Biomimetic delivery with micro- and nanoparticles

Abstract

The nascent field of biomimetic delivery with micro- and nanoparticles (MNP) has advanced considerably in recent years. Drawing inspiration from the ways that cells communicate in the body, several different modes of "delivery" (i.e., temporospatial presentation of biological signals) have been investigated in a number of therapeutic contexts. In particular, this review focuses on (1) controlled release formulations that deliver natural soluble factors with physiologically relevant temporal context, (2) presentation of surface-bound ligands to cells, with spatial organization of ligands ranging from isotropic to dynamically anisotropic, and (3) physical properties of particles, including size, shape and mechanical stiffness, which mimic those of natural cells. Importantly, the context provided by multimodal, or multifactor delivery represents a key element of most biomimetic MNP systems, a concept illustrated by an analogy to human interpersonal communication. Regulatory implications of increasingly sophisticated and "cell-like" biomimetic MNP systems are also discussed.

Figure 1

Schematic illustrating effects of soluble paracrine signaling factors and rational design of biomimetic MNP. (a) Soluble factors locally released by cells may promote proliferation, differentiation, and/or reorganization of cells to form structured tissues. Different paracrine factors act as instructions for diverse transitions from one “state” to another, where a “state” refers to the particular quantity, phenotype, and organization of cells. Although sequential secretion of factors X and Y is depicted, simultaneous secretion of multiple factors, and more complex temporal patterns with two or more factors also occur in nature. Such factors may also be secreted by the same cell or by multiple different cells. (b) For rational design of biomimetic MNP, the temporal patterns of local concentrations of factors can be input into mathematical models, used to guide the design of controlled release formulations. Outputs of the model include design parameters, in this case for two different MNP formulations. These design parameters serve as recipes for fabrication of MNP with release profiles that mimic the natural temporal patterns of factor secretion.

Figure 2

Two approaches to multifactor delivery. (a) An injected depot containing a mixture of two MNP formulations (red and blue) that each release distinct individual factors (squares and triangles) mimics the secretion of factors by different cell populations in a local area. Cells not immediately adjacent to a depot (i.e. distal cell) with segregated particles perceive a mixture of both factors coming from the same direction (top). In contrast, cells approaching the depot site would “see” the two factors originating from a different location (bottom). (b) A depot containing composite, multi-compartmental MNP (purple), which release both factors, can mimic dual factor secretion by a single cell. As with the mixed MNP depot, distal cells perceive both factors coming from the same source (top). However, cells immediately adjacent to composite particles now “see” both factors originating from the same location (bottom).

Figure 3

Three ligands (recognition (red), costimulatory (green), and adhesion (blue)) that could be presented on the surface of artificial antigen presenting cells (aAPCs) in various ways. (a) Isotropic surface presentation of randomly distributed ligands. All three ligands are presented uniformly over the particle surface. (b)Anisotropic presentation of ligands in a patch pattern on the surface of a particle. Recognition and costimulatory ligands are randomly distributed in the patch, with a surrounding field of adhesion ligands. (c) Dynamic anisotropic presentation of ligands on a fluid supported lipid bilayer (SLB; yellow). Before interactions with a cell (e.g. T cell), lower initial surface density of randomly distributed ligands may be placed on the SLB surface. Anisotropic reorganization of ligands occurs in response to interactions with a cell. The resulting bull’s eye pattern would be characteristic of a natural supramolecular activation clusters (SMAC) formed at immune synapse between a T cell and APC.

Figure 4

A method to achieve biomimetic ligand composition on the surface of nanoparticles (NPs) by coating them with cellular membranes, including associated membrane proteins. Reproduced with permission from ^[106]. Copyright 2011, National Academy of Sciences, USA.

Figure 5

Three approaches to protein ligand patterning on the surface of particles. (a) Electrodynamic jetting with parallel streams of two distinct polymer solutions (blue and grey) results in biphasic Janus particles. The presence of different functionalities (R1 and R2) on opposite hemispheres enables selective surface modification with two ligands (red circles and green triangles) via two bioconjugation schemes. A fluorescence micrograph shows Janus particles dually labeled with rhodamine (red) and BODIPY dye (green) (bar = 2µm). Adapted with permission from ^[51]. Copyright 2005, Nature Publishing Group. (b) Reactive ion etching, followed by gold vapor deposition on a colloidal crystal of microparticles, results in different patterns of gold patches on the third layer of particles, depending on the crystal structure. SEM images depict two possible patterns of gold patches achieved with the corresponding crystal structures (bars = 2µm). Subsequent conjugation of ligands (blue teardrops) to the gold patches may be possible through thiol (-SH) conjugation chemistry. Adapted with permission from ^[141]. (c) Liquid polydimethylsiloxane (PDMS) applied to a colloidal crystal selectively solidifies at points of contact between microspheres. The resulting patchy masks allows for sequential protein labeling of the different regions (masked and unmasked) via various bioconjugation methods. Fluorescence micrograph shows patchy particles with regions presenting different fluorescently labeled proteins (bar = 10µm). Adapted with permission from ^[142].

Figure 6

Dynamic surface ligand-receptor interactions between SLB protocells and Hep3B cancer cells. (a) A fluid SLB binds to a cell with high avidity by recruitment of SP94 peptide ligands to the cell surface, and internalization by receptor-mediated endocytosis follows the dynamic binding event. (b) When presented on a fluid SLB (green), Alexa Fluor 647-labeled SP94 peptide ligands (white) are recruited to the surface of a Hep3B cell (red). Such dynamic reorganization of presented ligands is not seen with a non-fluid SLB. Adapted with permission from ^[157]. Copyright 2011, Nature Publishing Group.

Figure 7

Two methods to produce particles that mimic the shape and mechanical properties of red blood cells (RBC). (a) PLGA microspheres produced by electrodynamic jetting collapse into a discoidal shape due to partial fluidization of the PLGA core by 2-propanol. The resulting template is uniformly coated with cross-linked proteins in a layer-by-layer (LbL) process, and the PLGA core dissolved by organic solvents, leaving flexible protein shell particles. The number of protein layers dictates particle stiffness, allowing for physiologically relevant mechanical properties. SEM images show the semblance between RBC-mimics and mouse RBCs (bars = 5µm). Adapted with permission from ^[184]. Copyright 2009, National Academy of Sciences, USA. (b) Cross-linked hydrogel, RBC-shaped particles fabricated by the PRINT® (Particle Replication in Non-wetting Templates) process. Prepolymer is pressed into the RBC-shaped wells of a mold, and cross-linked by UV light, with the degree of cross-linking dictating particle stiffness. Freezing in water, peeling away the mold from particles trapped in ice, and allowing the ice to melt results in free particles. Fluorescent image shows RBC-shaped hydrogel particles (bar = 20µm). Adapted with permission from ^[185]. Copyright 2011, National Academy of Sciences, USA.

Figure 8

Combinations of various types of information produce an integrated message. (a) Cell-to-cell communication between a dendritic cell (yellow) and a T cell (green) involves at least three signals: (i) MHC-peptide presentation to TCR, (ii) costimulatory ligand presentation to T cell, and (iii) secreted soluble cytokines. (b) Similarly, interpersonal communication between two individuals generally involves multiple forms of exchange, such as (i) eye contact, (ii) a handshake, and (iii) a verbal exchange.