Lipid-core Micelles Research Articles

Role of SNEDDS as Novel Approach for Targeted Drug Delivery: A Review

Nanotechnology has become a wide range in pharmaceutical sciences, which has an effect on various drug delivery research from the last 10 years. The developed technology is being explored for the better therapeutic performance of drugs by enhancing the solubility of water-hating drugs (hydrophobic drugs), increasing permeability, regulating drug disposition and biodistribution, and permitting the targeted delivery of drugs. Nanotechnology is broadly categorized into drug nanoparticles or nanosuspension, nanocarriers like lipids, polymeric, and inorganic nanocarriers, as these nanocarriers involve liposomes and microemulsions nanoemulsions, lipid core micelles, solid lipid nanoparticles which are used for the targeted drug delivery systems.2 Based on this technology, the drug components that have poor aqueous solubility, permeability, bioavailability, and instability in physiological medium, the nanoemulsions are selected to enhance the properties. Nanoemulsions are group of heterogeneous with two immiscible liquids as o/w or w/o with droplet size ranges between 20 to 200 nm after the method preparation, before the term nanoemulsions, these are termed as mini-emulsions, micro-emulsions, submicron emulsions, and ultrafine emulsion due to unclear emulsions based on their size of the particles present. Therefore, to overcome the confusion in identifying the actual term, the particles size is within limits or in range, and the main factor is the emulsion, which is indicating transparent, are termed as nanoemulsions and slightly different called microemulsions.

Improved Anti-Triple Negative Breast Cancer Effects of Docetaxel by RGD-Modified Lipid-Core Micelles.

PurposeA novel RGD-modified PEGylated lipid-core micelle delivery system was designed to improve the anti-cancer effect of docetaxel on triple negative breast cancer (TNBC).MethodsThe tumor-targeted lipid-core micelles loaded with docetaxel were prepared and characterized. Their morphology, particle size, zeta potential, entrapment efficiency, release profiles, and targeting effects were studied. The antitumor effects of the docetaxel-loaded nano-micelles were investigated in a MDA-MB-231 cell model in vitro and a MDA-MB-231 xenograft model in vivo.ResultsThe prepared RGD-modified docetaxel-loaded lipid-core micelles were spherical with a particle size of 16.44±1.35 nm, zeta potential of −19.24±1.24 mV, and an encapsulation efficiency of 96.52±0.43%. The drug delivery system showed sustained release properties and could significantly enhance docetaxel uptake by MDA-MB-231 tumor cells in vitro, which was proved to be a caveolae pathway mediated process requiring ATP, Golgi apparatus, and acid lysosomes. The results of the pharmacokinetic study displayed that the area under the curve of the targeted micelles was 3.2-times higher than that of docetaxel commercial injections. Furthermore, in a MDA-MB-231 tumor-bearing mice model, a higher antitumor efficacy than docetaxel commercial injections was displayed, and the safety experiments showed that the micellar material did not cause major organ damage after intravenous administration in mice.ConclusionThe novel RGD-modified PEGylated lipid-core micelle delivery system significantly improved the antitumor effects and reduced the side-effects of docetaxel, providing a promising therapeutics for the treatment of TNBC.

Drug-Loaded Lipid-Core Micelles in Mucoadhesive Films as a Novel Dosage Form for Buccal Administration of Poorly Water-Soluble and Biological Drugs.

The aim of the study was to develop a novel buccal dosage form to transport rhodamine 123 and human insulin as models for poorly water-soluble and biological drugs, using lipid-core micelles (LCMs)-loaded mucoadhesive films. LCMs were synthesized by a low-energy hot emulsification process, yielding spherically shaped, small-sized, monodispersed and negatively charged carriers with high entrapment efficiency. In vitro release studies demonstrated a higher release of insulin rather than rhodamine from LCMs in simulated physiological conditions, due to an initial burst release effect; however, both release profiles are mainly explained by a diffusion mechanism. Furthermore, LCMs-loaded mucoadhesive films were manufactured and preserved with similar mechanical properties and optimal mucoadhesive behavior compared to nonloaded films. Ex vivo permeation experiments using excised porcine buccal epithelium reveal that both rhodamine and insulin-loaded LCM films elicited a significantly enhanced permeation effect compared to LCMs in suspension and free drugs in solution as controls. Hence, LCMs-loaded mucoadhesive films are suitable as buccal dosage form for the transport and delivery of rhodamine 123 and insulin, as models for poorly water-soluble and biological drugs, respectively.

Aptamer-Functionalized Lipid-Core Micelles Loaded with Rhenium Tricarbonyl Complex

Due to its distinctive physicochemical properties, diimine rhenium(I) tricarbonyl complexes are one of the most common type of complexes used in cellular imaging. The reasonably simple synthesis and modification of rhenium complexes in addition to their stability and remarkable luminescent properties provide a robust method to perform this goal. In general, organometallic complexes must be biocompatible to development imaging agents. Consequently, modification and bio-functionalization of the transition complexes is crucial to enhance biocompatibility. Here, we synthesize and characterize the luminescent tricarbonyl rhenium complex, [(bpy)(H 2 O)Re(CO) 3 ] + , and propose a reasonably simple preparation of an aptamer-functionalized lipid core micelle (LCM), loaded with this complex, to endow it with suitable properties to be used in cellular imaging. The [(bpy)(H 2 O)Re(CO) 3 ] + exhibit a broad emission band centered around 550 nm at room temperature after excitation at 360 nm. The luminescent intensity is higher in nonpolar solvents such as chloroform. The complex was loaded into LCMs and, at the same time, the carrier was functionalized in situ with the nucleolin aptamer, AS1411, to improve the complex delivery and uptake to target cells. After physicochemical and spectroscopic characterization of the aptamer-functionalized vehicle, cellular studies were performed to evaluate its toxicity and its efficiency as cellular imaging agent. The combined AS1411 aptamer-functionalized lipid core micelle system effectively encapsulated the [(bpy)(H 2 O)Re(CO) 3 ] + complex, maintained its luminescent properties, and showed potential features to be used in cellular imaging experiments.

Enhanced uptake and cytotoxity of folate-conjugated mitoxantrone-loaded micelles via receptor up-regulation by dexamethasone

Folate conjugated amphiphilic polymeric micelles have attracted much attention for active targeted delivery of drugs in folate receptor α (FR-α) positive tumors. However, the efficacy improvement of targeted delivery folate-based nanovehicles was limited by the abundance of FR-α on the surface of tumor cells. Recently, it was found that FR-α expression of Hela cells could be up-regulated by modulators such as dexamethasone, which open a new avenue to enhance the efficiency of targeted delivery from the biological view. In this study, folate-conjugated or plain lipid-core micelles loaded with fluorescent coumarin 6 or mitoxantrone (MTN) were prepared by self-assembly. In addition, FOLR1 mRNA and cell surface FR-α levels were evaluated in Hela cells with dexamethasone treatment. The endocytosis of folate-conjugated or plain micelles loaded with coumarin 6 was examined with confocal microscopy and flow cytometry, which displayed that folate-conjugated micelles can be internalized more efficiently in dexamethasone-treated Hela cells than in normal Hela cells. Moreover, the antitumor activity of folate-conjugated micellar MTN was also improved through up-regulation of FR-α. Therefore, FR-α up-regulation using modulators has great potential to improve the therapeutic efficacy of folate-conjugated nanovehicles in some FR-α positive tumors via receptor-mediated endocytosis.

Lipid-Based Nanocarriers for CNS-Targeted Drug Delivery

Nanotechnology exerts an increasing impact on the development of more effective tools for the diagnosis and treatment of human diseases. This applies in particular to central nervous system (CNS) disorders. Development of therapeutics for CNS is, in fact, one of the most challenging areas in drug development, mainly due to the presence of the blood-brain barrier (BBB) which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the vast majority of neurotherapeutic agents. Among the several strategies which have been developed over the last years in order to overcome this problem, nanotechnology-based approaches have gained increasing attention as the most promising strategies for CNS targeted drug delivery. Nanocarriers offer several advantages such as the possibility to maintain drug levels in a therapeutically desirable range, as well as the increase of half-lives, solubility, stability and permeability of drugs. Furthermore, the system can be designed in such a way as to release the drug in a controlled way or in a triggered way. This review focuses on lipid-based nanocarriers and more specifically on liposomes, lipid-core micelles, and lipid nanocapsules, and provides an update on their composition and use, including recent patents in the field.

Recent developments in lipid-based pharmaceutical nanocarriers

Within the broad spectrum of nanoparticulate carriers, polymeric and lipid-core micelles, liposomes, solid nanoparticles and many others have demonstrated great biological properties which make them excellent pharmaceutical delivery systems. In particular, micelles and liposomes have been shown to have good longevity in the blood that allows their accumulation in pathological areas with a compromised vasculature; can possess specific targeting to disease sites when various targeting ligands are attached to the surface of the nanocarriers or to surface-attached cell-penetrating molecules (like TAT peptide) to enhance intracellular penetration; possess stimulus-sensitivity allowing for drug release from the carriers under certain pathological conditions; and show contrast properties with carrier loading of various contrast materials that allow for direct carrier visualization in vivo. The engineering of "multifunctional pharmaceutical nanocarriers" based on the combination of several useful properties in the same system can significantly enhance the efficacy of many therapeutic and diagnostic protocols. This review considers the current status and next future directions in the emerging area of nanomedicine with particular attention to two lipid-based nanoparticulate systems: liposomes and micelles.

PH-sensitive PEG-based micelles for tumor targeting

A new acid sensitive nanocarrier based on lipid core micelles has been investigated for tumor targeted drug delivery. Sulfadimethoxine-PEG-phospholipid unimer (SD-PEG-DSPE) was designed to endow micelles with pH responsiveness in the physiopathologic range. The unimer was synthesized according to a two-step procedure. Potentiometric analysis showed that SD-PEG-DSPE has pKa of 6.7. In water, the unimers assembled spontaneously in 20 nm size micelles with 60 μM critical micelle concentration. The particle size was not affected by the pH in the 6.2–7.4 range. The micelles loaded paclitaxel very efficiently and released the drug slowly regardless the incubation pH. Fluorescence spectroscopy and cytofluorimetry carried out by MCF7 tumor cell incubation with labeled SD-PEG-DSPE micelles at pH 7.4 and 6.2 showed that micelles associate with cells mostly at acidic pH with a time-dependent behavior. A cell subpopulation took up the nanocarrier more efficiently at pH 6.2. Confocal microscopy confirmed that under these conditions the systems are taken up by cells or fuse with cellular membrane. Cytotoxicity studies demonstrated that the SD-PEG-DSPE micelles deliver more efficiently paclitaxel at pH 6.2 than at neutral pH confirming that the cell internalization can be triggered by the external environmental conditions.

Multifunctionality of lipid-core micelles for drug delivery and tumour targeting

Phospholipid micelles have proven to be the versatile pharmaceutical nanocarrier of choice for the delivery of poorly soluble chemotherapeutics for cancer therapy using various treatment modalities. Phospholipid micelles are typically expected to increase the accumulation of the loaded drugs in tumour tissues by taking advantage of the enhanced permeability and retention effect and by ligand-mediated active targeting. Furthermore, by tailoring the composition of the micelles, it is possible to enhance the intracellular delivery of the cargo. This review highlights the important advancements in our laboratory with polyethyleneglycol phosphatidylethanolamine (PEG-PE)-based micellar drug delivery systems for improvement of the therapeutic efficacy of poorly soluble anticancer drugs.

Targeting Glioma Cells in Vitro with Ascorbate-Conjugated Pharmaceutical Nanocarriers

6-Ascorbate-PEG-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (6-ascorbate-PEG-PE) was synthesized according to a two-step procedure: (1) activation of ascorbic acid with bromine, and (2) synthesis of 6-ascorbate-PEG-PE by reacting 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (poly(ethylene glycol))-2000] with an excess of 6-Br-ascorbic acid. The 6-ascorbate-PEG-PE was recovered by precipitation in diethyl ether and purified by gel permeation chromatography. The analysis of the product by 1H NMR and UV-vis spectroscopy confirmed the identity of the conjugate. Liposomes and PEG-PE-based lipid-core micelles were prepared by thin film hydration technique incorporating 6-ascorbate-PEG-PE as targeting moiety. The targeting properties of the ascorbate-decorated nanosystems were tested by fluorescence-activated cell sorting (FACS) analysis and fluorescent microscopy on a panel of tumor cell lines preliminary selected for their ability to express the SVCT2 ascorbate transporter. Cell lines had been selected on the basis of the immunological properties assessed by FACS, which showed that two glioma cell lines, C6 and F98, and fibroblasts NIH/3T3 express plasma membrane-associated SVCT2 transporter for reduced ascorbic acid. Ascorbate-decorated pharmaceutical nanocarriers were endowed with selective targeting properties toward the SVCT2 transporter expressed in glioma cell models. This study shows that SVCT2 transporter for ascorbic acid expressed both in peculiar epithelial cells of the choroid plexus responsible for the filtering of vitamin C into the central nervous system (CNS) and, in some brain tumor cell lines, can be conceivably exploited as a potential target for delivery of drug-loaded pharmaceutical nanocarriers to the brain.

Antinucleosome Antibody-Modified Liposomes and Lipid-Core Micelles for Tumor-Targeted Delivery of Therapeutic and Diagnostic Agents

Liposomes and lipid-core micelles prepared of polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugates have been modified with nucleosome-specific monoclonal antinuclear autoantibody (ANA) 2C5 (mAb 2C5) specifically recognizing a broad variety of cancer cells through the cancer cell surface-bound nucleosomes. mAb 2C5 preserves its specific properties upon the binding with the lipid-based pharmaceutical nanocarriers, and 2C5-modified immunoliposomes and immunomicelles demonstrate an enhanced binding with tumor cells both in vitro and in vivo. We have investigated the delivery of therapeutic and diagnostic agents with such tumor-targeted immunoliposomes and immunomicelles to various tumors in vivo and in vitro. Both lipid-based nanocarriers provided enhanced tumor delivery of imaging agents (111In) and antitumor drugs (doxorubicin and photodynamic therapy agents) to tumor cells under different experimental settings. Pharmaceutical lipid-based nanoparticular carriers modified with mAb 2C5 could represent universal systems for tumor-specific delivery of various soluble and insoluble pharmaceuticals.

Micellar Nanocarriers: Pharmaceutical Perspectives

Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers.

Lipid-Core Micelles for Targeted Drug Delivery

Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used for the solubilization of various poorly soluble pharmaceuticals and demonstrate a series of attractive properties as drug carriers. Polymeric micelles, i.e. micelles formed by amphiphilic block co-polymers possess high stability both in vitro and in vivo and good biocompatibility. Among those micelles, lipid-core micelles, i.e. micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE) are of special interest. These micelles can effectively solubilize a broad variety of poorly soluble drugs (anticancer drugs in particular) and diagnostic agents. Drug-loaded lipid-core micelles can spontaneously target body areas with compromised vasculature (tumors, infarcts) via the enhanced permeability and retention (EPR) effect. Lipid-core mixed micelles containing certain specific components (such as positively charged lipids) are capable of escaping endosomes delivering incorporated drugs directly into the cell cytoplasm. Various specific targeting ligand molecules (such as antibodies) can be attached to the surface of the lipid-core micelles and bring drug-loaded micelles to and into target cells. Lipid-core micelles carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities.

Editorial [Hot Topic: Lipid-Based Nanosystems and Complexes in Experimental and Clinical Therapeutics (Guest Editors: A. Agrawal and S.M. Moghimi)

An intriguing spectrum of novel nanoparticulate systems and complex nanostructures, some with remarkable diagnostic and biomimetic properties and others suitable for site-specific drug delivery and targeting are in existence today. Examples include quantum dots, capable of labelling biological systems for detection by optical or electrical means, tris-malonic acid derivatives of the fullerene C60, which exhibit superoxide dismutase mimetic properties, and porous titanium oxide and silicon nanoparticulate systems with sustained drug release properties. The ability to create these assemblies as well as other unusual nanostructures such as bundles, tubes, and sheets holds promise for new and powerful diagnostic and drug delivery systems, which will surely change the foundations of disease treatment and diagnosis. These technological innovations and nanoscience approaches to particle design are the focus of the US National Institute of Health's Nanomedicine Roadmap Initiative and the National Cancer Institute's Alliance for Nanotechnology in Cancer and several new European Commission-funded initiatives. Indeed, February 2004 saw the birth of Nano2Life, Europe's first Network of Excellence in nanobiotechnology, and in February 2005, the European Science Foundation launched its Scientific Forward Look on Nanomedicine Initiative, with strong emphasis on engineering of smart nanoparticle-based medicines and nanodevices. Although within the remit of the above mentioned nanoscience initiatives, lipid-based nanosystems such as nanoemulsions, lipid-core micelles, small unilamellar vesicles and variations thereof, have long been in existence and some have long been improving patient's lives. Indeed, lipid-based nanoformulations are among the most attractive candidates for improving drug solubility and for site-specific targeting following parenteral administration. This Theme Issue of Current Drug Delivery features contributions focusing on selected molecularbased strategies and nanoscience approaches to design, development, and site-specific targeting of a wide range of lipid-based nanocarriers and complex systems currently at preclinical and clinical stages. Specifically, great strides are being made with such complexes and nanosystems in combating the growth and spread of cancerous tissues (e.g., through exploitation of angiogenic tumour vasculature, combination chemotherapy, and endogenous triggered activation and release of encapsulated lipid pro-drugs), treatment of macrophage infections (through exploitation of macrophage clearance mechanisms), gene transfer (by breaching the endo-lysosomal barrier with cationic lipid vectors) and stimulation of immune responses to antigens (with the aid of vesicular systems and lipid-complexes with self-adjuvanting properties), and are discussed in the first thirteen articles in this Theme Issue. Although, lipidbased nanocarriers may overcome solubility or stability issues for the drug and minimize drug-induced side effects through favourable pharmacokinetic profiles and site-specific targeting, there are significant toxicity issues with carriers themselves that need to be addressed. Selected toxicity issues are dealt with in the last two articles. The first contribution discusses toxicogenomics of the delivery system and the impact of the microarray technology; in assessing cellular toxicity, while in the final article, the reader's attention is drawn towards pseudoallergic reactions, which are believed to be secondary to complement activation. Here, endogenous lipid-based delivery vehicles (lipoproteins) seem to play a complex modulatory role in complement-mediated pseudoallergic responses to nanomedicines. We believe that this Issue has provided a broad sample of the state of the art. We are indebted to all contributors for their attempt to communicate and discuss the most promising ideas, approaches, applications and developments of the most advanced lipid-based nanomedicines.