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 NCs was 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 89 Å) were synthesized. The uptake of the NC with the 56 Å distance between mannoses was four- and two-fold higher than NCs with 39 Å and 89 Å distances, respectively. Confocal microscopy confirmed that the optimized (Man)2-PEG12kDa NC with the 56 Å 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 56 Å distance between adjacent mannose units.

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

“…It was displayed on efaviranz-packed dendrimers and the resultant dendrimer demonstrated macrophage targeting specificity and moderate anti-HIV activity [124]. Other potential ligands for NCs have also been explored, including a three-residue short peptide fMLF [125] and the monosaccharide mannose [126, 127]. …”

Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

“…Mannose has been used as a macrophagetargeting ligand by various scientists, with encouraging results, including antileishmanial activity of muramyl dipeptide (MDP) and increased macrophagic uptake of efavirenz, rifampin, MDP, etc. (8,(12)(13)(14)(15). The present work was designed to deliver a promising antiparasitic drug (AmB) by using mannose-anchored dendrimers for targeted delivery of AmB to macrophages for treatment of visceral leishmaniasis as a model infectious disease.…”

Targeted Gene Delivery to Macrophages by Biodegradable Star-Shaped Polymers

“…6−8 Thus, a proposed method for cancer treatment is to switch the phenotype of TAMs from M2 to M1 by nucleic acids therapy. 9 The therapeutic gene can be inserted into TAMs isolated from patients to avoid rejection reaction of xenograft in the next treatment procedures. After ex vivo transfection, the TAMs maybe propagated in culture, inoculated back to tumor, and used to modify the tumor microenvironment and to enhance antitumor immunity.…”