title: Optimal structural design of mannosylated nanocarriers for macrophage targeting.
abstract: 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 40 kDa linear PEG carriers showed an inverse relationship between PEG size and uptake. The 12 kDa 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.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. Electronic address: pmchenru@gmail.com.
authors.forename: Peiming
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. Electronic address: xzhang@rci.rutgers.edu.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350002, China. Electronic address: pharmlink@gmail.com.
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.affiliation: Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA. Electronic address: prudhomm@princeton.edu.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Prud'homme
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. Electronic address: zoltan@rci.rutgers.edu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szekely
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. Electronic address: sinko@rutgers.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
mesh_terms: D000818:Animals; D002460:Cell Line; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008358:Mannose / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D009569:Nitric Oxide / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats
chemical_list: D004337:Drug Carriers; D011108:Polymers; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D008358:Mannose
keywords: Drug delivery; HIV-1; Ligand design; Mannose receptor; Nanocarrier