TY - JOUR
T1 - Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers
AU - D'Addio, Suzanne M.
AU - Baldassano, Steven
AU - Shi, Lei
AU - Cheung, Lila
AU - Adamson, Douglas H.
AU - Bruzek, Matthew
AU - Anthony, John E.
AU - Laskin, Debra L.
AU - Sinko, Patrick J.
AU - Prud'Homme, Robert K.
N1 - Funding Information:
This work made use of the Confocal & Electron Microscopy Core Facility at Princeton University and the authors acknowledge Joe Goodhouse for the expert help with confocal microscopy. This research was supported with funding from the National Science Foundation NIRT award ( CBET-0506966 ), the National Institutes of Health ( RO1 CA155061 , R37 AI051214 , U54AR055073 , R01GM034310 , R01ES004738 , and P30ES005022 ), and the Lidlow Senior Thesis Fund .
PY - 2013/5/28
Y1 - 2013/5/28
N2 - Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly. Nanocarrier association with murine macrophage J774 cells expressing the MR is examined as a function of incubation time and temperature, nanocarrier size, dose, and PEG corona properties. Amphiphilic diblock copolymers are prepared with terminal hydroxyl, methoxy, or mannoside functionality and incorporated into nanocarrier formulations at specific ratios by Flash NanoPrecipitation. Association of nanocarriers protected by a hydroxyl-terminated PEG corona with J774 cells is size dependent, while nanocarriers with methoxy-terminated PEG coronas do not associate with cells, regardless of size. Specific targeting of the MR is investigated using nanocarriers having 0-75% mannoside-terminated PEG chains in the PEG corona. This is a wider range of mannose densities than has been previously studied. Maximum nanocarrier association is attained with 9% mannoside-terminated PEG chains, increasing uptake more than 3-fold compared to non-targeted nanocarriers with a 5 kg mol- 1 methoxy-terminated PEG corona. While a 5 kg mol- 1 methoxy-terminated PEG corona prevents non-specific uptake, a 1.8 kg mol- 1 methoxy-terminated PEG corona does not sufficiently protect the nanocarriers from nonspecific association. There is continuous uptake of MR-targeted nanocarriers at 37 C, but a saturation of association at 4 C. The majority of targeted nanocarriers associated with J774E cells are internalized at 37 C and uptake is receptor-dependent, diminishing with competitive inhibition by dextran. This characterization of nanocarrier uptake and targeting provides promise for optimizing drug delivery to macrophages for TB treatment and establishes a general route for optimizing targeted formulations of nanocarriers for specific delivery at targeted sites.
AB - Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly. Nanocarrier association with murine macrophage J774 cells expressing the MR is examined as a function of incubation time and temperature, nanocarrier size, dose, and PEG corona properties. Amphiphilic diblock copolymers are prepared with terminal hydroxyl, methoxy, or mannoside functionality and incorporated into nanocarrier formulations at specific ratios by Flash NanoPrecipitation. Association of nanocarriers protected by a hydroxyl-terminated PEG corona with J774 cells is size dependent, while nanocarriers with methoxy-terminated PEG coronas do not associate with cells, regardless of size. Specific targeting of the MR is investigated using nanocarriers having 0-75% mannoside-terminated PEG chains in the PEG corona. This is a wider range of mannose densities than has been previously studied. Maximum nanocarrier association is attained with 9% mannoside-terminated PEG chains, increasing uptake more than 3-fold compared to non-targeted nanocarriers with a 5 kg mol- 1 methoxy-terminated PEG corona. While a 5 kg mol- 1 methoxy-terminated PEG corona prevents non-specific uptake, a 1.8 kg mol- 1 methoxy-terminated PEG corona does not sufficiently protect the nanocarriers from nonspecific association. There is continuous uptake of MR-targeted nanocarriers at 37 C, but a saturation of association at 4 C. The majority of targeted nanocarriers associated with J774E cells are internalized at 37 C and uptake is receptor-dependent, diminishing with competitive inhibition by dextran. This characterization of nanocarrier uptake and targeting provides promise for optimizing drug delivery to macrophages for TB treatment and establishes a general route for optimizing targeted formulations of nanocarriers for specific delivery at targeted sites.
KW - Flash nanoprecipitation
KW - Macrophage
KW - Mannose receptor
KW - Nanoparticle
KW - Targeted drug delivery
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UR - http://www.scopus.com/inward/citedby.url?scp=84875486013&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2013.02.004
DO - 10.1016/j.jconrel.2013.02.004
M3 - Article
C2 - 23419950
AN - SCOPUS:84875486013
SN - 0168-3659
VL - 168
SP - 41
EP - 49
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -