Recent Progress of Lipid Nanoparticles-Based Lipophilic Drug Delivery: Focus on Surface Modifications

Numerous drugs have emerged to treat various diseases, such as COVID-19, cancer, and protect human health. Approximately 40% of them are lipophilic and are used for treating diseases through various delivery routes, including skin absorption, oral administration, and injection. However, as lipophilic drugs have a low solubility in the human body, drug delivery systems (DDSs) are being actively developed to increase drug bioavailability. Liposomes, micro-sponges, and polymer-based nanoparticles have been proposed as DDS carriers for lipophilic drugs.

However, their instability, cytotoxicity, and lack of targeting ability limit their commercialization. Lipid nanoparticles (LNPs) have fewer side effects, excellent biocompatibility, and high physical stability. LNPs are considered efficient vehicles of lipophilic drugs owing to their lipid-based internal structure. In addition, recent LNP studies suggest that the bioavailability of LNP can be increased through surface modifications, such as PEGylation, chitosan, and surfactant protein coating. Thus, their combinations have an abundant utilization potential in the fields of DDSs for carrying lipophilic drugs. In this review, the functions and efficiencies of various types of LNPs and surface modifications developed to optimize lipophilic drug delivery are discussed.

1. Introduction

Drug development is essential for treating incurable diseases and prolonging life. Over 40% of new drugs approved for treating various diseases are lipophilic [1]. However, the low solubility of lipophilic agents makes them inefficient for a direct administration in humans [2]. Therefore, the need for a special delivery system to compensate for this is emphasized. Chemotherapeutic drugs directly administered without a delivery vehicle have a short half-life, poor solubility, and severe side effects due to cytotoxicity and a lack of specificity [3]. In addition, drugs at off-target sites reduce treatment efficiency, have low bioavailability, and may cause side effects [4]. A representative example is an mRNA-based COVID-19 (SARS-CoV-2) pandemic vaccine. Although a unique delivery vehicle has been used to deliver the unstable mRNA vaccine into the body [5,6], considerable side effects have been reported in some patients [7,8,9]. This is due to the absent targeting ability of the vaccine, causing an off-target effect, and the carrier comprises some materials that can cause inflammation, including myocarditis [10,11,12,13,14]. Therefore, methods have been devised to deliver more stable, effective, and bioavailable drugs. Over the past several decades, various DDS platforms have been developed to solve these problems. The ongoing DDS studies aim to improve pharmacological efficacy and minimize toxic side effects [15,16].

Among the various DDSs, lipid-based colloidal carriers (LCCs) are biodegradable and non-toxic [17]. Most LCC components are lipids; therefore, LCCs are considered the safest DDS [18]. Liposomes are the most representative LCC and were first described in the 1960s by Alec D Bangham [19]. They have the same phospholipid bilayer structure as the cell membrane (Figure 1). Thus, many researchers have focused on the possibility of treating various diseases using LCCs [20,21]. Numerous studies have been conducted to improve the bioavailability of liposomes, such as drug loading, increased residence time in the body, extrusion to ensure uniform size, and antibody-based targeting [22,23]. These efforts have led to clinical trials in various medical fields, including liposome-based anticancer drugs, antibiotics, gene therapy, and anesthetics [20]. Currently, many liposome-based treatments, such as Doxyl^® (doxorubicin), AmBisome^® (Amphotericin B), and daunoXome^® (daunorubicin), have been approved and used in medicine [24]. However, the high production cost, limited physical stability, low drug-loading capacity, leakage of encapsulated drugs, and complexity and use of toxic organic solvents in the manufacturing process restrict the commercialization of liposomes [25,26]. This situation requires a new alternative; thus, lipid nanoparticles (LNPs) were developed as novel LCCs to overcome the limitations of liposomes [21,25].

Pharmaceutics 15 00772 g001 550 — Figure 1. Conventional lipid-based colloidal carriers (liposome and various LNP types).

LNPs comprise lipids, surfactants, polymers, and emulsions or colloidal nanoparticle structures [27,28]. Unlike liposomes, LNPs mainly consist of phospholipids, a surfactant-based monolayer, and an interior filled with hydrophobic materials (Figure 1) [24]. The synthesis of LNPs is more straightforward to scale up than that of liposomes because they are produced by emulsification between an organic phase and an aqueous phase using the properties of surfactants [29,30]. In addition, they have many advantages, such as a low cytotoxicity, low cost, high stability, and drug-loading efficiency [6]. Previous studies on LNP preparation, characterization, drug loading, and delivery have demonstrated their great potential as a DDS. Generally, drugs are loaded in the carrier during the manufacturing process. Thus, their hydrophobic internal structural characteristics make them suitable for lipophilic drug delivery. Furthermore, because LNPs have a hydrophilic surface that can be well dispersed in aqueous solutions, they have great potential for application as a lipophilic DDS platform in the body (Figure 1) [31].

Since many lipophilic drugs are currently being developed, DDSs to increase the bioavailability of the drug are attracting attention. LNPs can improve the bioavailability of lipophilic drugs owing to their hydrophobic internal and hydrophilic surface structures, excellent biodegradability, and low toxicity, which can overcome the limitations of conventional DDSs. In addition, recent studies have revealed that surface characterization through LNP surface modification can impart high functionality, such as a more precise targeting ability and high-endosome escape to LNP [32,33]. Therefore, many studies have been conducted to modify LNP surfaces to improve lipophilic drug delivery efficiency further [34,35,36]. Here, the various LNPs that deliver lipophilic drugs are considered in this review. In addition, the types and functions of surface modification in LNPs were discussed, and research trends for an efficient drug delivery were explored.

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Seo, Y.; Lim, H.; Park, H.; Yu, J.; An, J.; Yoo, H.Y.; Lee, T. Recent Progress of Lipid Nanoparticles-Based Lipophilic Drug Delivery: Focus on Surface Modifications. Pharmaceutics 2023, 15, 772.
https://doi.org/10.3390/pharmaceutics15030772

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