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Posted: May 10, 2011

Strapping backpacks on macrophages to deliver drugs

(Nanowerk Spotlight) Macrophages are white blood cells with a wide presence in various organs and tissues, that perform an essential role in keeping organisms healthy by scavenging cellular debris and disease agents. Since macrophages play an indispensable role in most pathological conditions, they represent an ideal target for therapeutic applications.
Several approaches seeking to use macrophages for targeted therapies involve feeding therapeutic nanoparticles to macrophages ex vivo, followed by re-injection of the macrophages to target the diseased site. In research conducted during the past few years, this has shown promising results for treating HIV infections ("Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery"), brain disorders ("Macrophage Delivery of Nanoformulated Antiretroviral Drug to the Brain in a Murine Model of NeuroAIDS"), and solid tumors ("A Cellular Trojan Horse for Delivery of Therapeutic Nanoparticles into Tumors"). These techniques are often hampered by reduced drug release rates and drug degradation.
Overcoming these limitations, scientists now report the ability of cellular backpacks to successfully encapsulate and controllably release drugs and avoid phagocytic internalization while remaining on the macrophage's surface.
"These characteristics point to new possibilities in creating cell-based bio-hybrid devices that leverage both the functions of the encapsulated cargo – drugs, nanoparticles, etc. – and the native functions of the cell," says Samir Mitragoti, a professor in the Department of Chemical Engineering at the University of California, Santa Barbara.
HA coated backpack attached to the surface of a macrophage
Backpacks for cell-based drug delivery devices: hyaluronic acid coated backpack attached to the surface of a macrophage (Reprinted with permission from Wiley-VCH Verlag)
Reporting their findings in a recent paper in Advanced Materials ("Cell-Based Drug Delivery Devices Using Phagocytosis-Resistant Backpacks"), Mitragoti's group and collaborators from MIT (Rubner Group, Cohen Group) say that cellular backpacks provide a unique opportunity for drug delivery and therapy since the polyelectrolyte multilayers that comprise much of the backpack are well studied for their biomedical applications and drug delivery properties.
The results show that cellular backpacks are capable of delivering a model protein in a controlled and sustained manner in vitro. Backpacks remained attached to macrophage surfaces without internalization even 50 minutes after introduction.
The team fabricated their cellular backpacks – i.e. nanoscale-thickness microparticles – using a standard photolithography lift-off technique of layer-by-layer and spray deposited film. The backpacks are engineered to contain therapeutic or diagnostic materials, such as small molecule drugs, proteins, nanoparticles, or functional polymers, and attach to the surface of a cell using a non-toxic mechanism relying upon a natural ligand-receptor interaction such as the HA-CD44-mediated adhesion used in this study.
"Macrophages are routinely recruited to diseased sites, potentially making them highly efficient targeting devices," write the authors. "If non-native entities could be attached to these macrophages without being phagocytosed, these cells could serve as ideal chaperones for delivering drugs or other therapeutic tools to various pathological tissues. This is particularly attractive for the treatment of cancer and inflammatory disorders, where macrophages are very strongly recruited."
The researchers point out that long-term immobilization of any particle on the surface of phagocytic cells like macrophages is extremely difficult. "Various properties of particles, particularly their size, surface chemistry, shape, and mechanical flexibility have been shown to play a critical role in phagocytosis."
According to the team, "voiding internalization by macrophages is a key feature of the backpack, but equally important is the observation that backpack attachment does not interfere with the macrophage's native cellular functions. The results of the MTT proliferation assay suggest that backpacks are not toxic and do not affect the cell proliferation capacity. Furthermore, backpack attachment did not adversely affect a macrophage's ability to internalize particles that are otherwise phagocytosable."
Although it appears that cellular backpacks provide a unique opportunity for drug delivery and therapy, further investigation is needed to understand whether or not backpack attachment affects other macrophage functions, including the release of chemokines and cytokines.
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