Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications

This was a critical review on research conducted in the field of pulmonary delivery of liposomes. Issues related to mechanism of the nebulization and liposome composition were appraised and correlated with the literature reports of liposome formulations used in clinical trials to understand the role of liposome size and composition on therapeutic outcome. A major highlight was the liposome inhalation for the treatment of lung cancers. Many in-vivo studies that explored the potential of liposomes as anticancer carrier systems were evaluated including animal studies and clinical trials. Liposomes can entrap anticancer drugs and localize their action in the lung following pulmonary delivery. Safety of inhaled liposomes incorporating anticancer drug depends on the anticancer agent used and the amount of drug delivered to the target cancer in the lung. The difficulty of efficient targeting of liposomal anticancer aerosols to the cancerous tissues within the lung may result in low dose reaching the target site. Overall, following the success of liposomes as inhalable carriers in the treatment of lung infections, it is expected that more focus from research and development will be given to designing inhalable liposome carriers for the treatment of other lung diseases including pulmonary cancers. Successful development of anticancer liposomes for inhalation may depend on future development of effective aerosolization devices and better targeted liposomes to maximize benefit of therapy and reduce potential of local and systemic adverse effects

An Ethanol-Based Proliposome Technology for Enhanced Delivery and Improved Respirability of Antiasthma Aerosols Generated Using a Micropump Vibrating-Mesh Nebulizer

Salbutamol sulphate liposomes were generated using ethanolbased proliposomes followed by nebulization using an Aeroneb Pro vibrating-mesh nebulizer. The droplet size, output and fine particle fraction (FPF) of the drug incorporated in liposome formulation were compared to those of a conventional drug solution. Aerosol output was determined gravimetrically and drug output was analyzed by using high performance liquid chromatography. The potential of aerosol deposition in deep lung was evaluated using inertial impaction and laser diffraction. The effect of formulation surface tension on the aerosol performance was studied. Output and FPF were improved using liposomes compared to the conventional solution, for instance, FPF values were 57.85% and 45.81% respectively. The volume median diameter as measured by laser diffraction was respectively 3.44 μm and 3.22 μm; however, the higher FPF of the liposome formulation is justified by the lower polydispersity of its aerosol. The improved aerosol performance using liposomes was attributed to the reduction of surface tension caused by the presence of phospholipid. This is the first study that demons trates the ability of liposomes to improve the nebulized drug output and FPF

Proliposome powder or tablets for generating inhalable liposomes using a medical nebulizer

Purpose: The aim of this study was to develop and compare proliposome powder and proliposome tablet formulations for drug delivery from a Pari-LC Sprint nebulizer. Methods: Proliposome powders were prepared by the slurry method and sorbitol or mannitol carbohydrate carrier were used in a 1:10 and 1:15 w/w lipid phase to carrier ratio. Beclometasone dipropionate (BDP; 2 mol%) was incorporated in the lipid phase. Proliposome powders were compressed into tablets, and liposomes were generated from proliposome powders or tablets within the nebulizer reservoir for subsequent aerosolization. Results: Comparatively, shorter sputtering times were reported for the tablet formulations (≈ < 2.7±0.45 min), indicating uniform aerosolization. Post-nebulization, liposomes size was larger in the nebulizer reservoir in the range of 7.79±0.48 µm–9.73±1.53 µm for both powder and tablet formulations as compared to freshly prepared liposomes (5.38±0.73 µm–5.85±0.86 µm), suggesting liposome aggregation/fusion in the nebulizer’s reservoir. All formulations exhibited more than 80% mass output regardless of formulation type, but greater BDP proportions (circa 50%) were delivered to the Two-stage Impinger when tablet formulations were used. Moreover, the nebulized droplet median size and size distribution were lower for all tablet formulations in comparison to the powder formulations. Proliposome tablet and powdered formulations demonstrated the ability to generate vesicles that sustained the release of BDP. Conclusion: Overall, this study showed that proliposome tablets could be disintegrated within a Pari-LC Sprint nebulizer to generate inhalable aerosol, with high drug output and hence can be manufactured on large scale to overcome the storage problems associated with powder formulations

Paclitaxel loaded lipid nanoemulsions for the treatment of brain tumour

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Spray-Dried Proliposome Microparticles for High-Performance Aerosol Delivery Using a Monodose Powder Inhaler

Proliposome formulations containing salbutamol sulphate (SS) were developed using spray drying, and the effects of carrier type (lactose monohydrate (LMH) or mannitol) and lipid to carrier ratio were evaluated. The lipid phase comprised soy phosphatidylcholine (SPC) and cholesterol (1:1), and the ratios of lipid to carrier were 1:2, 1:4, 1:6, 1:8 or 1:10 w/w. X-ray powder diffraction (XRPD) revealed an interaction between the components of the proliposome particles, and scanning electron microscopy (SEM) showed that mannitol-based proliposomes were uniformly sized and spherical, whilst LMH-based proliposomes were irregular and relatively large. Using a two-stage impinger (TSI), fine particle fraction (FPF) values of the proliposomes were higher for mannitol-based formulations, reaching 52.6%, which was attributed to the better flow properties when mannitol was used as carrier. Following hydration of proliposomes, transmission electron microscopy (TEM) demonstrated that vesicles generated from mannitol-based formulations were oligolamellar, whilst LMH-based proliposomes generated ‘worm-like’ structures and vesicle clusters. Vesicle size decreased upon increasing carrier to lipid ratio, and the zeta potential values were negative. Drug entrapment efficiency (EE) was higher for liposomes generated from LMH-based proliposomes, reaching 37.76% when 1:2 lipid to carrier ratio was used. The in vitro drug release profile was similar for both carriers when 1:6 lipid to carrier ratio was used. This study showed that spray drying can produce inhalable proliposome microparticles that can generate liposomes upon contact with an aqueous phase, and the FPF of proliposomes and the EE offered by liposomes were formulation-dependent

Amine functionalization of cholecyst-derived extracellular matrix with generation 1 PAMAM dendrimer

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Biomacromolecules, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/pdf/10.1021/bm701055k.A method to functionalize cholecyst-derived extracellular matrix (CEM) with free amine groups was established in an attempt to improve its potential for tethering of bioactive molecules. CEM was incorporated with Generation-1 polyamidoamine (G1 PAMAM) dendrimer by using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and N-hydroxysuccinimide cross-linking system. The nature of incorporation of PAMAM dendrimer was evaluated using shrink temperature measurements, Fourier transform infrared (FTIR) assessment, ninhydrin assay, and swellability. The effects of PAMAM incorporation on mechanical and degradation properties of CEM were evaluated using a uniaxial mechanical test and collagenase degradation assay, respectively. Ninhydrin assay and FTIR assessment confirmed the presence of increasing free amine groups with increasing quantity of PAMAM in dendrimer-incorporated CEM (DENCEM) scaffolds. The amount of dendrimer used was found to be critical in controlling scaffold degradation, shrink temperature, and free amine content. Cell culture studies showed that fibroblasts seeded on DENCEM maintained their metabolic activity and ability to proliferate in vitro. In addition, fluorescence cell staining and scanning electron microscopy analysis of cell-seeded DENCEM showed preservation of normal fibroblast morphology and phenotype

Proteína G - mecanismos moleculares de comunicação celular

In the present paper the authors commnent on the physiological role of G proteins in transmission signalling process and some alterations of this system. The review is directed to beginners and emphasize a visual approach to the theme.No presente artigo os autores comentam o papel fisiológico das proteínas G no processo de sinalização de transmissão e algumas alterações desses sistemas. A revisão é dirigida a iniciantes e enfatizar uma abordagem visual para o tema

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

open access articleOral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500 μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa

Amlexanox-loaded nanoliposomes showing enhanced anti-inflammatory activity in cultured macrophages: A potential formulation for treatment of oral aphthous stomatitis

Oral aphthous stomatitis is a common disorder treated with the immunomodulatory drug Amlexanox (AMX), that was administered as a mucoadhesive paste (Aphthasol®). This product was discontinued by FDA in 2014 due to the associated undesired adverse reactions of the formulation. Here, we have developed AMX-loaded nanoliposome formulation as a potential alternative for the localised oromucosal delivery of AMX. Nanoliposomes were prepared using Soya phosphatidylcholine (SPC) and Cholesterol (Chol) mixtures at three different molar ratios to formulate vesicles using thin-film hydration, and were characterised for size, zeta potential and entrapment efficiency. The optimal formulation was found to be SPC:Chol 3:1 with drug entrapment efficiency of 94%, post sonication. To evaluate anti-inflammatory activity, macrophages developed by differentiation of human leukaemia monocytic cell line, THP-1, were polarised by Interferon gamma (IFNγ) and lipopolysaccharide (LPS) to M1 state. Macrophages M1 cells treated with D-L1 formulation (SPC:Chol 3:1, 500 μg/mL total lipid, and 27.6 μM AMX) showed a significant suppression in TNF-α expression levels (43 ± 2.7% of untreated control, p < 0.05) compared to those treated with either empty liposomes or AMX alone. Notably, %TNF-α dramatically decreased to 57 ± 4.05% of control, for cells treated with drug-free liposomes (500 μg/mL total lipid) indicating the anti-inflammatory activity of SPC lipid component per se, which led to synergistic effect as evident from the augmentation of AMX anti-inflammatory activity in D-L1 formulation. Our findings highlight the potential of using AMX nanoliposomes as a promising advanced formulation for reviving AMX treatment for management of inflammatory conditions of oral mucosa