Liposome-based Drug Delivery Systems Research Articles

Liposome-Based Drug Delivery Systems in Cancer Research: An Analysis of Global Landscape Efforts and Achievements.

Lipid-bilayer-based liposomes are gaining attention in scientific research for their versatile role in drug delivery. With their amphiphilic design, liposomes efficiently encapsulate and deliver drugs to targeted sites, offering controlled release. These artificial structures hold great promise in advancing cancer therapy methodologies. Bibliometric research analyzes systematic literary data statistically. This study used bibliometric indicators to examine, map, and evaluate the applications of liposomes in cancer therapy. A Scopus search was conducted to identify all English-language peer-reviewed scientific publications on the applications of liposomes in cancer therapy within the past twenty years. Bibliometric indicators were calculated using VOSviewer and Biblioshiny. We produced thematic, conceptual, and visualization charts. A total of 14,873 published documents were obtained. The procedure of keyword mapping has effectively identified the main areas of research concentration and prevailing trends within this specific field of study. The significant clusters discovered through theme and hotspot analyses encompassed many topics such as the use of multiple strategies in chemotherapy and different forms of cancer, the study of pharmacokinetics and nanomedicine, as well as the investigation of targeted drug delivery, cytotoxicity, and gene delivery. Liposomes were employed as drug delivery systems so as to selectively target cancer cells and improve the bioavailability of anticancer drugs. The work showcased the capacity to tailor these liposomes for accurate drug delivery by including potent anticancer medications. Our findings not only bring attention to the latest progress in utilizing liposomes for cancer treatment but also underscore the vital need for ongoing research, collaborative efforts, and the effective translation of these breakthroughs into tangible clinical applications, emphasizing the dynamic and evolving nature of cancer therapeutics.

Engineered triphenylphosphonium-based, mitochondrial-targeted liposomal drug delivery system facilitates cancer cell killing actions of chemotherapeutics.

In addition to their classical role in ATP generation, mitochondria also contribute to Ca2+ buffering, free radical production, and initiation of programmed cell death. Mitochondrial dysfunction has been linked to several leading causes of morbidity and mortality worldwide including neurodegenerative, metabolic, and cardiovascular diseases as well as several cancer subtypes. Thus, there is growing interest in developing drug-delivery vehicles capable of shuttling therapeutics directly to the mitochondria. Here, we functionalized the conventional 10,12-pentacosadiynoic acid/1,2-dimyristoyl-sn-glycero-3-phosphocholine (PCDA/DMPC)-based liposome with a mitochondria-targeting triphenylphosphonium (TPP) cationic group. A fluorescent dansyl dye (DAN) group was also included for tracking mitochondrial drug uptake. The resultant PCDA-TPP and PCDA-DAN conjugates were incorporated into a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based lipid bilayer, and these modified liposomes (Lip-DT) were studied for their cellular toxicity, mitochondrial targeting ability, and efficacy in delivering the drug Doxorubicin (Dox) to human colorectal carcinoma (HCT116) and human breast (MCF7) cancer cells in vitro. This Lip-DT-Dox exhibited the ability to shuttle the encapsulated drug to the mitochondria of cancer cells and triggered oxidative stress, mitochondrial dysfunction, and apoptosis. The ability of Lip-DT-Dox to trigger cellular toxicity in both HCT116 and MCF7 cancer cells was comparable to the known cell-killing actions of the unencapsulated drug (Dox). The findings in this study reveal a promising approach where conventional liposome-based drug delivery systems can be rendered mitochondria-specific by incorporating well-known mitochondriotropic moieties onto the surface of the liposome.

Aromatized liposomes for sustained drug delivery

Insufficient drug loading and leakage of payload remain major challenges in designing liposome-based drug delivery systems. These phenomena can limit duration of effect and cause toxicity. Targeting the rate-limiting step in drug release from liposomes, we modify (aromatized) them to have aromatic groups within their lipid bilayers. Aromatized liposomes are designed with synthetic phospholipids with aromatic groups covalently conjugated onto acyl chains. The optimized aromatized liposome increases drug loading and significantly decreases the burst release of a broad range of payloads (small molecules and macromolecules, different degrees of hydrophilicity) and extends their duration of release. Aromatized liposomes encapsulating the anesthetic tetrodotoxin (TTX) achieve markedly prolonged effect and decreased toxicity in an application where liposomes are used clinically: local anesthesia, even though TTX is a hydrophilic small molecule which is typically difficult to encapsulate. Aromatization of lipid bilayers can improve the performance of liposomal drug delivery systems.

Formulation and Characterization of Griseofulvin Liposome Loaded Topical Film

This research paper explores the formulation and characterization of a liposome-loaded topical film containing griseofulvin, an antifungal drug. Liposome-based drug delivery systems offer enhanced drug concentration, prolonged residence time, and reduced side effects. This study aims to improve the efficacy of griseofulvin by incorporating it into liposomes and formulating it into a topical film for transdermal delivery. Liposomes were used as carriers to encapsulate Griseofulvin and incorporated into a topical film for ease of application. The paper reviews the principles of liposome-based drug delivery, transdermal film technology, and the potential benefits of this approach. The work plan includes preformulation studies, liposome preparation and evaluation, formulation of liposome-loaded topical films, and evaluation of film properties. The results demonstrated that the developed formulation has the potential to improve the delivery and efficacy of Griseofulvin in the treatment of cutaneous fungal infections.

NANOPARTICLE BASED DRUG DELIVERY SYSTEMS FOR TARGETING TUMOR MICRO ENVIRONMENT

Nanoparticle-based drug delivery systems have emerged as promising tools in cancer therapy, offering enhanced precision and effectiveness in targeting tumor cells while minimizing damage to healthy tissues. This review provides a comprehensive exploration of the tumor microenvironment, emphasizing its critical role in cancer progression. It highlights the significance of targeted drug delivery in improving treatment outcomes and introduces nanoparticle-based delivery systems as innovative strategies to address these challenges. The first section delves into various types of nanoparticles used for tumor targeting. Liposomes, known for their versatility and biocompatibility, are discussed alongside examples of liposome-based drug delivery systems tailored for tumor-specific applications. Polymeric nanoparticles, employing a range of polymers, offer unique advantages and applications in tumor targeting. Metallic nanoparticles, with distinctive properties, have shown promise in drug delivery systems designed to target tumors effectively.

Insights into Asymmetric Liposomes as a Potential Intervention for Drug Delivery Including Pulmonary Nanotherapeutics

Liposome-based drug delivery systems are nanosized spherical lipid bilayer carriers that can encapsulate a broad range of small drug molecules (hydrophilic and hydrophobic drugs) and large drug molecules (peptides, proteins, and nucleic acids). They have unique characteristics, such as a self-assembling bilayer vesicular structure. There are several FDA-approved liposomal-based medicines for treatment of cancer, bacterial, and viral infections. Most of the FDA-approved liposomal-based therapies are in the form of conventional "symmetric" liposomes and they are administered mainly by injection. Arikace® is the first and only FDA-approved liposomal-based inhalable therapy (amikacin liposome inhalation suspension) to treat only adults with difficult-to-treat Mycobacterium avium complex (MAC) lung disease as a combinational antibacterial treatment. To date, no "asymmetric liposomes" are yet to be approved, although asymmetric liposomes have many advantages due to the asymmetric distribution of lipids through the liposome's membrane (which is similar to the biological membranes). There are many challenges for the formulation and stability of asymmetric liposomes. This review will focus on asymmetric liposomes in contrast to conventional liposomes as a potential clinical intervention drug delivery system as well as the formulation techniques available for symmetric and asymmetric liposomes. The review aims to renew the research in liposomal nanovesicle delivery systems with particular emphasis on asymmetric liposomes as future potential carriers for enhancing drug delivery including pulmonary nanotherapeutics.

Interaction of Phospholipid, Cholesterol, Beta-Carotene, and Vitamin C Molecules in Liposome-Based Drug Delivery Systems: An In Silico Study.

This paper investigates the interaction within a liposome-based drug delivery system in silico. Results confirmed that phospholipids, cholesterol, beta-carotene, and vitamin C in the liposome structures interact noncovalently. The formation of noncovalent interactions indicates that the liposomal structures from phospholipid molecules will not result in chemical changes to the drug or any molecules encapsulated within. Noncovalent interactions formed include (i) moderate-strength hydrogen bonds with interaction energies ranging from -73.6434 kJ·mol-1 to -45.6734 kJ·mol-1 and bond lengths ranging from 1.731 Å to 1.827 Å and (ii) van der Waals interactions (induced dipole-induced dipole and induced dipole-dipole interactions) with interaction energies ranging from -4.4735 kJ·mol-1 to -1.5840 kJ·mol-1 and bond lengths ranging from 3.192 Å to 3.742 Å. The studies for several phospholipids with short hydrocarbon chains show that changes in chain length have almost no effect on interaction energy, bond length, and partial atomic charge.

Interaction of GC376, a SARS-COV-2 MPRO inhibitor, with model lipid membranes

Partitioning and effect of antiviral GC376, a potential SARS-CoV-2 inhibitor, on model lipid membranes was studied using dynamic light scattering (DLS), UV–VIS spectrometry, Excimer fluorescence, Differential scanning calorimetry (DSC) and Small- and Wide-angle X-ray scattering (SAXS/WAXS). Partition coefficient of GC376 between lipid and water phase was found to be low, reaching KP = 46.8 ± 18.2. Results suggest that GC376 partitions into lipid bilayers at the level of lipid head-groups, close to the polar/hydrophobic interface. Changes in structural and thermodynamic properties strongly depend on the GC376/lipid mole ratio. Already at lowest mole ratios GC376 induces increase of lateral pressures, mainly in the interfacial region of the bilayer. Hereby, the pre- and main-transition temperature of the lipid system increases, what is attributed to tighter packing of acyl chains induced by GC376. At GC376/DPPC ≥ 0.03 mol/mol we detected formation of domains with different GC376 content resulting in the lateral phase separation and changes in both, main transition temperature and enthalpy. The observed changes are attributed to the response of the system on the increased lateral stresses induced by partitioning of GC376. Obtained results are discussed in context of liposome-based drug delivery systems for GC376 and in context of indirect mechanism of virus replication inhibition.

Peptide-Folding Triggered Phase Separation and Lipid Membrane Destabilization in Cholesterol-Rich Lipid Vesicles

Liposome-based drug delivery systems are widely used to improve drug pharmacokinetics but can suffer from slow and unspecific release of encapsulated drugs. Membrane-active peptides, based on sequences derived or inspired from antimicrobial peptides (AMPs), could offer means to trigger and control the release. Cholesterol is used in most liposomal drug delivery systems (DDS) to improve the stability of the formulation, but the activity of AMPs on cholesterol-rich membranes tends to be very low, complicating peptide-triggered release strategies. Here, we show a de novo designed AMP-mimetic peptide that efficiently triggers content release from cholesterol-containing lipid vesicles when covalently conjugated to headgroup-functionalized lipids. Binding to vesicles induces peptide folding and triggers a lipid phase separation, which in the presence of cholesterol results in high local peptide concentrations at the lipid bilayer surface and rapid content release. We anticipate that these results will facilitate the development of peptide-based strategies for controlling and triggering drug release from liposomal drug delivery systems.

Influence of Acetaminophen on Molecular Adsorption and Transport Properties at Colloidal Liposome Surfaces Studied by Second Harmonic Generation Spectroscopy.

Time-resolved second harmonic generation (SHG) spectroscopy is used to investigate acetaminophen (APAP)-induced changes in the adsorption and transport properties of malachite green isothiocyanate (MGITC) dye to the surface of unilamellar 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes in an aqueous colloidal suspension. The adsorption of MGITC to DOPC liposome nanoparticles in water is driven by electrostatic and dipole–dipole interactions between the positively charged MGITC molecules and the zwitterionic phospholipid membranes. The SHG intensity increases as the added MGITC dye concentration is increased, reaching a maximum as the MGITC adsorbate at the DOPC bilayer interface approaches a saturation value. The experimental adsorption isotherms are fit using the modified Langmuir model to obtain the adsorption free energies, adsorption equilibrium constants, and the adsorbate site densities to the DOPC liposomes both with and without APAP. The addition of APAP is shown to increase MGITC adsorption to the liposome interface, resulting in a larger adsorption equilibrium constant and a higher adsorption site density. The MGITC transport times are also measured, showing that APAP decreases the transport rate across the DOPC liposome bilayer, especially at higher MGITC concentrations. Studying molecular interactions at the colloidal liposome interface using SHG spectroscopy provides a detailed foundation for developing potential liposome-based drug-delivery systems.

Liposome-based delivery of biological drugs

Biological drugs are attracting tremendous attention in disease treatment. However, their application is significantly limited by their inherent properties, such as high hydrophilicity, poor membrane-permeability, low stability, and larger size. Liposome-based drug delivery systems are emerging as promising tools to improve their delivery, owing to their ability to reduce toxicity, improve bioavailability, and enhance the therapeutic efficacy of the drug by optimizing delivery to the specific target site. Here, we reviewed the types of liposomes and their applications as carriers for biological drugs to treat various diseases, emphasized the commercial products, and ultimately provided perspectives in this field.

Recent advances with liposomes as drug carriers for treatment of neurodegenerative diseases.

A major challenge in treating neurogenerative diseases is delivering drugs across the blood-brain barrier (BBB). In this review, we summarized the development of liposome-based drug delivery system with enhanced BBB penetration for efficient brain drug delivery. We focused on the liposome-based therapeutics targeting Alzheimer's disease and Parkinson's disease because they are most common types of adult chronic neurodegenerative disorders. A variety of liposome with surface modification of BBB-targeting ligands have been created to cross the BBB via transcytosis to the therapeutic efficacy of Alzheimer's disease and Parkinson's disease drugs. Recent advances in liposome are providing alternatives to overcome BBB for more efficient therapeutic strategy. To improve the BBB penetration of liposomes, we need to completely understand the pathophysiological changes at the BBB.

Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations.

Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE–CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

Multifunctional Liposomes Enable Active Targeting and Twinfilin 1 Silencing to Reverse Paclitaxel Resistance in Brain Metastatic Breast Cancer.

Paclitaxel (PTX) is a first-line chemotherapeutic drug for breast cancer, but PTX resistance often occurs in metastatic breast cancer. In addition, due to the poor targeting of chemotherapeutic drugs and the presence of the blood-brain barrier (BBB), it is hard to effectively treat brain metastatic breast cancer using paclitaxel. Thus, it is urgent to develop an effective drug delivery system for the treatment of brain metastatic breast cancer. The current study found that TWF1 gene, an epithelial-mesenchymal transition-associated gene, was overexpressed in brain metastatic breast cancer (231-BR) cells and was associated with the PTX resistance of 231-BR cells. Knockdown of TWF1 by small interference RNA (siRNA) in 231-BR cells could effectively increase the sensitivity of brain metastatic breast cancer cells to paclitaxel. Then, a liposome-based drug delivery system was developed for PTX delivery across BBB, enhancing PTX sensitivity and brain metastases targeting via BRBP1 peptide modification. The results showed that BRBP1-modified liposomes could effectively cross the BBB, specifically accumulate in brain metastases, and effectively interfere TWF1 gene expression in vitro and in vivo, and thus they enhanced proliferation inhibition, cell cycle arrest, and apoptosis induction, thereby inhibiting the formation and growth of brain metastases. In summary, our results indicated that BRBP1-modified and PTX- and TWF1 siRNA-loaded liposomes have the potential for the treatment of brain metastatic breast cancer, which lays the foundation for the development of a new targeted drug delivery system.

When Albumin Meets Liposomes: A Feasible Drug Carrier for Biomedical Applications.

Albumin, the most abundant protein in plasma, possesses some inherent beneficial structural and physiological characteristics that make it suitable for use as a drug delivery agent, such as an extraordinary drug-binding capacity and long blood retention, with a high biocompatibility. The use of these characteristics as a nanoparticle drug delivery system (DDS) offers several advantages, including a longer circulation time, lower toxicity, and more significant drug loading. To date, many innovative liposome preparations have been developed in which albumin is involved as a DDS. These novel albumin-containing liposome preparations show superior deliverability for genes, hydrophilic/hydrophobic substances and proteins/peptides to the targeting area compared to original liposomes by virtue of their high biocompatibility, stability, effective loading content, and the capacity for targeting. This review summarizes the current status of albumin applications in liposome-based DDS, focusing on albumin-coated liposomes and albumin-encapsulated liposomes as a DDS carrier for potential medical applications.

Optimized 5-Fluorouridine Prodrug for Co-Loading with Doxorubicin in Clinically Relevant Liposomes.

Liposome-based drug delivery systems have allowed for better drug tolerability and longer circulation times but are often optimized for a single agent due to the inherent difficulty of co-encapsulating two drugs with differing chemical profiles. Here, we design and test a prodrug based on a ribosylated nucleoside form of 5-fluorouracil, 5-fluorouridine (5FUR), with the final purpose of co-encapsulation with doxorubicin (DOX) in liposomes. To improve the loading of 5FUR, we developed two 5FUR prodrugs that involved the conjugation of either one or three moieties of tryptophan (W) known respectively as, 5FUR−W and 5FUR−W3. 5FUR−W demonstrated greater chemical stability than 5FUR−W3 and allowed for improved loading with fewer possible byproducts from tryptophan hydrolysis. Varied drug ratios of 5FUR−W: DOX were encapsulated for in vivo testing in the highly aggressive 4T1 murine breast cancer model. A liposomal molar ratio of 2.5 5FUR−W: DOX achieved a 62.6% reduction in tumor size compared to the untreated control group and a 33% reduction compared to clinical doxorubicin liposomes in a proof-of-concept study to demonstrate the viability of the co-encapsulated liposomes. We believe that the new prodrug 5FUR−W demonstrates a prodrug design with clinical translatability by reducing the number of byproducts produced by the hydrolysis of tryptophan, while also allowing for loading flexibility.

Liposome-Based Drug Delivery Systems in Cancer Immunotherapy.

Cancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even stronger immune responses by improving cell type-specific delivery and enhancing drug efficacy. Liposomes can offer solutions to common problems faced by several cancer immunotherapies, including the following: (1) Vaccination: Liposomes can improve the delivery of antigens and other stimulatory molecules to antigen-presenting cells or T cells; (2) Tumor normalization: Liposomes can deliver drugs selectively to the tumor microenvironment to overcome the immune-suppressive state; (3) Rewiring of tumor signaling: Liposomes can be used for the delivery of specific drugs to specific cell types to correct or modulate pathways to facilitate better anti-tumor immune responses; (4) Combinational therapy: Liposomes are ideal vehicles for the simultaneous delivery of drugs to be combined with other therapies, including chemotherapy, radiotherapy, and phototherapy. In this review, different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed.

Thermosensitive Liposomes Encapsulating Anti-Cancer Agent Lomustine, and Contrast Medium Iohexol, for Thermochemotherapy: Preparation, Characterization, and In Vivo Evaluation.

Thermosensitive liposome-based drug delivery systems (DDS) are powerful tools for site-specific delivery of chemotherapeutics, especially when combined with regional hyperthermia. The objective of this work was to develop a novel thermosensitive liposomal DDS loaded with lomustine, a chemotherapeutic compound, and iohexol, a contrast medium for visualization by CT. Thermosensitive compound liposomes (TSCLs) composed of DPPC were prepared by reverse-phase evaporation and investigated for encapsulation efficiency, temperature-sensitivity, release kinetics, and In Vivo pharmacokinetics. The size and zeta-potential of TSCLs ranged from 250 to 300 nm and -15 to -30 mV, respectively. At 41 °C, TSCLs were shown to release over 90% of iohexol and lomustine within 4 h. The in vitro release profiles of iohexol and lomustine at 41 °C conformed to first-order kinetics and Weibullmodel, respectively. Phase-transition did not occur after incorporation of cholesterol and soybean phospholipids. In Vivo evaluation performed with C6 glioma model rats proved the prolonged half-lives and improved bioavailability by liposomal encapsulation for both compounds under mild local hyperthermia. The TSCLs used in this study may offer a clinically promising mean of increasing efficacy and controlling toxicity.

Liposome-based targeting of dopamine to the brain: a novel approach for the treatment of Parkinson's disease.

Delivery of drugs into the brain is poor due to the blood brain barrier (BBB). This study describes the development of a novel liposome-based brain-targeting drug delivery system. The liposomes incorporate a diacylglycerol moiety coupled through a linker to a peptide of 5 amino acids selected from amyloid precursor protein (APP), which is recognized by specific transporter(s)/receptor(s) in the BBB. This liposomal system enables the delivery of drugs across the BBB into the brain. The brain-directed liposomal system was used in a mouse model of Parkinson's disease (PD). Intra-peritoneal (IP) administration of liposomes loaded with dopamine (DA) demonstrated a good correlation between liposomal DA dose and the behavioral effects in hemiparkinsonian amphetamine-treated mice, with an optimal DA dose of 60 µg/kg. This is significantly lower dose than commonly used doses of the DA precursor levodopa (in themg/kgrange). IP injection of the APP-targeted liposomes loaded with a DA dose of 800 µg/kg, resulted in a significant increase in striatal DA within 5 min (6.9-fold, p < 0.05), in amphetamine-treated mice. The increase in striatal DA content persisted for at least 3 h after administration, which indicates a slow DA release from the delivery system. No elevation in DA content was detected in the heart or the liver. Similar increases in striatal DA were observed also in rats and mini-pigs. The liposomal delivery system enables penetration of compounds through the BBB and may be a candidate for the treatment of PD and other brain diseases.

Cholesterol Reduces Partitioning of Antifungal Drug Itraconazole into Lipid Bilayers.

Cholesterol plays a crucial role in modulating the physicochemical properties of biomembranes, both increasing mechanical strength and decreasing permeability. Cholesterol is also a common component of vesicle-based delivery systems, including liposome-based drug delivery systems (LDSs). However, its effect on the partitioning of drug molecules to lipid membranes is very poorly recognized. Herein, we performed a combined experimental/computational study of the potential for the use of the LDS formulation for the delivery of the antifungal drug itraconazole (ITZ). We consider the addition of cholesterol to the lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability is limited. Use of an LDS has thus been proposed. We studied lipid membranes composed of cholesterol, 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), and ITZ using a combination of computational molecular dynamics (MD) simulations of lipid bilayers and Brewster angle microscopy (BAM) experiments of monolayers. Both experimental and computational results show separation of cholesterol and ITZ. Cholesterol has a strong preference to orient parallel to the bilayer normal. However, ITZ, a long and relatively rigid molecule with weakly hydrophilic groups along the backbone, predominantly locates below the interface between the hydrocarbon chain region and the polar region of the membrane, with its backbone oriented parallel to the membrane surface; the orthogonal orientation in the membrane could be the cause of the observed separation. In addition, fluorescence measurements demonstrated that the affinity of ITZ for the lipid membrane is decreased by the presence of cholesterol, which is thus probably not a suitable formulation component of an LDS designed for ITZ delivery.