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

Abstract

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.

Keywords: PEGylation; chitosan coating; drug delivery systems; lipid nanoparticles; lipid-based colloidal carriers; lipophilic drugs; solubility; surfactant protein.

Figure 1

Conventional lipid-based colloidal carriers (liposome and various LNP types).

Figure 2

Examples of various LNP emulsification methods. (A) Ultra-sonication method. (B) High-pressure homogenizer method. (C) Solvent injection method. (D) Solvent evaporation method. Reproduced with permission from [39] published by Elsevier, 2017, and [37,40] published by MDPI, 2020, 2021.

Figure 3

Newly proposed lipid nanoparticles-based drug delivery systems: (A) oleosome; (B) cubosome. Reproduced with permission from [50,54] and published by the American Chemical Society, 2015, 2018.

Figure 4

Various surface modifications for high-functionality of lipid nanoparticles.

Figure 5

LNP Functionality by polymer-based surface modification. (A) LNPs stabilized by PEGylation. (B) Mitigation of microglia activation by injecting LNPs through PEGylation. After injecting nanoparticles, the microglia activation was examined via immunostaining (ED1-based). ED1-positive cells with amoeboid morphology are indicated using Arrow (scale bar = 20 μm). (C) Mitigation of neurovascular damage by PEGylation. Immunoblot images of mouse brains according to LNP injection probed with anti-MMP-9 (blood–brain barrier integrity marker), caspase-1 (inflammatory signal marker), and phospho-CaMKII (synaptic stimulation marker) antibodies. Anti-β-actin was used as a loading control. (D) Absorptive characteristics of SLN and PEGylated SLN in the everted rat gut sac system on three intestines. Reproduced with permission from [139], published by Elsevier, 2013, and [121,122] published by the American Chemical Society, 2004, 2013.

Figure 6

Functionalization of LNPs through chitosan coating. (A) In vitro dose-dependent NLC and CS-NLC cytotoxicity profiles on (left) Caco-2 and (right) Hela cells. (B) In vivo tumor distribution of fluorescent-CS-SLN loaded with 25-NBD-cholesterol following inhalation on the M109 model. Confocal images of fluorescent SLN untreated or treated M109 mouse lung. (Red: vessels labeled with isolectinB4), (green: 25-NBD-cholesterol labeling SLN), (blue: Alexa Fluor 405-grafted-F-PEG-HTCC labeling the coating). (C) Pulmonary exposure to paclitaxel after administering intravenous (black: Taxol), inhaled (gray: Taxol), and inhaled (green: F-PEG-HTCC-coated SLN). (D) The evaluation of chitosan coating’s targeting efficiency in mouse organs, including the heart, liver, spleen, lung, and kidney. The relative uptake ratio (left), targeting efficiency (right). CS: chitosan coating. Reproduced with permission from [83,127] published by Elsevier, 2015, 2017, 2020, and [130] published by the American Chemical Society, 2018.

Figure 7

Functionalization of liposome and LNPs coated with surfactant protein. (A) Schematic illustration of the formation of luteolin-loaded liposomes coated with soybean oleosin (SOP-LUT-Lips). (B) Encapsulation efficiency of LUT-Lip and SOP-LUT-Lip under different pH conditions and ionic strength conditions. (C) Selectivity test of GM-oleosome. EGFR is not specific for either breast cancer cell line. However, HER2 is selective for SK-BR-3. Observation was conducted via confocal microscopy. Scale bar is 100 μm. (D) Increased carmustine delivery capacity of GM-oleosome (* p < 0.001 compared to G2 and G3). Reproduced with permission from [135], published by Elsevier, 2022, and [50] published by the American Chemical Society, 2018.