Top-down particle fabrication: control of size and shape for diagnostic imaging and drug delivery

Abstract

This review discusses rational design of particles for use as therapeutic vectors and diagnostic imaging agent carriers. The emerging importance of both particle size and shape is considered, and the adaptation and modification of soft lithography methods to produce nanoparticles are highlighted. To this end, studies utilizing particles made via a process called Particle Replication In Non-wetting Templates are discussed. In addition, insights gained into therapeutic cargo and imaging agent delivery from related types of polymer-based carriers are considered.

Figure 1

Schematic representation of the PRINT process. a.) Empty mold (green), high surface energy polymer sheet (clear), roller (black) is brought into contact with the particle precursor solution (red) and the mold; b.) Roller evenly distributes particle precursor solution into the cavities of mold. Excess particle precursor solution is wicked away by the high surface energy polymer sheet; c.) Particles are cured in the mold; d.) Particles are removed from the mold; e.) Particles are collected or harvested using a number of different film based techniques and ultimately are dispersed in solution.

Figure 2

Continuous thin mold manufacturing for the PRINT process. Patterned surface can be seen in green. Reprinted with permission from Liquidia Technologies.[71]

Figure 3

SEM images of particles of various sizes, shapes, and compositions prepared via the PRINT process: (A) Hydrogel rods containing antisense oligonucleotide; (B) crosslinked degradable matrix cubes containing Doxorubicin HCl; (C) Abraxane^™ harvested onto medical adhesive; (D) Insulin particles harvested onto a medical adhesive; (E) Hydrogel “boomerangs” containing 15 wt% iron oxide; (F) Hydrogel cylinders containing 10 wt% Omniscan^™. Reprinted with permission from references (B) [47];(C) [48]; (D) [48]; (E) [46].

Figure 4

TEM showing HeLa cell internalization of 150 nm × 450 nm (top) or 200 nm × 200 nm (bottom) cylindrical particles fabricated via the PRINT process. Reprinted with permission from [44].

Figure 5

SEM images of S-FIL imprinted (100% w/v, MW 3400) PEGDA nanoparticles: (A) 50 nm squares (scale bar = 100 nm), (B) 100 nm squares (scale bar = 200 nm), (C) 200 nm squares (scale bar = 300 nm), (D) 200 nm triangles (scale bar = 200 nm), (E) 400 nm triangles (scale bar = 300 nm), and (F) 400 nm pentagonal particles (scale bar = 200 nm). Reprinted with permission from [68]

Figure 6

a) Scanning electron micrographs and 3D illustrations of PS particles created for phagocytosis experiments. (A) Spheres. (B) Oblate ellipsoids (13%). (C) Prolate ellipsoids (7%). (D) Elliptical disks (9%). (E) Rectangular disks (5%). (F) UFOs (12%). Particles are monodispersed with average standard deviations of measured dimensions for each shape listed in parentheses. A portion of this variation is due to 2–5%standard deviation in the diameter of spheres used as starting materials. (Scale bars: 5 m.) Reprinted with permission from [62]

Figure 7

Magneto-polymer composite polymer particles of well defined size and shape prepared via the PRINT process: (A) SEM image of 200 nm × 200 nm cylinders, (B) SEM image of 2×2×2 micron cubes (C) TEM of biocompatible 200 × 200 nm particle containing 15 wt% PEG-silane coated iron oxide nanocrystals, and (D) T2 phantom study of iron oxide containing particles in agarose gel. Equimolar concentrations of PRINT particles with increasing iron oxide loading.

Figure 8

T1 weighted MR images a bolus injection of 200 × 200 nm cylindrical particles (a) just before (b) and 60 minutes post (c) injection.

Figure 9

MicroPET imaging with 64Cu-DOTA PRINT particles. Time resolved PET images consisting of a two hour dynamic scan. The PET/CT images are overlayed. Mouse was injected with 136.2 μCi of ⁶⁴Cu-labeled DOTA-nanoparticle. Both the coronal view (top), and sagittal view (bottom) are presented. Reprinted with permission from [45]