Review
Lipid-based nanoformulations for peptide delivery

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Abstract

Nanoformulations have attracted a lot of attention because of their size-dependent properties. Among the array of nanoformulations, lipid nanoformulations (LNFs) have evoked increasing interest because of the advantages of their high degree of biocompatibility and versatility. The performance of lipid nanoformulations is greatly influenced by their composition and structure. Therapeutic peptides represent a growing share of the pharmaceutical market. However, the main challenge for their development into commercial products is their inherent physicochemical and biological instability. Important peptides such as insulin, calcitonin and cyclosporin A have been incorporated into LNFs. The association or encapsulation of peptides within lipid-based carriers has shown to protect the labile molecules against enzymatic degradation. This review describes strategies used for the formulation of peptides and some methods used for the assessment of association efficiency. The advantages and drawbacks of such carriers are also described.

Graphical abstract

Introduction

Lipidic systems have the potential to enhance the internalization of drugs into the cell due to the affinity of the lipid materials to the membrane. In the case of lipid nanoformulations, the submicronic size of the particles is another parameter that favors cell internalization (Yuan et al., 2008). They have also been explored as potential vehicles for specific-site drug delivery to various organs/tissues/systems such as the lymphatic system, brain, lung and the skin (Khan et al., 2013, Liu et al., 2007b, Müller and Keck, 2004, Pandey and Khuller, 2005). In the field of nanomedicine, they offer interesting alternatives to other colloidal systems, enhancing drug efficacy, and providing controlled and convenient drug release.

The lipid components of lipid-based nanoformulations (LNFs) are generally phospholipids, cholesterol and triglycerides (Copland et al., 2005, Rawat et al., 2008), but also bile salts and free fatty acids (Liu et al., 2007a). These excipients are relatively innocuous, biocompatible and biodegradable in vivo. They are extracted from natural sources or can be the derivatives of natural substances. A number of these lipids, such as phosphatidylcholine, stearic acid, cholesterol and glycerol monooleate have been used in FDA-approved pharmaceutical applications and have well-established safety profiles with appropriate toxicological data (Rowe et al., 2009, Working and Dayan, 1996); this is their major advantage compared to other carriers such as polymeric particles (e.g., dendrimers), carbon nanotubes, quantum dots and metal nanoparticules (e.g., gold and iron nanoparticles) (Goodman et al., 2004, Hu et al., 2011, Jain et al., 2010, Kostarelos, 2008, Soenen and De Cuyper, 2010). Although lipid nanoparticles can be considered as relatively safe, and the type of lipid is an important factor affecting toxicity. Cationic lipids promote non-specific binding to circulating blood cells such as erythrocytes, lymphocytes and endothelial cells (Pedroso de Lima et al., 2001). Cationic liposomes also demonstrate a greater activation of the human complement system compared to neutral liposomes (Semple et al., 1998). Conversely, the presence of negatively charged lipids (e.g., phosphatidylglycerol, phosphatidylserine) on nanoparticle surfaces decreases their ability to penetrate the negatively-charged cell membranes (Fischer et al., 2003, Larson et al., 2007). They can also constitute binding sites for plasma opsonins, which favor nanoparticle uptake by macrophages (Nichols, 1993). Coating the nanocarrier with hydrophilic polyethylene glycol (PEG) is a prevalent strategy used to decrease the immunogenicity of charged particles (Nichols, 1993, Samad et al., 2007). Currently-approved liposomal products are composed of neutral lipids with or without PEGylated phospholipids (Samad et al., 2007, Sarker, 2005).

When formulating nanoemulsions and nanosuspensions, PEGylated lipids, glycerophospholipids and derivatives are preferred to conventional surfactants. The latter are known to insert themselves into the membrane bilayers and induce hemolysis when incubated with erythrocytes. Lipid surfactants act via the formation of steric barriers to prevent colloid destabilization (coalescence, aggregation,…) (Sarker, 2005). Lipid nanoparticulate delivery systems can be adjusted so as to have drugs adsorbed or linked to the particle surface, incorporated into the polymer/lipid shell, or encapsulated within the particle core. As a consequence, the pharmacokinetic and pharmacodynamic parameters of the drug can be improved and release can be controlled. Furthermore, drugs can be protected from a harsh environment, and undesired side effects can be avoided due to targeted delivery.

Significant advances in biotechnology and molecular biology over recent years have resulted in the emergence of novel molecules with the potential to offer significant improvement in the treatment and prevention of diseases. The new biotherapeutics include novel peptide and protein drugs. Therapeutic peptides are typically molecules made of 2–100 amino-acids, presenting interesting biological functions and, being derived from natural components, are well tolerated following administration. Peptides can be used to treat a broad range of diseases including cancer, cardiovascular diseases, infection, metabolic diseases and central nervous system disorders (Parmar, 2004).

Since Lypressin, a vasopressin analogue, was launched by Novartis (Pichereau and Allary, 2005); efforts have not ceased to multiply in an attempt to exploit the therapeutic potential of many peptides. Peptide-based therapeutics now constitute one of the fastest-growing classes of new drugs. In fact, almost half of the molecules in the pipelines of pharmaceutical companies are peptides (Dimond, 2010). However, the therapeutic potential of peptides is hampered by a number of physico-chemical and biological instabilities that impede their development and translation to the clinic. These inherent limitations include: Low stability (proteolytic degradation); low oral bioavailability (injection required); risk of immunogenic effects; as well as a challenging and costly synthesis process.

Moreover, peptides can be prone to chemical and/or physical instability, mainly related to manufacturing and formulation processes such as solvents, pH, temperature, ionic strength, high pressure, detergents, agitation and shearing (Hillery, 2001). Several peptide modifications have been explored to improve peptide in vivo half-lives: The addition of carbohydrate chains; synthetic amino acids; polyethylene glycol molecules; as well as lipidation or cyclization strategies (Gentilucci et al., 2010). However, altering the chemical structure of the peptide drug can potentially impair its therapeutic effect (Gante, 1994, Hruby and Balse, 2000). Recent advances in drug delivery technology offer a novel alternative to the drawbacks of using peptides. Indeed, nanocarriers such as, polymeric nanoparticles, liposomes and micelles seem to be a promising innovation to increase peptide pharmacodistribution.

Among drug delivery systems, lipid carriers offer a number of advantages making them interesting delivery vehicles for peptide administration. In general, a nanocarrier needs to be composed of inert and biodegradable material and to be able to efficiently encapsulate and protect peptides against degradation, while at the same time maintaining proper drug activity. Lipid-based nanoformulations can meet these requirements. The drug can be adsorbed onto the particle surface or encapsulated within it. Due to their amphiphilic nature, some peptides and proteins are known to adsorb at solid-liquid interfaces in biological and non-biological mechanisms such enzyme immobilization (Cao, 2005). The adsorption efficiency depends on the nature of the peptide (charge, length, hydrophobicity) and its concentration in solution, by the properties of the adsorption matrix and by the solvent (Haynes and Norde, 1994). This review describes a general state of the art dealing with the principal lipidic systems that can be used as peptide carriers, their properties and their application in the field of peptide delivery.

Section snippets

Nanoemulsions (NEs)

Microemulsions can be assimilated to swollen micelles (filled with water and/or oil) in thermodynamic equilibrium. These systems are excluded from this review that focuses more on nanoparticulate systems. Nanoemulsions (NEs) are kinetically-stable liquid isotropic dispersions composed of water, oil and surfactants. At defined stoichiometric ratios of the ingredients, the formation of translucent nanoemulsions is spontaneous. NEs can be considered as being conventional emulsions that contains

Conclusion

LNFs have attracted great attention in the last decades, thanks to their potential in clinical applications, for the delivery of wide range of hydrophobic and hydrophilic cargos. LNFs are prepared with FDA approved excipients, using simple and green preparation methods, that yield reproducible, versatile and mono-disperse formulations. Due to their lipidic nature, they have extensively demonstrated their ability to encapsulate and improve bioavailability of poorly-soluble drugs.

In this review

Acknowledgements

We would like to thank the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement 604182.

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