Cell-mediated delivery of nanoparticles: taking advantage of circulatory cells to target nanoparticles

Abstract

Cellular hitchhiking leverages the use of circulatory cells to enhance the biological outcome of nanoparticle drug delivery systems, which often suffer from poor circulation time and limited targeting. Cellular hitchhiking utilizes the natural abilities of circulatory cells to: (i) navigate the vasculature while avoiding immune system clearance, (ii) remain relatively inert until needed and (iii) perform specific functions, including nutrient delivery to tissues, clearance of pathogens, and immune system surveillance. A variety of synthetic nanoparticles attempt to mimic these functional attributes of circulatory cells for drug delivery purposes. By combining the advantages of circulatory cells and synthetic nanoparticles, many advanced drug delivery systems have been developed that adopt the concept of cellular hitchhiking. Here, we review the development and specific applications of cellular hitchhiking-based drug delivery systems.

Keywords: Blood; Cell-mediated drug delivery; Cellular hitchhiking; Nanomedicine; Nanoparticles; Nanotechnology.

Figure 1

Advantages of nanoparticles and circulatory cells in drug delivery. (A) Nanoparticle drug delivery systems provide a platform for the synthesis of application specific nanoparticles. Nanoparticles have advantages over their free drug counterparts, such as: (i) the encapsulation and subsequent prevention of rapid degradation of drugs in vivo, (ii) improved targeting via tissue specific ligand conjugation, (iii) controlled rate of drug release via polymer choice and (iv) the potential to mass produce batches of particles. (B) Circulatory cells, including red blood cells, monocytes, platelets, and lymphocytes have natural drug delivery abilities such as: (i) long circulation times, (ii) small molecule delivery systems, (iii) high mobility and flexibility, (iv) antibody production, (v) immune surveillance and (vi) inherent targeting abilities.

Figure 2

Attachment of nanoparticles to circulatory cells. Various methods for incorporating nanoparticles either into or onto the surface of circulatory cells have been employed. (A) Passive adsorption: in this case, adsorption was mediated via hydrophobic, electrostatic, van der Waals and hydrogen bonding to reversibly attach polystyrene nanoparticles to the surface of red blood cells. Adapted with permission from [30]. Copyright (2013) American Chemical Society. (B) Receptor-ligand conjugation: in this case, hyaluronic acid (ligand) functionalized cellular backpacks were attached to the CD44 (receptor) rich surface of macrophages, T-cells (inset i) and B-cells (inset ii). Inset scale bars = 10μm (B) Adapted with permission from [59]. Inset 2B(i) and 2B(ii) adapted with permission from [56]. Copyright (2008) American Chemical Society. (C) Covalent conjugation: in this case, the thiol rich T-cell surface was directly conjugated with maleimide functionalized liposomes. Scale bar = 2μm. Adapted by permission from Macmillan Publishers Ltd: Nature Medicine [60], copyright (2010). (D and E) Internalization of nanoparticles by cells: in this case, gold nanoparticles (D) and catalase nanozymes (E) were incubated with, and internalized by, macrophages. (D) Adapted with permission from [61]. Copyright (2007) American Chemical Society. (E) Adapted with permission from [62]. Copyright (2007) American Chemical Society

Figure 3

Cells are not damaged and maintain their innate functions following nanoparticle hitchhiking. (A) 500 nm polystyrene nanoparticles leave an indent on red blood cells when red blood cell membrane is fixed prior to nanoparticle detachment (inset i). However, upon membrane fixation after nanoparticle detachment, no indent is seen (inset ii). This suggests that while nanoparticles are attached, the red blood cell membrane spreads to accommodate attachment but upon detachment, the red blood cell membrane reversibly returns to its normal structure. Adapted with permission from [30]. Copyright (2013) American Chemical Society. (B) Macrophages functionalized with cellular backpacks via the CD44 receptor are still able to phagocytose polystyrene beads (inset i). The cellular backpack was not internalized for the duration of the experiment (inset ii). (B) Adapted with permission from [59]. (C) Macrophages with gold nanoshells internalized (black) travel into tumor spheroids and accumulate around the hypoxic areas (pink stained cells). (C) Adapted with permission from [61]. Copyright (2007) American Chemical Society. (D) A cellular backpack laden T-cell migrates on ICAM-1 coated slides, mimicking the routine migration that T-cells undergo in vivo. Scale bar = 25μm. Adapted with permission from [56]. Copyright (2008) American Chemical Society. (E) T-cells homogenously functionalized with liposomes interact with target cancer cells. Liposomes reorient at the point of contact and improve T-cell receptor activation during interaction with cancer cells. Scale bar = 2μm. Reprinted from [65] with permission from Elsevier. (F) T-cells with affinity for OVA and functionalized with liposomes are able to home to EG7-OVA tumors exclusively. Adapted by permission from Macmillan Publishers Ltd: Nature Medicine [60], copyright (2010).

Figure 4

Applications of Cellular Hitchhiking. (A) Histology images of brain tissues showing macrophages loaded with iron oxide nanoparticles (stained blue) are able to traverse the blood brain barrier and home to HIV infected brain tissue (stained brown) in HIV infected mice (inset i). No nanoparticles or HIV infection are detected in control mice (inset ii). Adapted with permission from [66]. Copyright 2009. The American Association of Immunologists, Inc. (B) Histology images of brain tissues showing: (inset i) negative control in normal mice, (inset ii) positive control of HIV infected cells (stained brown) in mouse brain and (inset iii) indinavir loaded macrophage treated mice showing reduced infection. Adapted with permission from [66]. Copyright 2009. The American Association of Immunologists, Inc. (C) Real time tracking of nanozymes in an MPTP induced Parkinson's Disease model shows increased delivery of nanozymes via macrophages (inset i), and likely catalase, and persistence in the brain compared to nanozymes alone (inset ii). Adapted from Nanomedicine [63] with permission of Future Medicine Ltd. (D) Human whole blood derived monocytes/macrophages target brain metastases. Adapted with permission from [67]. (E) Hitchhiked T-cells functionalized with adjuvant liposomes completely eradicate lung and bone metastases unlike T-cells alone, T-cells with non-hitchhiked adjuvants and control groups. Adapted by permission from Macmillan Publishers Ltd: Nature Medicine [60], copyright (2010).