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Advances in Liposome-Based Drug Delivery Systems

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 43842

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Special Issue Editor

Prof. Dr. Zacharias Suntres

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Guest Editor

Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, ON P7B 5E1, Canada
Interests: liposomes; drug delivery systems; antioxidants; antibacterial; anti-inflammatory; chemotherapeutic agents; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liposomes are small artificial vesicular structures composed of one or more phospholipid bilayers enclosing distinct aqueous spaces. They are biocompatible, biodegradable, and essentially non-toxic preparations used as carrier systems to deliver hydrophilic and hydrophobic molecules to target cells or organs. The rationale for developing liposome-based drug formulations is to improve the therapeutic efficacy of drugs by reducing drug toxicity, improving drug solubility and stability, and/or enhancing drug delivery to specific target sites of interest. The diverse application of liposomes as carriers for the delivery of drugs and other molecules has been attributed to the physicochemical and biophysical characteristics of the liposomal membrane. Clinical applications of liposomal drugs include formulations for the treatment of cancer, fungal infections, viral infections, and pain management.

The theme of this Special Issue deals with all aspects of liposomal drug delivery systems including the design, development, and characterization of liposomal drug formulations, their pharmacodynamic and pharmacokinetic properties, and their use as strategies for the prevention or treatment of medical conditions such as cancer, infection, inflammation, oxidant-induced tissue injuries, and dermatological diseases.

Prof. Dr. Zacharias Suntres
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

liposomes
drug delivery
liposome targeting
liposome-based therapeutics
controlled release
liposome technology
encapsulation
active targeting

Published Papers (10 papers)

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Research

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16 pages, 2415 KiB

Open AccessArticle

Liposomal 5-Fluorouracil Polymer Complexes Facilitate Tumor-Specific Delivery: Pharmaco-Distribution Kinetics Using Microdialysis

by Wen Wang, Paul Joyce, Kristen Bremmell, Robert Milne and Clive A. Prestidge

Pharmaceutics 2022, 14(2), 221; https://doi.org/10.3390/pharmaceutics14020221 - 18 Jan 2022

Cited by 6 | Viewed by 3367

Abstract

Liposomes are widely used as carriers for anticancer drugs due to their ability to prolong the retention of encapsulated drugs in blood plasma while directing their distribution increasingly into tumor tissue. We report on the development of stealth liposomal formulations for the common chemotherapy drug 5-fluorouracil, where pharmacokinetic studies were undertaken using a microdialysis probe to specifically quantify drug accumulation in tumor, which was contrasted to drug exposure to healthy tissue. Greater accumulation of the drug into the tumor than into healthy subcutaneous tissue was observed for neutral and cationic liposomal 5-fluorouracil polymer complexes in comparison to the conventional delivery by an injected solution. Increased drug accumulation in tumor also correlated to reduced tumor growth. This research has generated new mechanistic insight into liposomal-specific delivery to tumors with potential to improve the efficacy and reduce the toxicity of chemotherapy. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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25 pages, 4869 KiB

Open AccessArticle

Fabrication and Appraisal of Simvastatin via Tailored Niosomal Nanovesicles for Transdermal Delivery Enhancement: In Vitro and In Vivo Assessment

by Heba F. Salem, Rasha M. Kharshoum, Heba A. Abou-Taleb, Hanan Osman Farouk and Randa Mohammed Zaki

Pharmaceutics 2021, 13(2), 138; https://doi.org/10.3390/pharmaceutics13020138 - 21 Jan 2021

Cited by 31 | Viewed by 2663

Abstract

Simvastatin (SIM) is a HMG-CoA reductase inhibitor employed in the management of hyperlipidemia. However, its low bioavailability limits its clinical efficacy. The objective of this study was to overcome the poor bioavailability of SIM via the transdermal application of a SIM-loaded niosomal gel. Niosomes loaded with SIM were fabricated by means of the thin-film hydration method and optimized through a 3³-factorial design utilizing Design Expert^® software. The prepared niosomes were evaluated for entrapment efficiency (EE%), zeta potential, vesicle size, and cumulative percentage of drug release. The optimum niosomal formulation was loaded on the gel and evaluated for physical properties such as color, clarity, and homogeneity. It was also evaluated for spreadability, and the cumulative % drug release. The best niosomal gel formula was appraised for ex vivo permeation as well as pharmacokinetic study. The SIM-loaded niosomes showed EE% between 66.7–91.4%, vesicle size between 191.1–521.6 nm, and zeta potential ranged between −0.81–+35.6 mv. The cumulative percentage of drug released was ranged from 55% to 94% over 12 h. SIM-loaded niosomal gels were clear, homogenous, spreadable, and the pH values were within the range of physiological skin pH. Furthermore, about 73.5% of SIM was released within 24 h, whereas 409.5 µg/cm² of SIM passed through the skin over 24 h in the ex vivo permeation study. The pharmacokinetic study revealed higher AUC_0–∞ and Cmax with topical application of SIM-loaded niosomal gel compared to topical SIM gel or oral SIM suspension. The topical application of SIM-loaded niosomal gel ascertained the potential percutaneous delivery of SIM. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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27 pages, 5061 KiB

Open AccessArticle

In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy

by Mingjuan Li, M. Ingmar van Raath, Shervin Khakpour, Ahmet Seçilir, Bart C. Sliggers, Xuan Huang, Baoyue Ding, Gert Storm, René R. van der Hulst, Anton I.P.M. de Kroon and Michal Heger

Pharmaceutics 2020, 12(6), 591; https://doi.org/10.3390/pharmaceutics12060591 - 25 Jun 2020

Cited by 3 | Viewed by 3210

Abstract

Antifibrinolytic site-specific pharmaco-laser therapy (SSPLT) is an experimental treatment modality for refractory port wine stains (PWS). Conceptually, antifibrinolytic drugs encapsulated in thermosensitive liposomes are delivered to thrombi that form in semi-photocoagulated PWS blood vessels after conventional laser treatment. Local release of antifibrinolytics is induced by mild hyperthermia, resulting in hyperthrombosis and complete occlusion of the target blood vessel (clinical endpoint). In this study, 20 thermosensitive liposomal formulations containing tranexamic acid (TA) were assayed for physicochemical properties, TA:lipid ratio, encapsulation efficiency, and endovesicular TA concentration. Two candidate formulations (DPPC:DSPE-PEG, DPPC:MPPC:DSPE-PEG) were selected based on optimal properties and analyzed for heat-induced TA release at body temperature (T), phase transition temperature (T_m), and at T > T_m. The effect of plasma on liposomal stability at 37 °C was determined, and the association of liposomes with platelets was examined by flow cytometry. The accumulation of PEGylated phosphocholine liposomes in laser-induced thrombi was investigated in a hamster dorsal skinfold model and intravital fluorescence microscopy. Both formulations did not release TA at 37 °C. Near-complete TA release was achieved at T_m within 2.0–2.5 min of heating, which was accelerated at T > T_m. Plasma exerted a stabilizing effect on both formulations. Liposomes showed mild association with platelets. Despite positive in vitro results, fluorescently labeled liposomes did not sufficiently accumulate in laser-induced thrombi in hamsters to warrant their use in antifibrinolytic SSPLT, which can be solved by coupling thrombus-targeting ligands to the liposomes. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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24 pages, 3066 KiB

Open AccessArticle

Liposomal and Ethosomal Gels for the Topical Delivery of Anthralin: Preparation, Comparative Evaluation and Clinical Assessment in Psoriatic Patients

by Dina Fathalla, Eman M. K. Youssef and Ghareb M. Soliman

Pharmaceutics 2020, 12(5), 446; https://doi.org/10.3390/pharmaceutics12050446 - 11 May 2020

Cited by 80 | Viewed by 6323

Abstract

To enhance anthralin efficacy against psoriasis and reduce its notorious side effects, it was loaded into various liposomal and ethosomal preparations. The nanocarriers were characterized for drug encapsulation efficiency, size, morphology and compatibility between various components. Optimum formulations were dispersed in various gel bases and drug release kinetics were studied. Clinical efficacy and safety of liposomal and ethosomal Pluronic^®F-127 gels were evaluated in patients having psoriasis (clinicaltrials.gov identifier is NCT03348462). Safety was assessed by recording various adverse events. Drug encapsulation efficiency ≥97.2% and ≥77% were obtained for liposomes and ethosomes, respectively. Particle sizes of 116 to 199 nm and 146 to 381 nm were observed for liposomes and ethosomes, respectively. Fourier-Transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) studies confirmed the absence of interaction between anthralin and various nanocarrier components. Tested gel bases showed excellent ability to sustain drug release. At baseline, the patients had a median Psoriasis Area and Severity Index (PASI) of 3.4 for liposomes and 3.6 for ethosomes without significant difference. After treatment, mean PASI change was −68.66% and −81.84% for liposomes and ethosomes, respectively with a significant difference in favor of ethosomes. No adverse effects were detected in both groups. Anthralin ethosomes could be considered as a potential treatment of psoriasis. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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13 pages, 4783 KiB

Open AccessArticle

Anticancer Effect of Metformin in Herceptin-Conjugated Liposome for Breast Cancer

by Ji-Yeon Lee, Dae Hwan Shin and Jin-Seok Kim

Pharmaceutics 2020, 12(1), 11; https://doi.org/10.3390/pharmaceutics12010011 - 20 Dec 2019

Cited by 20 | Viewed by 4005

Abstract

Metformin (MET) is an anti-diabetic drug effective against breast cancer, targeting breast cancer stem cells (BCSCs). MET-encapsulating liposome (LP-MET) and Herceptin-conjugated LP-MET (Her-LP-MET) were evaluated for their anti-cancer effect in vitro and in vivo. Size and zeta potentials of LP-MET and Her-LP-MET were suitable for enhanced permeability and retention effects. Her-LP-MET yielded greater inhibition of BCSC proliferation in vitro than free MET or LP-MET, as well as a dose-dependent long-term anti-proliferation effect. Further, the anti-migration effect of Her-LP-MET on BCSCs was superior to that of MET or LP-MET, and was enhanced when used in concert with doxorubicin (DOX). In a mouse model, Her-LP-MET combined with free DOX was more effective than free MET, free DOX, or Her-LP-MET. Moreover, Her-LP-MET combined with free DOX yielded tumor remission, whereas free DOX alone resulted in metastasis or death. As such, Her-LP-MET formulation is expected to provide a new therapeutic modality targeting BCSCs. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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19 pages, 3627 KiB

Open AccessArticle

Bolalipid-Doped Liposomes: Can Bolalipids Increase the Integrity of Liposomes Exposed to Gastrointestinal Fluids?

by Sindy Müller, Kai Gruhle, Annette Meister, Gerd Hause and Simon Drescher

Pharmaceutics 2019, 11(12), 646; https://doi.org/10.3390/pharmaceutics11120646 - 3 Dec 2019

Cited by 16 | Viewed by 3768

Abstract

The use of archaeal lipids and their artificial analogues, also known as bolalipids, represents a promising approach for the stabilization of classical lipid vesicles for oral application. In a previous study, we investigated the mixing behavior of three single-chain alkyl-branched bolalipids PC-C32(1,32Cn)-PC (n = 3, 6, 9) with either saturated or unsaturated phosphatidyl-cholines. We proved, that the bolalipids PC-C32(1,32C6)-PC and PC-C32(1,32C9)-PC show miscibility with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). In the present work, we extended our vesicle system to natural lipid mixtures using phosphatidylcholine from soy beans, and we investigated the effect of incorporated bolalipids on the integrity of these mixed liposomes (bolasomes) in different gastrointestinal fluids using a dithionite assay and a calcein release assay in combination with particle size measurements. Finally, we also studied the retention of calcein within the bolasomes during freeze-drying. As a main result, we could show that in particular PC-C32(1,32C6)-PC is able to increase the stability of bolasomes in simulated gastric fluid—a prerequisite for the further use of liposomes as oral drug delivery vehicles. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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14 pages, 1975 KiB

Open AccessArticle

Thermosensitive Liposome-Mediated Drug Delivery in Chemotherapy: Mathematical Modelling for Spatio–temporal Drug Distribution and Model-Based Optimisation

by Yu Huang, Boram Gu, Cong Liu, Justin Stebbing, Wladyslaw Gedroyc, Maya Thanou and Xiao Yun Xu

Pharmaceutics 2019, 11(12), 637; https://doi.org/10.3390/pharmaceutics11120637 - 29 Nov 2019

Cited by 12 | Viewed by 2908

Abstract

Thermosensitive liposome-mediated drug delivery has shown promising results in terms of improved therapeutic efficacy and reduced side effects compared to conventional chemotherapeutics. In order to facilitate our understanding of the transport mechanisms and their complex interplays in the drug delivery process, computational models have been developed to simulate the multiple steps involved in liposomal drug delivery to solid tumours. In this study we employ a multicompartmental model for drug-loaded thermosensitive liposomes, with an aim to identify the key transport parameters in determining therapeutic dosing and outcomes. The computational model allows us to not only examine the temporal and spatial variations of drug concentrations in the different compartments by utilising the tumour cord concept, but also assess the therapeutic efficacy and toxicity. In addition, the influences of key factors on systemic plasma concentration and intracellular concentration of the active drug are investigated; these include different chemotherapy drugs, release rate constants and heating duration. Our results show complex relationships between these factors and the predicted therapeutic outcome, making it difficult to identify the “best” parameter set. To overcome this challenge, a model-based optimisation method is proposed in an attempt to find a set of release rate constants and heating duration that can maximise intracellular drug concentration while minimising systemic drug concentration. Optimisation results reveal that under the operating conditions and ranges examined, the best outcome would be achieved with a low drug release rate at physiological temperature, combined with a moderate to high release rate at mild hyperthermia and 1 h heating after injection. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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25 pages, 5385 KiB

Open AccessArticle

Metformin-Encapsulated Liposome Delivery System: An Effective Treatment Approach against Breast Cancer

by Snehal K. Shukla, Nishant S. Kulkarni, Amanda Chan, Vineela Parvathaneni, Pamela Farrales, Aaron Muth and Vivek Gupta

Pharmaceutics 2019, 11(11), 559; https://doi.org/10.3390/pharmaceutics11110559 - 28 Oct 2019

Cited by 57 | Viewed by 5966

Abstract

This study aimed at developing metformin hydrochloride (Met) encapsulated liposomal vesicles for enhanced therapeutic outcomes at reduced doses against breast cancer. Liposomal Met was prepared using thin-film hydration through various loading methods; passive loading, active loading, and drug-loaded lipid film. The drug-loaded film method exhibited maximum entrapment efficiency (~65%) as compared to active loading (~25%) and passive loading (~5%) prepared Met-loaded liposomes. The therapeutic efficacy of these optimized liposomes was evaluated for cellular uptake, cytotoxicity, inhibition of metastatic activity, and apoptosis-inducing activity. Results demonstrated significantly superior activity of positively charged liposomes resulting in reduced IC₅₀ values, minimal cell migration activity, reduced colony formation, and profound apoptosis-induced activity in breast cancer cells as compared to Met. The anti-tumor activity was investigated using a clinically relevant in vitro tumor simulation model, which confirmed enhanced anti-tumorigenic property of liposomal Met over Met itself. To the authors’ knowledge, this is the first report of Met-loaded liposomes for improving the efficacy and therapeutic effect of Met against breast cancer. With the results obtained, it can be speculated that liposomal encapsulation of metformin offers a potentially promising and convenient approach for enhanced efficacy and bioavailability in breast cancer treatment. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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16 pages, 3499 KiB

Open AccessArticle

Modified Spraying Technique and Response Surface Methodology for the Preparation and Optimization of Propolis Liposomes of Enhanced Anti-Proliferative Activity against Human Melanoma Cell Line A375

by Hesham Refaat, Youssef W. Naguib, Mahmoud M. A. Elsayed, Hatem A. A. Sarhan and Eman Alaaeldin

Pharmaceutics 2019, 11(11), 558; https://doi.org/10.3390/pharmaceutics11110558 - 28 Oct 2019

Cited by 36 | Viewed by 3847

Abstract

Propolis is a honeybee product that contains a mixture of natural substances with a broad spectrum of biological activities. However, the clinical application of propolis is limited due to the presence of a myriad of constituents with different physicochemical properties, low bioavailability and lack of appropriate formulations. In this study, a modified injection technique (spraying technique) has been developed for the encapsulation of the Egyptian propolis within liposomal formulation. The effects of three variables (lipid molar concentration, drug loading and cholesterol percentage) on the particle size and poly dispersity index (PDI) were studied using response surface methodology and the Box–Behnken design. Response surface diagrams were used to develop an optimized liposomal formulation of the Egyptian propolis. A comparative study between the optimized liposomal formulation prepared either by the typical ethanol injection method (TEIM) or the spraying method in terms of particle size, PDI and the in-vitro anti-proliferative effect against human melanoma cell line A375 was carried out. The spraying method resulted in the formation of smaller propolis-loaded liposomes compared to TEIM (particle sizes of 90 ± 6.2 nm, and 170 ± 14.7 nm, respectively). Furthermore, the IC50 values against A375 cells were found to be 3.04 ± 0.14, 4.5 ± 0.09, and 18.06 ± 0.75 for spray-prepared propolis liposomes (PP-Lip), TEIM PP-Lip, and propolis extract (PE), respectively. The encapsulation of PE into liposomes is expected to improve its cellular uptake by endocytosis. Moreover, smaller and more uniform liposomes obtained by spraying can be expected to achieve higher cellular uptake, as the ratio of liposomes or liposomal aggregates that fall above the capacity of cell membrane to “wrap” them will be minimized. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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Review

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28 pages, 2763 KiB

Open AccessReview

Formulation Strategies for Folate-Targeted Liposomes and Their Biomedical Applications

by Parveen Kumar, Peipei Huo and Bo Liu

Pharmaceutics 2019, 11(8), 381; https://doi.org/10.3390/pharmaceutics11080381 - 2 Aug 2019

Cited by 74 | Viewed by 6337

Abstract

The folate receptor (FR) is a tumor-associated antigen that can bind with folic acid (FA) and its conjugates with high affinity and ingests the bound molecules inside the cell via the endocytic mechanism. A wide variety of payloads can be delivered to FR-overexpressed cells using folate as the ligand, ranging from small drug molecules to large DNA-containing macromolecules. A broad range of folate attached liposomes have been proven to be highly effective as the targeted delivery system. For the rational design of folate-targeted liposomes, an intense conceptual understanding combining chemical and biomedical points of view is necessary because of the interdisciplinary nature of the field. The fabrication of the folate-conjugated liposomes basically involves the attachment of FA with phospholipids, cholesterol or peptides before liposomal formulation. The present review aims to provide detailed information about the design and fabrication of folate-conjugated liposomes using FA attached uncleavable/cleavable phospholipids, cholesterol or peptides. Advances in the area of folate-targeted liposomes and their biomedical applications have also been discussed. Full article

(This article belongs to the Special Issue Advances in Liposome-Based Drug Delivery Systems)

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