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

Paclitaxel loaded lipid nanoemulsions for the treatment of brain tumour

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PEGylated graphene oxide for tumor-targeted delivery of paclitaxel.

AIM: The graphene oxide (GO) sheet has been considered one of the most promising carbon derivatives in the field of material science for the past few years and has shown excellent tumor-targeting ability, biocompatibility and low toxicity. We have endeavored to conjugate paclitaxel (PTX) to GO molecule and investigate its anticancer efficacy. MATERIALS & METHODS: We conjugated the anticancer drug PTX to aminated PEG chains on GO sheets through covalent bonds to get GO-PEG-PTX complexes. The tissue distribution and anticancer efficacy of GO-PEG-PTX were then investigated using a B16 melanoma cancer-bearing C57 mice model. RESULTS: The GO-PEG-PTX complexes exhibited excellent water solubility and biocompatibility. Compared with the traditional formulation of PTX (Taxol®), GO-PEG-PTX has shown prolonged blood circulation time as well as high tumor-targeting and -suppressing efficacy. CONCLUSION: PEGylated graphene oxide is an excellent nanocarrier for paclitaxel for cancer targeting

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

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

Studies of the Precipitation Pattern of Paclitaxel in Intravenous Infusions and Rat Plasma Using Laser Nephelometry

Cremophor EL (CrEL) is commonly used to solubilize paclitaxel (Ptx); a widely established anticancer agent used against many types of cancer. Using laser-based microplate nephelometry, in this work we assessed the precipitation kinetics of Ptx in CrEL-containing formulations upon dilutions with different infusion media or upon introduction into rat plasma. The precipitation profile of Ptx was assessed for a Taxol-like formulation and compared with a preparation with reduced CrEL content. These two formulations were diluted at various ratios in compatible infusion media and with or without rat plasma. The percentages of Ptx precipitated in dilution media and protein-binding in plasma were quantified using HPLC. The findings of turbidity measurements were in good agreement with HPLC. Despite the presence of albumin, it was possible to assess turbidity within infusion solutions and predict Ptx precipitation. Upon addition to plasma, no precipitation in Taxol-like formulation occurred after 2 h. In contrast, precipitation occurred immediately in CrEL-reduced formulation. It is possible that the high percentage of protein-bound Ptx in plasma (98.5–99.2%) has inhibited drug precipitation. Turbidity measurements using laser nephelometry can provide a rapid screening tool when developing intravenous formulations for poorly soluble drugs, such as Ptx and assess its stability upon dilution in animal plasma

Liposome Mediated-CYP1A1 Gene Silencing Nanomedicine Prepared Using Lipid Film-Coated Proliposomes as a Potential Treatment Strategy of Lung Cancer

The occurrence of lung cancer is linked with tobacco smoking, mainly through the generation of polycyclic aromatic hydrocarbons (PAHs). Elevated activity of cytochrome P4501A1 (CYP1A1) plays an important role in the metabolic processing of PAHs and its carcinogenicity. The present work aimed to investigate the role of CYP1A1 gene in PAH-mediated growth and tumor development in vitro and using an in vivo animal model. RNAi strategy was utilized to inhibit the overexpression of CYP1A1 gene using cationic liposomes generated using a lipid film-coated proliposome microparticles. Treatment of PAH-induced human alveolar adenocarcinoma cell line with cationic liposomes carrying CYP1A1 siRNA resulted in down regulation of CYP1A1 mRNA, protein as well as its enzymatic activity, triggering apoptosis and inhibiting multicellular tumor spheroids formation in vitro. Furthermore, silencing of CYP1A1 gene in BALB/c nude xenografts inhibited tumor growth via down regulation of CYP1A1 expression. Altogether, our findings showed that liposome-based gene delivery technology is a viable and stable approach for targeting cancer causing genes such as CY1PA1. This technology facilitated by the use of sugar particles coated with lipid films has demonstrated ability to generate anticancer effects that might be used in the future for therapeutic intervention and treatment of lung cancer. [Abstract copyright: Copyright © 2019. Published by Elsevier B.V.

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