaging reveals that over this time frame, pools of liposomes within the tumor migrate to adjacent regions, possibly leading to altered spatial distribution during triggered drug release. Although further characterization of cargo loading and release is required, this proof-of-principle study suggests that multimodal theranostic IT delivery approaches hold potential to both guide injections and interpret outcomes, in particular when combined with chemo-phototherapy.

In Vitro Permeation and Skin Retention of α-Mangostin Proniosome.

The current investigation evaluated the potential of proniosome as a carrier to enhance skin permeation and skin retention of a highly lipophilic compound, α-mangostin. α-Mangostin proniosomes were prepared using the coacervation phase seperation method. Upon hydration, α-mangostin loaded niosomes were characterized for size, polydispersity index (PDI), entrapment efficiency (EE) and ζ-potential. The in vitro permeation experiments with dermis-split Yucatan Micropig (YMP) skin revealed that proniosomes composed of Spans, soya lecithin and cholesterol were able to enhance the skin permeation of α-mangostin with a factor range from 1.8- to 8.0-fold as compared to the control suspension. Furthermore, incorporation of soya lecithin in the proniosomal formulation significantly enhanced the viable epidermis/dermis (VED) concentration of α-mangostin. All the proniosomal formulations (except for S20L) had significantly (p<0.05) enhanced deposition of α-mangostin in the VED layer with a factor range from 2.5- to 2.9-fold as compared to the control suspension. Since addition of Spans and soya lecithin in water improved the solubility of α-mangostin, this would be related to the enhancement of skin permeation and skin concentration of α-mangostin. The choice of non-ionic surfactant in proniosomes is an important factor governing the skin permeation and skin retention of α-mangostin. These results suggested that proniosomes can be utilized as a carrier for highly lipophilic compound like α-mangostin for topical application.

Microwave-Triggered Smart Drug Release from Liposomes Co-encapsulating Doxorubicin and Salt for Local Combined Hyperthermia and Chemotherapy of Cancer.

The microwave and temperature sensitive liposomes were fabricated successfully from 1,2-dipalmityol-sn-glycero-3-phosphocholine (DPPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) with a molar ratio of 4:1:0.26 by co-encapsulating NaCl and doxorubicin (DOX) through the thin-film hydration method to externally manipulate drug release at a predetermined location in the body at a desired time in the right dosage for combination microwave hyperthermia and chemotherapy of cancer to afford a synergistic therapeutic effect. It was found that the confinement of the high concentration of NaCl ions inside the small size of the liposomes led to a more-rapid temperature elevation than the dissociative ions upon microwave treatment. More than 67.6% doxorubicin was released from the DOX and NaCl co-loaded liposomes (DOX&NaCl@liposomes) upon microwave irradiation for 2 min. After incubation with 2 mg/mL DOX&NaCl@liposomes for 4 h followed by treatment with microwave for 2 min, the inhibition rate of human breast cancer cell MDA-MB-231 was evaluated as 76.1%, much higher than that for NaCl@liposomes (29.8%) and DOX@liposomes (40.2%). The tumor growth inhibition was evaluated to be 73.4% after intravenous injection of DOX&NaCl@liposomes followed by microwave irradiation, much higher than that with only NaCl@liposomes (41.5%) or DOX@liposomes (45.5%) combined with microwave irradiation. Therefore, DOX&NaCl@liposomes could serve as a promising thermochemotherapy nanomedicine for cancer treatment because of its excellent microwave susceptible property and good biocompatibility.

Pulmonary Delivery of Anti-Tubercular Drugs Using Ligand Anchored pH Sensitive Liposomes for the Treatment of Pulmonary Tuberculosis.

BACKGROUND: Mycobacterium tuberculosis (M. TB) remains the prime cause of bacterial mortality and morbidity world-wide. Therefore, effective delivery and targeting of drug to the cellular tropics is essentially required to generate significant results for tuberculosis treatment. The aim of the present study was to develop and characterize ligand anchored pH sensitive liposomes (TPSL) as dry powder inhaler for the targeted delivery of drugs in the target site i.e. lungs. METHOD: Ligand anchored PSL (TPSL) was prepared by thin film hydration for the combined delivery of Isoniazid (INH) and Ciprofloxacin HCl (CIP HCl) using 4-aminophenyl-α-D mannopyranoside (Man) as surface functionalized ligand and characterized using different parameters. RESULTS: It was observed that size of the ligand anchored liposomes (TPSL) was slightly more than the non-ligand anchored liposomes (PSL). Drug release was studied at different pH for 24 hrs and it was observed that liposomes exhibited slow release at alkaline pH (58-64%) as compared to macrophage pH (81-87%) where it increased dramatically due to the destabilization of pH sensitive liposome (PSL). In vitro cellular uptake study showed that much higher concentration was achieved in the alveolar macrophage using ligand anchored liposomes as compared to its counterpart. In vivo study showed that maximum drug accumulation was achieved in the lung by delivering drug using ligand anchored PSL as compared to conventional PSL. CONCLUSION: It was concluded that ligand anchored pH sensitive liposome is one of the promising systems for the targeted drug therapy in pulmonary tuberculosis.

Crossing the barrier: treatment of brain tumors using nanochain particles.

Despite advancements in surgery and radiotherapy, the aggressive forms of brain tumors, such as gliomas, are still uniformly lethal with current therapies offering only palliation complicated by significant toxicities. Gliomas are characteristically diffuse with infiltrating edges, resistant to drugs and nearly inaccessible to systemic therapies due to the brain-tumor barrier. Currently, aggressive efforts are underway to further understand brain-tumor's microenvironment and identify brain tumor cell-specific regulators amenable to pharmacologic interventions. While new potent agents are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. To tackle the drug delivery issues, a multicomponent chain-like nanoparticle has been developed. These nanochains are comprised of iron oxide nanospheres and a drug-loaded liposome chemically linked into a 100-nm linear, chain-like assembly with high precision. The nanochain possesses a unique ability to scavenge the tumor endothelium. By utilizing effective vascular targeting, the nanochains achieve rapid deposition on the vascular bed of glioma sites establishing well-distributed drug reservoirs on the endothelium of brain tumors. After reaching the target sites, an on-command, external low-power radiofrequency field can remotely trigger rapid drug release, due to mechanical disruption of the liposome, facilitating widespread and effective drug delivery into regions harboring brain tumor cells. Integration of the nanochain delivery system with the appropriate combination of complementary drugs has the potential to unfold the field and allow significant expansion of therapies for the disease where success is currently very limited. WIREs Nanomed Nanobiotechnol 2016, 8:678-695. doi: 10.1002/wnan.1387 For further resources related to this article, please visit the WIREs website.

[Tissue distribution of galactosyl daphnoretin liposomes in rats].

To study the tissue distribution of galactosyl daphnoretin liposomes in rats. At the dose of 10 mg•kg⁻¹, daphnoretin solution, daphnoretin liposomes, and galactosyl daphnoretin liposomes were administered to healthy SD rats via tail vein injection. The blood and tissue of heart, liver, spleen, lung, kidney, stomach, small intestine, brain and thymus were collected at 5, 15, 30, 45, 60, 120, 240, 360 min after administration. The concentrations of daphnoretin in plasma and tissue samples were determined by HPLC. The results showed that galactosyl daphnoretin liposomes group had the highest concentration of daphnoretin in liver of unit weight at different time points; and at all of the time points, the target index DTI values of galactosyl daphnoretin liposomes to liver were greater than that of daphnoretin liposomes. Compared with daphnoretin solution, the AUC0-6 and Cmax of galactosyl daphnoretin liposomes in liver were 2.23, 5.22 times, respectively. This indicated that galactosyl daphnoretin liposomes can be concentrated at liver, with a significant liver targeting effect.

Improvement of Antitumor Efficacy by Combination of Thermosensitive Liposome with High-Intensity Focused Ultrasound.

High intensity focused ultrasound (HIFU), allowing for precise heating of the deep and local area, is emerging as the source of mild hyperthermia for delivery of doxorubicin (DOX) using thermosensitive liposomes (TSLs). Conventionally, HIFU has been used for intravascular drug release at tumor tissue by inducing mild hyperthermia immediately upon systemic administration of DOX-TSLs. This immediate heating approach (IHA), however, limits the deep penetration of DOX for high anticancer efficacy. In an attempt to maximize the accumulation of DOX at tumor, the delayed heating approach (DHA) has been explored. In this approach, DOX-TSLs were intravenously administered into the tumor-bearing mice after pre-treatment of tumor tissue with HIFU to increase vascular permeability. We developed the fatty acid-cojugated elastinlike polypeptide bearing TSL (FTSL). The DOX-loaded FTSLs had a hydrodynamic size of 142 nm. In vivo biodistribution study demonstrated that DOX-FTSLs were selectively accumulated at tumor tissue with the maximum amount of DOX at 6 h post-injection. Thereafter, the tumor tissue was heated to 42 °C to induce rapid release of DOX from FTSLs. The results have demonstrated that, compared to IHA, DHA significantly enhances the antitumor efficacy of DOX-FTSLs because of their effective penetration to tumor tissue via the enhanced permeation retention effect, followed by rapid release of DOX.

Current nanotechnological approaches for an effective delivery of bio-active drug molecules in the treatment of acne.

Acne is a chronic inflammatory human skin disease, characterized by areas of skin with seborrhoea, comedones, papules, nodules, pimples, and possibly scarring with lesions occurring on face, neck, and back. Nanotechnological approaches such as particulate (solid lipid nanoparticles and microspheres), vesicular (liposomes and niosomes), colloidal drug delivery systems (micro-emulsion and nano-emulsion), and miscellaneous systems (aerosol foams and micro-sponges) have an important place in acne therapy. These approaches have an enormous opportunity for the designing of a novel, low-dose and effective treatment systems to control acne disease. In this review, we specially focus on the different nanotechnological approaches for an effective treatment of acne.

Liposomal formulations of amphotericin B: differences according to the scientific evidence.

This article presents an overview of the characteristics of liposomes as drug carriers, particularly in relation to liposomal formulations of amphotericin B. General features regarding structure, liposome-cell interactions, stability, encapsulation of active substances and elimination of liposomes are described. Up to the present time extensive efforts to produce similar or bioequivalent products of amphotericin B formulations, in particular in the case of liposomal amphotericin B, have been unsuccessful in spite of having a very similar composition and even an apparently identical manufacturing process. Guidelines for the development of generic liposomal formulations developed by the FDA and EMA are also summarized. Based on the available evidence of the composition of liposomes, any differences in the manufacturing process even if the same lipid composition is used may result in different final products. Therefore, it seems unreasonable to infer that all amphotericin B liposomal formulations are equal in efficacy and safety.

Genotoxicity, acute and subchronic toxicity studies of nano liposomes of Orthosiphon stamineus ethanolic extract in Sprague Dawley rats.

BACKGROUND: Orthosiphon stamineus (OS) Benth is a medicinal plant and native in Southeast Asia. Pharmacological effects of OS are attributed to the presence of lipophilic flavones. However; lipophilic compounds suffer from poor aqueous solubility which limits the OS oral bioavailability and therapeutic applications. Therefore, OS was prepared in nano formulation form using liposomes from soybean phospholipids. The aim of the present study is to evaluate the in vitro genotoxicity and in vivo oral toxicity of nano liposomes of OS ethanolic extract (OS-EL). METHODS: In the acute toxicity study Sprague Dawley female rats were given a single dose of the OS-EL at 5000 mg/kg/day orally and screened for two weeks after administration. In the subchronic study, three different doses of OS-EL were administered for 28 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological parameters were monitored during the study. Genotoxicity was assessed using the Ames test with the TA98 and TA100 Salmonella typhimurium strains. High-performance liquid chromatography was performed for identification and quantification of the major marker compounds in OS-EL. Heavy metal detection was performed using an atomic absorption spectrometer. RESULTS: The acute toxicity study showed that the LD50 of the extract was greater than 5000 mg/kg. In the repeated dose 28-day oral toxicity study, the administration of 250 mg/kg, 500 mg/kg, and 1000 mg/kg/day of OS-EL per body weight revealed no significant difference in food and water consumptions, bodyweight change, haematological and biochemical parameters, relative organ weights, gross findings or histopathology compared to the control group. The Ames test revealed that the OS-EL did not have any potential to induce gene mutations in S. Typhimurium. CONCLUSIONS: Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of OS-EL for 28 days does not cause sub-chronic toxicity.

(177)Lu-Labeled Cerasomes Encapsulating Indocyanine Green for Cancer Theranostics.

This Article reported the fabrication of a robust theranostic cerasome encapsulating indocyanine green (ICG) by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DSPE-PEG2000-DOTA), followed by chelating radioisotope of (177)Lu. Its applications in optical and nuclear imaging of tumor uptake and biodistribution, as well as photothermal killing of cancer cells, were investigated. It was found that the obtained cerasome could act efficiently as fluorescence contrast agent as well as nuclear imaging tracer. Encapsulating ICG into cerasome could protect ICG from degradation, aggregation, and fast elimination from body, resulting in remarkable improvement in near-infrared fluorescence imaging, photothermal stability, and in vivo pharmacokinetic profile. Both fluorescence and nuclear imaging showed that such agent could selectively accumulate in tumor site after intravenous injection of the cerasome agent into Lewis lung carcinoma tumor bearing mice, resulting in efficient photothermal ablation of tumor through a one-time NIR laser irradiation at the best time window. The ability to track the uptake of cerasomes on a whole body basis could provide researchers with an excellent tool for developing cerasome-based drug delivery agents, especially the strategy of labeling cerasomes with theranostic radionuclide (177)Lu, enabling the ability of the (177)Lu-labeled cerasomes for radionuclide cancer therapy and even the combined therapy.