Polymeric carriers: role of geometry in drug delivery

Abstract

The unique properties of synthetic nanostructures promise a diverse set of applications as carriers for drug delivery, which are advantageous in terms of biocompatibility, pharmacokinetics, targeting and controlled drug release. Historically, more traditional drug delivery systems have focused on spherical carriers. However, there is a growing interest in pursuing non-spherical carriers, such as elongated or filamentous morphologies, now available due to novel formulation strategies. Unique physiochemical properties of these supramolecular structures offer distinct advantages as drug delivery systems. In particular, results of recent studies in cell cultures and lab animals indicate that rational design of carriers of a given geometry (size and shape) offers an unprecedented control of their longevity in circulation and targeting to selected cellular and subcellular locations. This article reviews drug delivery aspects of non-spherical drug delivery systems, including material selection and formulation, drug loading and release, biocompatibility, circulation behavior, targeting and subcellular addressing.

Figure 1. DDS geometries

Schematics of the different geometry carriers are shown in order of increasing aspect ratio. It should be noted that PRINT particles are crosslinked PEG nanogels, as opposed to the other PEGylated drug delivery systems (DDS) where one end of the PEG is free. Blue indicates PEGylation. Red indicates hydrophobic polymer. Thick black lines on liposomes represent polar groups of phospholipids, while yellow indicates non-polar tails. A blown-up fluorescence microscopy image of PEO – PCL filomicelle is shown, where the carrier was stained with the lipophilic dye PKH26. Scale bar is 10 μm. Filomicelles were formed with standard film casting/dehydration and subsequent rehydration with polymer purchased from Polymer Source Inc., Dorval (Montreal), Quebec, Canada. The common chemical structure is shown in the blown-up image of CNT. Structure is 5,5-armchair conformation for a non-spiraled SWNT.

Figure 2. Degradation and crystallinity

A. Crystallinity is enhanced by tighter packing of polymer chains, depicted as black bars. Higher crystallinity reduces water penetration, depicted as blue circles, and thus slows down hydrolytic polymer degradation. B. Introduction of sidegroups with a uniformly chiral carbon backbone (shorter, red bars), such as methyl or ethyl groups, increase the minimum space between packed polymer chains, thus further enhancing water penetration and polymer degradation. C. This reduced efficiency in polymer chain packing is exacerbated when randomly two-handed polymers, that is a racemic mixture, are combined into a structure, yet again enhancing water penetration/degradation.

Figure 3. Size and shape effects on circulation

A. Size of the spherical drug delivery system determines the mechanism and rate of clearance. Structures which are smaller than 20nm readily pass through the fenestrated endothelium of the kidney, liver and spleen, resulting in a relatively rapid rate of clearance from the circulation. When the spherical particle diameter increases to > 1 μm, momentum effects begin to dominate and collision with macrophages become common, resulting in increased clearance. However, when the size falls between these two extremes, circulation times are greatly enhanced due the avoidance of these size-dependant clearance mechanisms. B. Effect of aspect ratio on circulation. A particle moving in along with a fluid has an internal momentum force and is being acted upon by the surrounding fluid forces. When a directional change in the vessel occurs, the fluid force acts upon the carried particle to change its direction. If the particle’s momentum force exceeds the capability of the fluid force to change direction, it will collide with the vascular wall. Wall collisions increase the likelihood of interactions with the macrophages, thereby increasing the clearance rate. Flexible, elongated structures, like filomicelles, have an increased sensitivity to fluid forces, due to the aerodynamic properties brought upon by their shape. This results in structures whose momentum can be easily changed to match that of the fluid and thereby reduce the number of wall collisions. EC: Endothelial cell; f: Small intra-endothelial fenestrae (<200 nm diameter); F: Large inter-endothelial fenestrae (1–5 micron) in the reticuloendothelial system.

Figure 4. Phagocytosis of anisotropic geometries

The initial point of contact of a disk-shaped carrier (e.g., 0.1 × 1 ×3 μm) with a macrophage determines whether or not phagocytosis/internalization occurs. A. The angle, θ, between the vector normal to the surface of the cell (T⃑) at the point of contact and the vector from the point of contact through the midline of the carrier (N⃑) predicts whether complete phagocytosis occurs [19]. B. For larger θ, phagocytosis is inhibited. C. However, for small θ, internalization is possible, even when the major axis of the carrier is larger than a few microns.