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Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting.

ABSTRACT: Our goal was to design nanocarriers that specifically target and deliver therapeutics to polarized macrophages. Mannose receptors are highly overexpressed on polarized macrophages. In this study, we constructed Pluronic® -F127 polymer and tannic acid (TA) based nanoparticles (F127-TA core nanoparticles) with varying mannose densities. The particle size of the optimized mannose-decorated F127-TA hybrid nanoparticles (MDNPs) was found to be ~?265?nm with a negative zeta potential of ~ -?4.5?mV. No significant changes in the size and zeta potentials of nanoparticles were observed, which demonstrated structural integrity and stability of the nanoformulation. Physicochemical characteristics of MDNPs were evaluated by FTIR and TGA and demonstrated the presence of mannose units on surface nanoparticles. A mannose-dependent cellular targeting and uptake of MDNPs was found in U937 macrophages. The uptake process was found to vary directly with time and volume of MDNPs nanoparticles. The uptake pattern is higher in M2 than M1. This behavior was also evident from the instantaneous and superior binding profile of M2 macrophage lysate protein with MDNPs over that of M1 macrophage lysate protein. These results demonstrated that an appropriate mannose ligand density was confirmed, suggesting efficient targeting of M2. Altogether, these data support that the MDNPs formulation could serve as a targeted therapeutic guide in the generation of nanomedicine to treat various conditions as an anti-inflammation therapy.

SUBMITTER: Hatami E

PROVIDER: S-EPMC6351286 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting.

Hatami Elham E Mu Ying Y Shields Deanna N DN Chauhan Subhash C SC Kumar Santosh S Cory Theodore J TJ Yallapu Murali M MM

Biochemistry and biophysics reports 20190125

Our goal was to design nanocarriers that specifically target and deliver therapeutics to polarized macrophages. Mannose receptors are highly overexpressed on polarized macrophages. In this study, we constructed Pluronic® -F127 polymer and tannic acid (TA) based nanoparticles (F127-TA core nanoparticles) with varying mannose densities. The particle size of the optimized mannose-decorated F127-TA hybrid nanoparticles (MDNPs) was found to be ~ 265 nm with a negative zeta potential of ~ - 4.5 mV. No ...[more]

PMID: 30723809

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Project description:Novel PEGtide dendrons of generations 1 through 5 (G1.0–5.0) containing alternating discrete poly(ethylene glycol) (dPEG) and amino acid/peptide moieties were designed and developed. To demonstrate their targeting utility as nanocarriers, PEGtide dendrons functionalized with mannose residues were developed and evaluated for macrophage targeting. PEGtide dendrons were synthesized using 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis (SPPS) protocols. The N-α-Fmoc-N-ε-(5-carboxyfluorescein)-l-lysine (Fmoc-Lys(5-FAM)-OH) and monodisperse Fmoc-dPEG6-OH were sequentially coupled to Fmoc-β-Ala-resin to obtain the resin-bound intermediate Fmoc-dPEG6-Lys(5-FAM)-β-Ala (1). G1.0 dendrons were obtained by sequentially coupling Fmoc-Lys(Fmoc)-OH, Fmoc-β-Ala-OH, and Fmoc-dPEG6-OH to 1. Dendrons of higher generation, G2.0–5.0, were obtained by repeating the coupling cycles used for the synthesis of G1.0. Dendrons containing eight mannose residues (G3.0-mannose8) were developed for mannose receptor (MR) mediated macrophage targeting by conjugating α-d-mannopyranosylphenyl isothiocyanate to G3.0 dendrons. In the present study PEGtide dendrons up to G5.0 were synthesized. The molecular weights of the dendrons determined by MALDI-TOF were in agreement with calculated values. The hydrodynamic diameters measured using dynamic light scattering (DLS) ranged from 1 to 8 nm. Cell viability in the presence of G3.0 and G3.0-mannose8 was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and was found to be statistically indistinguishable from that of untreated cells. G3.0-mannose8 exhibited 12-fold higher uptake than unmodified G3.0 control dendrons in MR-expressing J774.E murine macrophage-like cells. Uptake was nearly completely inhibited in the presence of 10 mg/mL mannan, a mannose analogue and known MR substrate. Confocal microscopy studies demonstrated the presence of significant intracellular punctate fluorescence colocalized with a fluid endocytosis marker with little surface fluorescence in cells incubated with G3.0-mannose8. No significant cell-associated fluorescence was observed in cells incubated with G3.0 dendrons that did not contain the targeting ligand mannose. The current studies suggest that PEGtide dendrons could be useful as nanocarriers in drug delivery and imaging applications.

Project description:Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions. Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions. Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site. Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells.

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Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting.

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Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting.

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