Document Detail


Optimal structural design of mannosylated nanocarriers for macrophage targeting.
MedLine Citation:
PMID:  25220160     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Macrophages are involved in a number of diseases, such as HIV infection/AIDS, tuberculosis, tumor development and atherosclerosis. Macrophages possess several cell surface receptors (e.g., the mannose receptor, MR) that may serve as drug delivery cellular portals for nanocarriers (NCs). In this study, the optimal structural configuration for cell uptake of mannosylated poly(ethylene glycol)-conjugate type NCs was determined. A series of NCs were synthesized to systematically evaluate the effects of the number of mannose units (Man), the PEG carrier size and the mPEG spacer length between adjacent mannose units on NC uptake into MR-expressing J774.E murine macrophage-like cells. Among NCs with 0, 1, 2 or 4 units of mannose, the uptake of (Man)2-NC was the highest, suggesting a trade-off between avidity and NC-MR clustering on the cell surface that sterically hinders endocytosis. This optimal (Man)2-NC configuration was built into subsequent NCs to optimize the other two parameters, PEG carrier size and spacer length. NCs with 0, 5, 12, 20, 30 or 40kDa linear PEG carriers showed an inverse relationship between PEG size and uptake. The 12kDa PEG carrier was chosen for investigating the third parameter, the Man-Man distance, since it may represent the best trade off (i.e., tissue penetration vs. systemic clearance) for in vivo macrophage targeting. Three (Man)2-PEG12kDa NCs with different Man-Man distances (39, 56 or 89Å) were synthesized. The uptake of the NC with the 56Å distance between mannoses was four- and two-fold higher than NCs with 39Å and 89Å distances, respectively. Confocal microscopy confirmed that the optimized (Man)2-PEG12kDa NC with the 56Å Man-Man distance was internalized via endocytosis consistent with temperature-dependent active uptake. In conclusion, the optimal NC structural parameters for targeting the MR on macrophage-like J774.E cells are (i) a small PEG polymer carrier, (ii) two mannose units per NC and (iii) a 56Å distance between adjacent mannose units.
Authors:
Peiming Chen; Xiaoping Zhang; Lee Jia; Robert K Prud'homme; Zoltan Szekely; Patrick J Sinko
Publication Detail:
Type:  Journal Article     Date:  2014-09-16
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  194     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-12-02     Completed Date:  -     Revised Date:  2014-12-04    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  341-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 Elsevier B.V. All rights reserved.
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Grant Support
ID/Acronym/Agency:
R01 AI051214/AI/NIAID NIH HHS; R01 CA155061/CA/NCI NIH HHS; U54 AR055073/AR/NIAMS NIH HHS

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