期刊
JOURNAL OF CONTROLLED RELEASE
卷 168, 期 1, 页码 41-49出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.02.004
关键词
Flash nanoprecipitation; Mannose receptor; Nanoparticle; Macrophage; Targeted drug delivery
资金
- National Science Foundation NIRT award [CBET-0506966]
- National Institutes of Health [RO1 CA155061, R37 AI051214, U54AR055073, R01GM034310, R01ES004738, P30ES005022]
- Lidlow Senior Thesis Fund
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 degrees C, but a saturation of association at 4 degrees C. The majority of targeted nanocarriers associated with J774E cells are internalized at 37 degrees 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. (C) 2013 Elsevier B.V. All rights reserved.
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