Trends and developments in liposome drug delivery systems

Since the discovery of liposomes or lipid vesicles derived from self-forming enclosed lipid bilayers upon hydration, liposome drug delivery systems have played a significant role in formulation of potent drugs to improve therapeutics. Currently, most of these liposome formulations are designed to reduce toxicity and to some extent increase accumulation at the target site(s) in a number of clinical applications. The current pharmaceutical preparations of liposome-based therapeutics stem from our understanding of lipid-drug interactions and liposome disposition mechanisms including the inhibition of rapid clearance of liposomes by controlling size, charge, and surface hydration. The insight gained from clinical use of liposome drug delivery systems can now be integrated to design liposomes targeted to tissues and cells with or without expression of target recognition molecules on liposome membranes. Enhanced safety and heightened efficacy have been achieved for a wide range of drug classes, including antitumor agents, antivirals, antifungals, antimicrobials, vaccines, and gene therapeutics. Additional refinements of biomembrane sensors and liposome delivery systems that are effective in the presence of other membrane-bound proteins in vivo may permit selective delivery of therapeutic compounds to selected intracellular target areas.     

Liposomal drug delivery systems: an update review

The discovery of liposome or lipid vesicle emerged from self forming enclosed lipid bi-layer upon hydration; liposome drug delivery systems have played a significant role in formulation of potent drug to improve therapeutics. Recently the liposome formulations are targeted to reduce toxicity and increase accumulation at the target site. There are several new methods of liposome preparation based on lipid drug interaction and liposome disposition mechanism including the inhibition of rapid clearance of liposome by controlling particle size, charge and surface hydration. Most clinical applications of liposomal drug delivery are targeting to tissue with or without expression of target recognition molecules on lipid membrane. The liposomes are characterized with respect to physical, chemical and biological parameters. The sizing of liposome is also critical parameter which helps characterize the liposome which is usually performed by sequential extrusion at relatively low pressure through polycarbonate membrane (PCM). This mode of drug delivery lends more safety and efficacy to administration of several classes of drugs like antiviral, antifungal, antimicrobial, vaccines, anti-tubercular drugs and gene therapeutics. Present applications of the liposomes are in the immunology, dermatology, vaccine adjuvant, eye disorders, brain targeting, infective disease and in tumour therapy. The new developments in this field are the specific binding properties of a drug-carrying liposome to a target cell such as a tumor cell and specific molecules in the body (antibodies, proteins, peptides etc.); stealth liposomes which are especially being used as carriers for hydrophilic (water soluble) anticancer drugs like doxorubicin, mitoxantrone; and bisphosphonate-liposome mediated depletion of macrophages. This review would be a help to the researchers working in the area of liposomal drug delivery.     

Combining kinase inhibitors for optimally co‐targeting cancer and drug escape by exploitation of drug target promiscuities

Cancers resist targeted therapeutics by drug‐escape signaling. Multitarget drugs co‐targeting cancer and drug‐escape mediators (DEMs) are clinically advantageous. DEM coverage may be expanded by drug combinations. This work evaluated to what extent the kinase DEMs (KDEMs) can be optimally co‐targeted by drug combinations based on target promiscuities of individual drugs. We focused on 41 approved and 28 clinical trial small molecule kinase inhibitor drugs with available experimental kinome and clinical pharmacokinetic data. From the kinome inhibitory profiles of these drugs, drug combinations were assembled for optimally co‐targeting an established cancer target (EGFR, HER2, ABL1, or MEK1) and 9–16 target‐associated KDEMs at comparable potency levels as that against the cancer target. Each set of two‐, three‐, and four‐drug combinations co‐target 36–71%, 44–89%, 50–88%, and 27–55% KDEMs of EGFR, HER2, ABL1, and MEK1, respectively, compared with the 36, 33, 38, and 18% KDEMs maximally co‐targeted by an existing drug or drug combination approved or clinically tested for the respective cancer. Some co‐targeted KDEMs are not covered by any existing drug or drug combination. Our work suggested that novel drug combinations may be constructed for optimally co‐targeting cancer and drug escape by the exploitation of drug target promiscuities.     

Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective

Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7–10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5–7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.     

Preparation of nanoemulsions and solid lipid nanoparticles by premix membrane emulsification

In an attempt to overcome problems of conventional high-energy preparation processes for colloidal drug carrier systems, premix membrane emulsification was investigated for the first time as an alternative low-energy input process for the preparation of pharmaceutical nanoemulsions and solid lipid nanoparticles. The effect of process parameters on dispersions based on nonpolar lipids (medium-chain triglycerides, soybean oil, and trimyristin) and different emulsifiers (sodium dodecyl sulfate, poloxamer 188, polyglyceryl-10-laurate, and sucrose laurate) was studied in a small-volume device and a larger scale-up approach. For emulsions and suspensions, mean particle sizes in a range from about 100 to 200 nm were observed for monomodal to monodisperse particle size distributions after 21 cycles of extrusion through polycarbonate membrane filters. As the mass ratio of matrix lipid to emulsifier (4:3, w/w concentrations) usually applied for the preparation of stable colloidal lipid particles was quite high, the amount of emulsifier in the dispersions was minimized. It was observed that the minimal concentration of emulsifier increased with decreasing membrane pore size. The possibility to prepare colloidal drug carrier systems with a high concentration of matrix lipid (up to 20%) by an optimized membrane extrusion process offers new opportunities for the processing of sensitive substances.     

Cancer-targeted polymeric drugs

A major challenge in cancer chemotherapy is the selective delivery of small molecule anti cancer agents to tumor cells. Water-soluble polymer-drug conjugates exhibit good water solubility, increased half-life, and potent anti tumor effects. By localizing the drug at the desired site of action, macromolecular therapeutics have improved efficacy and enhanced safety at lower doses. Since small molecule drugs and macromolecular drugs enter cells by different pathways, multi-drug resistance (MDR) can be minimized. Anti-cancer polymer-drug conjugates can be divided into two targeting modalities: passive and active. Tumor tissues have anatomic characteristics that differ from normal tissues. Macromolecules penetrate and accumulate preferentially in tumors relative to normal tissues, leading to extended pharmacological effects. This "enhanced permeability and retention" (EPR) effect is the principal reason for current successes with macromolecular anti-cancer drugs. Both natural and synthetic polymers have been used as drug carriers, and several bioconjugates have been clinically approved or are in human clinical trials. While clinically useful anti-tumor activity has been achieved using passive macromolecular drug delivery systems, further selectivity is possible by active targeting. Attachment of targeting moieties to the polymer backbone can further exploit differences between cancer and normal cells through selective receptor-mediated endocytosis. This strategy would augment the EPR effect, thereby further improving the therapeutic index of the macromolecular drug. This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy. Specific examples are selected to illustrate the basic design principles for soluble polymeric drug delivery systems.     

Transporter-mediated drug delivery: recent progress and experimental approaches

A comprehensive list of drug transporters has recently become available as a result of extensive genome analysis, as well as membrane physiology and molecular biology studies. This review covers recent progress in identification and characterization of drug transporters, illustrative cases of successful drug delivery to, or exclusion from, target organs via transporters, and novel experimental approaches to therapeutics using heterologously transduced transporters in tissues. We aim to provide clues that could lead to efficient strategies for the use of transporters to deliver drugs and/or to optimize lead compounds.     

Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated into liposomes

In order to confirm the efficacy of ciprofloxacin (CPFX) incorporated into liposomes (CPFX–liposomes) for treatment of respiratory intracellular parasite infections, the influence of particle size on drug delivery to rat alveolar macrophages (AMs) following pulmonary administration of CPFX–liposomes was investigated. CPFX–liposomes were prepared with hydrogenated soybean phosphatidylcholine (HSPC), cholesterol (CH) and dicetylphosphate (DCP) in a lipid molar ratio of 7/2/1 by the hydration method and then adjusted to five different particle sizes (100, 200, 400, 1000 and 2000 nm). In the pharmacokinetic experiment, the delivery efficiency of CPFX to rat AMs following pulmonary administration of CPFX–liposomes increased with the increase in the particle size over the range 100–1000 nm and became constant at over 1000 nm. The concentrations of CPFX in rat AMs until 24 h after pulmonary administration of CPFX–liposomes with a particle size of 1000 nm were higher than the minimum inhibitory concentration of CPFX against various intracellular parasites. In a cytotoxic test, no release of lactate dehydrogenase (LDH) from rat lung tissues by pulmonary administration of CPFX–liposomes with a particle size of 1000 nm was observed. These findings indicate that efficient delivery of CPFX to AMs by CPFX–liposomes with a particle size of 1000 nm induces an excellent antibacterial effect without any cytotoxic effects on lung tissues. Therefore, CPFX–liposomes may be useful in the development of drug delivery systems for the treatment of respiratory infections caused by intracellular parasites, such as Mycobacterium tuberculosis, Chlamydia pneumoniae and Listeria monocytogenes.     

Mammalian carboxylesterases: from drug targets to protein therapeutics

Our understanding of the detailed recognition and processing of clinically useful therapeutic agents has grown rapidly in recent years, and we are now able to begin to apply this knowledge to the rational treatment of disease. Mammalian carboxylesterases (CEs) are enzymes with broad substrate specificities that have key roles in the metabolism of a wide variety of clinical drugs, illicit narcotics and chemical nerve agents. Here, the functions, mechanism of action and structures of human CEs are reviewed, with the goal of understanding how these proteins are able to act in such a non-specific fashion, yet catalyze a remarkably specific chemical reaction. Current approaches to harness these enzymes as protein-based therapeutics for drug and chemical toxin clearance are described, as well as their uses for targeted chemotherapeutic prodrug activation. Also included is an outline of how selective CE inhibitors could be used as co-drugs to improve the efficacy of clinically approved agents.     

Mechanisms of drug resistance in kinases

INTRODUCTION: because of their important roles in disease and excellent 'druggability', kinases have become the second largest drug target family. The great success of the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia illustrates the high potential of kinase inhibitor (KI) therapeutics, but also unveils a major limitation: the development of drug resistance. This is a significant concern as KIs reach large patient populations for an expanding array of indications. AREAS COVERED: we provide an up-to-date understanding of the mechanisms through which KIs function and through which cells can become KI-resistant. We review current and future approaches to overcome KI resistance, focusing on currently approved KIs and KIs in clinical trials. We then discuss approaches to improve KI efficacy and overcome drug resistance and novel approaches to develop less drug resistance-prone KI therapeutics. EXPERT OPINION: although drug resistance is a concern for current KI therapeutics, recent progress in our understanding of the underlying mechanisms and promising technological advances may overcome this limitation and provide powerful new therapeutics.     

SLN, NLC, LDC: state of the art in drug and active delivery

Drug delivery system focuses on the regulation of the in vivo dynamics, in order to improve the effectiveness and safety of the incorporated drugs by use of novel drug formulation technologies. Lipids such as fatty acids, triglycerides, vegetable oils and their derivatives, used for developing multiparticulate dosage forms, may be available in solid, semi-solid or liquid state. Solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid drug conjugate (LDCs) nanoparticles are novel lipid drug delivery systems. They were devised to address some of the challenges of conventional drug delivery systems ranging from low drug encapsulation efficiency to low bioavailability of Biopharmaceutical Classification Systems (BCS) class II and class IV drugs. SLNs are based on melt-emulsified lipids, which are solid at room temperature and consist of physiologically well tolerated ingredients often generally recognised as safe. NLCs are colloidal carriers characterized by a solid lipid core consisting of a mixture of solid and liquid lipids, and having a mean particle size in the nanometer range. LDC are nanoparticles contain drugs linked to lipid particles. This minireview highlights these three different but related technologies in lipid drug delivery. The objectives of their introduction, current applications, major challenges and some patented formulations are highlighted.     

Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: In vitro study with finite and infinite dosage application

The aim of the present research is to evaluate the influence of different lipid vesicular systems as well as the effect of application mode on skin penetration and deposition behaviors of carboxyfluorescein (hydrophilic model drug) and temoporfin (lipophilic model drug). All of the lipid vesicular systems, including conventional liposomes, invasomes and ethosomes, were prepared by film hydration method and characterized for particle size distribution, ζ-potential, vesicular shape and surface morphology, in vitro human skin penetration and skin deposition. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) defined that all of lipid vesicles had almost spherical structures with low polydispersity (PDI < 0.2) and nanometric size range (z-average no more than 150 nm). In addition, all lipid vesicular systems exhibited a negative zeta potential. In vitro skin penetration and deposition experiments demonstrated that, in the case of CF with finite dose application (10 μl/cm2) and infinite dose application (160 μl/cm2), lipid vesicular systems, especially ethosomes and invasomes, compared with non-vesicular systems, can significantly improve the delivery of hydrophilic drug such as carboxyfluorescein into skin deep layers or across the skin. While in the case of mTHPC with finite and infinite dose application, most of drug accumulation was observed in the skin superficial layer for both lipid vesicular systems and non-vesicular systems. The results also revealed that the factors influencing the drug skin distribution concern the physicochemical characteristics of the drug, the choice of the vehicle formulation and the application mode applied.     

Recent advances in the use of microspheres for targeted therapy

In recent years the concept of using small colloidal particles for the selective delivery of drugs has been explored experimentally using a variety of different physical systems (for example, phospholipid vesicles (liposomes), triglyceride emulsions, albumin microspheres) and routes of administration. In such studies the aim has been to target a potent pharmacological agent on an organ or tissue site, thereby reducing adverse reactions and side-effects, or to provide a means of controlled release. The design of appropriate delivery systems must take into account the nature of the target and physiological barriers to targeting as well as factors such as drug loading and drug release, stability of the carrier system and its biocompatibility and biodegradation. Targeting with microspheres can be divided into passive methods that rely upon physiological and physicochemical determinants such as entrapment in capillary beds (lungs - particle size) or uptake by phagocytic cells (liver-surface characteristics), an active method whereby the particle is directed to a specific site through the use of surface coatings (surfactants, glycolipids, monoclonal antibodies) or a material sensitive to an external influence. Candidate systems presently under study are described. These include lipid emulsions for intravenous administration and microspheres for intra-articular delivery.     

An investigation into the mechanism of dissolution rate enhancement of poorly water-soluble drugs from spray chilled gelucire 50/13 microspheres

The production and physicochemical characterisation of spray chilled Gelucire 50/13 microspheres is described with a view to improving the dissolution of a poorly water-soluble drug, piroxicam, and understanding the fundamental mechanisms associated with the improved drug release. Thermorheological testing was developed as a fast screening method for predicting the processability of dispersions for spray chilling preparation. Spray chilled piroxicam loaded microspheres were spherical in shape with a median diameter of circa 150 µm. DSC indicated no interaction between piroxicam and lipid matrix, while HSM studies performed in polarized light mode indicated that the spheres contained distinct drug crystals. Polarising light microscopy and small-angle XRD investigations on the hydration behaviour of the lipid and the spray chilled microspheres revealed the formation of liquid crystalline phases depending on the degree of hydration. The dissolution behaviour of the piroxicam loaded microspheres showed significant improvements compared to drug alone. The particle size, drug loading and aging of the microspheres were all found to have an influence on the release behaviour. It was proposed that Gelucire 50/13 microspheres release the entrapped piroxicam via formation of a lyotropic liquid crystalline phase, which allows dissolution of the drug particles in a finely divided, high surface area and well-wetted state. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:262–274, 2010     

Design of fine particles for pulmonary drug delivery

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in ‘smart’ therapeutics capable of active targeting and intracellular trafficking.     

Design of fine particles for pulmonary drug delivery

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in 'smart' therapeutics capable of active targeting and intracellular trafficking.     

Specific features of drug encapsulation in liposomes (A review)

Liposomes are hollow particles, the internal space of which is bounded by a lipid membrane. Liposomes are promising drug delivery systems for organs and tissues because of their colloidal properties, controlled size, surface characteristics, membrane action, and biocompatibility. Liposomal drugs have found wide use in the diagnosis and chemotherapy of cancer, vaccinology, ophthalmology, pulmonology, and the treatment of other pathologies. This review describes the methods of encapsulation of biologically active compounds with various physicochemical properties in liposomes, which is very important for the production of liposomal drugs.     

Pharmaceutical applications of the Calu-3 lung epithelia cell line

Introduction: The Calu-3 lung cell line has been shown to be a promising in vitro model of airway epithelia due to its similarity to in vivo physiology. Hence, over the past decade, it has found increasing applications in the pharmaceutical industry.

Areas covered: This review focuses on the pharmaceutical applications of the Calu-3 cell line in areas such as mechanisms of drug transport, studying aerosol deposition, controlled release studies and identification of possible drug–drug interactions. The main findings of various studies, as well as the predictive potential of this model, are presented and discussed in this review.

Expert opinion: There is still a lack of mechanistic knowledge regarding transport of inhaled therapeutics across the lungs. Cell culture models such as Calu-3 provide a simple and reproducible system to study the underlying mechanisms by which inhaled therapeutics interact with the lungs. However, more complex systems that integrate particle deposition onto different cell culture systems may be useful in addressing some fundamental questions to generate a better understanding of determinants that influences pulmonary drug dissolution, absorption, metabolism and efficacy. Ultimately the use of the Calu-3 cell line provides a basic research tool that enables the development of safer and more effective inhaled therapeutics.