Multi-stage delivery nano-particle systems for therapeutic applications

Abstract

Background: The daunting task for drug molecules to reach pathological lesions has fueled rapid advances in Nanomedicine. The progressive evolution of nanovectors has led to the development of multi-stage delivery systems aimed at overcoming the numerous obstacles encountered by nanovectors on their journey to the target site.

Scope of review: This review summarizes major findings with respect to silicon-based drug delivery vectors for cancer therapeutics and imaging. Based on rational design, well-established silicon technologies have been adapted for the fabrication of nanovectors with specific shapes, sizes, and porosities. These vectors are part of a multi-stage delivery system that contains multiple nano-components, each designed to achieve a specific task with the common goal of site-directed delivery of therapeutics.

Major conclusions: Quasi-hemispherical and discoidal silicon microparticles are superior to spherical particles with respect to margination in the blood, with particles of different shapes and sizes having unique distributions in vivo. Cellular adhesion and internalization of silicon microparticles is influenced by microparticle shape and surface charge, with the latter dictating binding of serum opsonins. Based on in vitro cell studies, the internalization of porous silicon microparticles by endothelial cells and macrophages is compatible with cellular morphology, intracellular trafficking, mitosis, cell cycle progression, cytokine release, and cell viability. In vivo studies support superior therapeutic efficacy of liposomal encapsulated siRNA when delivered in multi-stage systems compared to free nanoparticles. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.

Figure 1

The schematic representation of three generations of nanovectors shows first generation vectors with passive tumor targeting by means of EPR (top), followed by externally activated (A) or actively targeted (B) second generation vectors (middle), and multi-functional, third generation vectors comprised of multiple components that perform time-sequences of events (bottom). Reproduced from Sakamoto et al [90] courtesy of Elsevier.

Figure 2

Flow chamber determination of the number of particles (n), based on shape, marginating towards endothelial cells per second as a function of shear rate. Discoidal particles marginate at the highest frequency for all shear rates, followed by quasi-hemispherical particles, and then spherical particles. Reproduced from Gentile et al. [40], courtesy of Elsevier.

Figure 3

Tissue distribution of silicon relative to the injected dose of silicon microparticles. The percentage of silicon is reflective of the number of particles of various shapes accumulating in each organ 6 hrs after intravascular injection of microparticles into mice containing orthotopic breast tumors. Reproduced from Decuzzi et al.[43], courtesy of Elsevier.

Figure 4

Outline of the fabrication protocol for porous silicon particles (a–d) and SEM micrographs of the resulting particles (e–g). (a) A silicon substrate masked with silicon nitride is patterned through photolithography; (b) trenches are formed in the silicon by reactive ion etch; (c) the trenches are selectively porosified by electrochemical etch in a solution of hydrofluoric acid and ethanol; (d) the particles are released from the substrate by sonication in isopropanol; (e) backside of a 1.6 µm particle laying on the external corona of a 3.2 µm particle; (f) overview of a collection of 3.2 µm discoidal particles. (g) left: typical porous structure ranging from 10 to 20 nm; right: typical porous structure for pores larger than 20 nm.

Figure 5

Biocompatibility of porous silicon microparticles. A) Scanning electron micrographs show endothelial binding (left) and internalization (right) of silicon (Si) microparticles loaded with gold nanoparticles (scale bars 1 µm). B) Endothelial proliferation (formazan absorbance at 570 nm) is unaffected by either control or nanoparticle [iron oxide (IO) or gold (Au)] loaded silicon microparticles (left 5:1; right 10:1; particles:cells). Adapted from Serda et al. [88], courtesy of RSC Publishing.

Figure 6

Loading of annamycin liposomes into porous silicon microparticles. Fluorescence associated with hemispherical nanoporous particles before (left panel) and after (right panel) loading.

Figure 7

Scanning electron micrographs show endothelial binding and engulfment of 1.6 µm (top row) and 3.2 µm (bottom row) silicon microparticles [bars 5 µm (left) and 1 µm (right)]. Reproduced from Serda et al. [88], courtesy of RSC Publishing.

Figure 8

Endothelial cells internalize silicon microparticles by rearrangement of the actin cytoskeleton. Transmission electron micrographs show internalization of larger, 3.2 µm particles by phagocytosis (A) and smaller, 1.6 µm, particles by macropinocytosis (B). Adapted from Serda et al. [87], courtesy of Elsevier.

Figure 9

Endothelial cells undergo mitosis with equal partitioning of silicon microparticle-encapsulated endosomes between the daughter cells, as captured by real-time confocal imaging. Adapted from Serda et al. [88], courtesy of RSC Publishing.