Designer nanoparticles: incorporating size, shape and triggered release into nanoscale drug carriers

Abstract

Importance of the field: Although significant progress has been made in delivering therapeutic agents through micro and nanocarriers, precise control over in vivo biodistribution and disease-responsive drug release has been difficult to achieve. This is critical for the success of next generation drug delivery devices, as newer drugs, designed to interfere with cellular functions, must be efficiently and specifically delivered to diseased cells. The chief constraint in achieving this has been our limited repertoire of particle synthesis methods, especially at the nanoscale. Recent developments in generating shape-specific nanocarriers and the potential to combine stimuli-responsive release with nanoscale delivery devices show great promise in overcoming these limitations.

Areas covered in this review: How recent advances in fabrication technology allow synthesis of highly monodisperse, stimuli-responsive, drug-carrying nanoparticles of precise geometries is discussed. How particle properties, specifically shape and stimuli responsiveness, affect biodistribution, cellular uptake and drug release is also reviewed.

What the reader will gain: The reader is introduced to recent developments in intelligent drug nanocarriers and new nanofabrication approaches that can be combined with disease-responsive biomaterials. This will provide insight into the importance of controlling particle geometry and incorporating stimuli-responsive materials into drug delivery.

Take home message: The integration of responsive biomaterials into shape-specific nanocarriers is one of the most promising avenues towards the development of next generation, advanced drug delivery systems.

Figure 1. Schematics of shape-specific nano and microcarrier fabrication methods

(A) Modified Step and Flash Imprint Lithography (S-FIL) method [54]; (B) Particle Replication In Non-wetting Templates process (PRINT)[64]; (C) Solvent molding-based manipulation of spherical particles into non-spherical geometries [61].

Figure 2. Various shape and size specific nanoparticles fabricated using S-FIL, PRINT and Solvent Molding

(A–C) Modified Step and Flash Imprint Lithography (S-FIL) fabricated nanoparticles composed of 75%(v) PEG-diacrylate.[54]: (A) 50 nm × 50 nm × 100 nm pillars, (scale bar = 100 nm), (B) 400 nm × 400 nm × 525 nm particles released from the substrate (scale bar = 2μm), (C) 200 nm × 200nm × 525 nm pillars (scale bar = 500 nm); (D–E) Particle replication in non-wetting templates (PRINT) process: (D) 2 μm wide pillar PRINT particles that are composed of insulin (25%wt) (scale bar = 5 μm) [65], (E) 1 μm diameter by ~500 nm long cylindrical particles composed of 67 wt% trimethylolpropane ethoxylate triacrylate, 20 wt% PEG monomethylether monometharcylate, 10 wt% aminoethyl methacrylate hydrochloride, 2 wt% fluorescein-o-acrylate, and 1 wt% 2,2-diethoxyacetophenone (scale bar = 5 μm) [124]; (F–H) Non-spherical particle geometries formed by solvent molding-based manipulation of spherical polystyrene particles: (F) Elliptical disks (scale bar = 2 μm) [61], (G) “UFOs” (scale bar = 2 μm) [61], and (H) Barrels (scale bar = 2 μm) [61].

Figure 3. Effects of particle shape and size on cellular internalization

(A) Internalization profile of PRINT fabricated particles in HeLa cells over 4 hours. The legend indiates particle diameter and volume [57]. (B–I) SEM images of PRINT particles (all composed of 67 wt% trimethylolpropane ethoxylate triacrylate, 20 wt% PEG monomethylether monometharcylate, 10 wt% aminoethyl methacrylate hydrochloride, 2 wt% fluorescein-o-acrylate, and 1 wt% 2,2-diethoxyacetophenone) evaluated in the internalization study shown in panel A (scale bars = 1μm) [57]: (B) 150 by 450 nm particles, (C) 100 by 300 nm particles, (D) 200 by 200 nm particles; (E–F) Cylindrical microparticles that are 1 μm tall but vary in diameter (scale bars = 1 μm): (E) 0.5 μm and (F) 1 μm; (G–I) Cubic microparticles of varying widths (scale bars = 20 μm): (G) 2 μm, (H) 3 μm, and (I) 5 μm; (J–L) Colored SEM images of aveolar marcophages (brown) interacting with different shape polystyrene particles (purple) [62]: (J) cell membrane engulfing the particle; (scale bar = 10μm) (K) cell attaching itself to the flat side of the elliptical particle (scale bar = 5 μm), and (L) the cell membrane progressing around a spherical particle (scale bar = 5 μm).

Figure 4. Examples of responsive nanocarriers for triggered drug release

(A–C) SEM images demonstrating the enzymatic degradation of imprinted 75% (v) PEGDA-GFLGK-diacrylate nanocarriers: (A) Control particles after 48 h in PBS (i.e., no Cathepsin B) (scale bar = 2 μm), (B) Particles after 12 h in Cathepsin B (25 U/mL) (scale bar = 10 μm), (C) Particles after 48 h in Cathepsin B (25 U/mL) (scale bar = 2 μm). (D) Release profile of stimuli-responsive imprinted PEG-DAGFLGK-DA particles encapsulating 0.16% (w/w) plasmid DNA in response to 20 U/mL Cathepsin B[54]. (E, F) Time-dependent cryogenic transmission electron microscopy of 3:97 (R)-1,2-di-O-(1′Z,9′Z-octadecadienyl)-glyceryl-3-(ω-methoxy-poly(ethylene glycolate), MW5000)/fusogenic lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (BVEP/DOPE) unilamellar liposomes at pH 4.5. Liposomes undergo fusing and drug release over time[17]. (G, H) Photoinduced changes in the aggregation of light sensitive nanoparticles. TEM images for 1.4 wt % 1:3 cetyltrimethylamonium bromide/sodium 4-hexylphenylazosulfonate (CTAB/C6PAS) systems in D₂O (G) before and (H) after irradiation [18].