Organic and Polymeric Micro/Nanocarriers: History
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Subjects: Nanoscience & Nanotechnology
Contributor:
Jahir Orozco
,
Pedro Mena-Giraldo

Micro/nanocarriers are organic and polymeric materials that are structurally oriented to act like capsules in aqueous and organic media in order to protect, transport, and release cargo, among other applications. Liposomes are organic micro/nanocarriers based on phospholipids that form vesicles. In contrast, polymeric micro/nanocarriers are based on amphiphilic and backbone polymers that form micelles, polymersomes, and polymeric spheres. Micro/nanocarriers are usually produced via precipitation and emulsion techniques, using a hydrophobic/hydrophilic solvent mixture, an emulsifier or surfactant, and crosslinker agents acting as template-like reaction initiators to orientate the amphiphilic backbone polymers, forming their structure. Cargo is loaded either during the assembly process, by solubilizing the cargo in the hydrophobic or hydrophilic solvent, or after the carrier’s formation, by dispersing the carriers into a high-cargo-concentration solution, followed by further cargo diffusion through the carrier.

  • liposomes
  • polymeric nanomicelles
  • nanopolymersomes
  • polymeric micro/nanospheres
  • cargo delivery

1. Introduction

Cargo is released by diffusion and osmotic pumping mechanisms, as well as polymeric matrix erosion and degradation [1]. Unbalanced external/internal cargo concentration produces a concentration gradient with the loaded cargo and, consequently, its release via diffusion or osmotic pressure mechanisms through the water-filled cavities, polymeric matrix, and nanostructural porosity of the micro/nanocarriers [2][3][4]. Conversely, hydrolysis in the medium and external stimulus causes polymeric carrier erosion and degradation, delivering the cargo [5]. Furthermore, the cargo release time is directly affected by π-π electrostatic and adsorption interactions between the cargo and the polymeric matrix, preventing immediate delivery [6]. In the same manner, cargo precipitation in the medium caused by changes in the temperature, pH, and polarity can act as barriers in the release mechanism, causing slower delivery kinetics [7]. Superficial fluid velocity improves the cargo delivery, because it is removed from the surface faster via convection, preventing saturation and increasing the concentration gradient for a constant cargo release [8]. The polymeric micro/nanocarriers’ features and properties—such as their permeability, thickness, and polymer and carrier sizes—play an essential role in the cargo loading/release time, because these characteristics and the cargo release kinetics are inversely related [9].
The transport, protection, and delivery of the cargo are strategies for drug delivery [10], enzymatic activity protection [11], bioremediation [12], biosensing [13], and medical intervention [14]. Reproducibility, flexibility [15], malleability [16], and biocompatibility [17] of those based on polymeric micro/nanocarriers make them promising candidates for developing the next generation of micro/nanocarriers [18]. 

2. Liposomes

Liposomes are synthetic micro/nanovesicles composed of phospholipid bilayers with a hydrophilic core, a hydrophobic bilayer, and a hydrophilic shell [19] (Figure 1(Aa)). The aqueous internal core of the liposome can encapsulate polar cargo, while the lipid bilayer can incorporate apolar cargo, providing many possibilities for amphiphilic cargo encapsulation [20]. Nanoliposomes can release the cargo for intracellular drug delivery, because they may directly interact with the external cellular membrane, followed by cellular uptake [21]. The cargo is released intracellularly, either passively via liposome disruption, or via disintegration after fusion with cell membranes [22]. For example, Guo et al. developed a nanoliposome encapsulating ferric ammonium citrate in the hydrophilic core, transporting and releasing the cargo to a rat brain, thus increasing the local iron concentration for iron-deficiency anemia therapy (Figure 1A) [23].
Polymers 13 03920 g002 550
Figure 1. Schematic illustration of different types of micro/nanocarriers: TEM images of (A) liposomes based on a red hydrophobic head and blue hydrophilic segments (a), reprinted with permission from [23], copyright 2017, Springer Nature; (B) polymeric nanomicelles based on red hydrophobic and green hydrophilic segments (b), reprinted with permission from [24], copyright 2021, Penske Media Corporation; (C) nanopolymersomes based on red hydrophobic and blue hydrophilic segments (c), reprinted with permission from [25], copyright 2020, Springer Nature, and SEM images of (D) polymeric microspheres based on red backbone polymer (d), reprinted with permission from [26], copyright 2021, Elsevier.

3. Polymeric Micro/Nanomicelles

Copolymer micro/nanomicelles (MNMs) are composed of two polymer blocks with different hydrophilic/hydrophobic natures [27]. In aqueous environments, these MNMs spontaneously assemble into a core–shell-like structure. The hydrophobic segment aggregates integrate into the core, while the hydrophilic segment segregates the shell block [28], showing a high distribution and high hydrophobic cargo-loading capacity into the core [29] (Figure 1(Bb)). For example, in a strategy recently developed by our group, polymeric nanomicelles based on an amphiphilic poly (lactic acid-co-glycolic acid) (PLGA) polymer were self-assembled. The nanomicelles were formed via the nanoemulsion method, with a hydrophobic core and a hydrophilic shell, charging itraconazole with high loading capacity and encapsulation efficiency, taking advantage of the drug–core hydrophobic nature. The nanomicelles’ surface was further functionalized with an F4/80 antibody and mannose via the adsorption and carbodiimide methods, for an enhanced uptake by macrophages. The itraconazole released specifically into the cells from the nanomicelles, following a Fickian diffusion mechanism, and demonstrating enhanced efficacy and efficiency in eliminating the Histoplasma capsulatum fungus as a drug delivery strategy to fight intracellular infections (Figure 1B) [24]. On the other hand, different micelle properties have been investigated to improve the cargo release effect, such as critical micellization temperature (CMT) and the micelle formation’s minimum temperature. For example, Umapathi et al. studied a smart-responsive triblock copolymer based on poly(ethylene glycol) (PEG)-poly(propylene glycol)-PEG to understand the behavior of the CTM, with specific anion effects, which are directly related to the drug delivery mechanisms [30].

4. Micro/Nanopolymersomes

Micro/nanopolymersomes are amphiphilic-membrane bilayer vesicles with a hydrophilic core, hydrophobic interphase, and a hydrophilic shell (Figure 1(Cc)), permitting oily and aqueous cargo encapsulation and transport in aqueous solutions [31]. Co-solubilization in hydrophobic and hydrophilic solvents promotes structure formation via self-assembly, followed by elimination of hydrophobic solvents via evaporation and dialysis [32]. Polymersomes provide a dual hydrophobic/hydrophilic cargo transport alternative due to having a hydrophilic core and a hydrophobic interface [33]. Furthermore, the cargo release kinetics are controlled by varying the thickness of the hydrophobic interface, where it being thinner promotes a faster cargo release, but its hydrophobic loading capacity is lower [34]. As a way of illustrating such a dual carrying capability, Khan et al. synthesized nanopolymersomes for anticancer drug release, based on a poly((mPEG-SS-amino) (N,N-diisopropylethylenediamino)phosphazenes). Nanopolymersomes loaded hydrophobic and hydrophilic anticancer drugs in the hydrophilic core and hydrophobic interface, respectively, providing a nanoplatform for dual drug delivery (Figure 1C) [25].

5. Polymeric Micro/Nanospheres

Unlike micro/nanomicelles and micro/nanopolymersomes, polymeric micro/nanospheres are structures characterized as having the backbone polymer agglomerated to form solid carriers with the ability to transport cargo with different polarities [35] (Figure 1(Dd)). Nanoprecipitation and crosslinking methodologies are used to form polymeric micro/nanospheres, producing a solid polymeric micro/nanocarrier via polymer self-dispersion or crosslinking of available terminal groups by chemical reactions. Solid spheres have a long cargo release timeframe and cargo immobilization ability, enabling a compact structure with long life to prevent rapid degradation [36][37]. Ceron et al. synthesized polymeric microspheres based on a chitosan polymer crosslinked with glutaraldehyde. Microspheres immobilized lysozyme via the aldehyde available in the polymer and the free amines from the enzyme. The lysozyme-linked microspheres efficiently produced the lysis of Micrococcus lysodeikticus, demonstrating antimicrobial activity by inhibiting Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa bacteria (Figure 1D) [26].

This entry is adapted from the peer-reviewed paper 10.3390/polym13223920

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