Parameters and characteristics governing cellular internalization and trans-barrier trafficking of nanostructures

Abstract

Cellular internalization and trans-barrier transport of nanoparticles can be manipulated on the basis of the physicochemical and mechanical characteristics of nanoparticles. Research has shown that these factors significantly influence the uptake of nanoparticles. Dictating these characteristics allows for the control of the rate and extent of cellular uptake, as well as delivering the drug-loaded nanosystem intra-cellularly, which is imperative for drugs that require a specific cellular level to exert their effects. Additionally, physicochemical characteristics of the nanoparticles should be optimal for the nanosystem to bypass the natural restricting phenomena of the body and act therapeutically at the targeted site. The factors at the focal point of emerging smart nanomedicines include nanoparticle size, surface charge, shape, hydrophobicity, surface chemistry, and even protein and ligand conjugates. Hence, this review discusses the mechanism of internalization of nanoparticles and ideal nanoparticle characteristics that allow them to evade the biological barriers in order to achieve optimal cellular uptake in different organ systems. Identifying these parameters assists with the progression of nanomedicine as an outstanding vector of pharmaceuticals.

Keywords: cellular uptake; charge; nanoparticles; shape; size; transport mechanisms.

Figure 1

The transport mechanisms of a typical biological barrier. Notes: (A) Cellular internalization of nanoparticle into cell via endocytosis; (B) transcellular transport of nanoparticles through cell; (C) paracellular transport of nanoparticle between cells through the tight junction; and (D) receptor-mediated transcytosis.

Figure 2

Mechanisms of endocytosis subdivided into categories of cell uptake.

Figure 3

Mechanism of clathrin-mediated endocytosis of nanoparticles.

Figure 4

The mechanisms of caveolin-mediated endocytosis, macropinocytosis, and phagocytosis.

Figure 5

Representation of the internalization potential dependent on particle size. Note: The larger surface area of the nanoparticle allows for increased surface contact with the cell membrane for higher internalization rates as described in the investigation of Nicolete et al.

Figure 6

Particle internalization based on orientation to the membrane. Notes: (A) Schematic showing the angle between the long axis of the particle and the bilayer normal; (B) minimum driving forces required to guide the ellipsoid with different initial orientations of the long axis through the lipid bilayer; (C) time evolution of particle orientations during the ellipsoid penetration processes with different initial orientations. Reprinted by permission from Macmillan Publishers Ltd: Nature Nanotechnology. Yang K, Ma YQ. Computer simulation of the translocation of nanoparticles with different shapes across a lipid bilayer. Nat Nanotechnol. 2010;5(8):579–583. Copyright © 2010.

Figure 7

(1) Pathway of uncoated hydrophobic nanoparticle; (2) pathway of coated hydrophilic nanoparticle. Notes: (1) (A) Nanoparticle in blood circulation; (B) opsonins recognize nanoparticle as a foreign body due to the hydrophobic surface; (C) opsonization of nanoparticle; (D) and (E) phagocytosis by phagocyte and elimination of nanoparticle. (2) (A) Hydrophilic polymer-coated nanoparticle in blood circulation; (B) steric hindrance maintains repulsive forces between opsonins and nanoparticle; (C) nanoparticle continues to circulate until target site reached; (D) and (E) endocytosis by target cell.

Figure 8

Stimulating endocytosis through CPP and antibody conjugation of nanoparticles. Abbreviation: CPP, cell-penetrating protein or peptide.