Self-Assembly of Amphiphilic Compounds as a Versatile Tool for Construction of Nanoscale Drug Carriers

Abstract

This review focuses on synthetic and natural amphiphilic systems prepared from straight-chain and macrocyclic compounds capable of self-assembly with the formation of nanoscale aggregates of different morphology and their application as drug carriers. Since numerous biological species (lipid membrane, bacterial cell wall, mucous membrane, corneal epithelium, biopolymers, e.g., proteins, nucleic acids) bear negatively charged fragments, much attention is paid to cationic carriers providing high affinity for encapsulated drugs to targeted cells. First part of the review is devoted to self-assembling and functional properties of surfactant systems, with special attention focusing on cationic amphiphiles, including those bearing natural or cleavable fragments. Further, lipid formulations, especially liposomes, are discussed in terms of their fabrication and application for intracellular drug delivery. This section highlights several features of these carriers, including noncovalent modification of lipid formulations by cationic surfactants, pH-responsive properties, endosomal escape, etc. Third part of the review deals with nanocarriers based on macrocyclic compounds, with such important characteristics as mucoadhesive properties emphasized. In this section, different combinations of cyclodextrin platform conjugated with polymers is considered as drug delivery systems with synergetic effect that improves solubility, targeting and biocompatibility of formulations.

Keywords: amphiphile; cationic surfactants; drug delivery; endosomal escape; liposome; macrocycle; mucoadhesion; polymer.

Figure 1

Chemical formulas of carbamate-containing amphiphiles bearing ammonium (a) and imidazolium (b) moieties.

Figure 2

Schematic illustration of selected amphiphilic compounds bearing natural fragments and their benefits.

Figure 3

Schematic representation of nature-inspired amphiphiles and their possible various morphological structures.

Figure 4

Some representatives of cationic pyrimidine-based nucleolipids [102,103,104,105].

Figure 5

Chemical formulas of cationic tetrasiloxane gemini surfactants bearing ammonium (a) and imidazolium (b) groups.

Figure 6

Chemical structures of cationic ammonium- (a), pyridine- (b) and piperidine-based (c) silicone surfactants.

Figure 7

Possible models of morphological transition between aggregates of silicone-based surfactants at different concentration. Reprinted with permission from [123]. Copyright 2017 Elsevier.

Figure 8

Examples of cytoplasmic delivery via endosomal escape. Three main strategies are available for nanoparticles to break through and escape endosomal barriers. (a) Membrane-disrupting surface modifications and mechanisms (e.g., poly(ethyleneimine) PEI; cell-penetrating peptides (CPPs); and lipid fusion with endosomal membrane); (b) pH-responsive materials (e.g., hydrazone bonds); and (c) enzyme-cleavable materials (e.g., ester linkages, cathepsin B cleavable peptides). Reprinted with permission from [174]. Copyright 2019 Elsevier.

Figure 9

Schematic illustration of the building blocks and diversity of obtainable nanocarriers using non-covalent bilayer modification.

Figure 10

Electrostatic adsorption mediated transcytosis can be a mechanism to penetrate the BBB to reactivate brain AChE. Reprinted with permission from [216]. Copyright 2020 Elsevier.

Figure 11

Structural formulas of single-tailed cationic surfactants.

Figure 12

Structures of cationic surfactants with double, long chains.

Figure 13

Structural formulas of gemini surfactants.

Figure 14

Principal mechanics of pH-sensitive PEG-shedding carriers. In the bloodstream, they utilize the stealth effect, then they accumulate in the tumor region due to the EPR effect, where a mildly acidic pH is responsible for PEG cleavage and enhanced absorption of the unpegylated liposome.

Figure 15

Graphic outline of the mixed macrocycle–polymer systems as mucoadhesive formulations.

Figure 16

Schematic view of the complex formation between α-CD and alkylated polysaccharides followed by platelet organization in water. Reprinted with permission from [268]. Copyright 2018 American Chemical Society.