In vivo targeting of alveolar macrophages via RAFT-based glycopolymers

Abstract

Targeting cell populations via endogenous carbohydrate receptors is an appealing approach for drug delivery. However, to be effective, this strategy requires the production of high affinity carbohydrate ligands capable of engaging with specific cell-surface lectins. To develop materials that exhibit high affinity towards these receptors, we synthesized glycopolymers displaying pendant carbohydrate moieties from carbohydrate-functionalized monomer precursors via reversible addition-fragmentation chain transfer (RAFT) polymerization. These glycopolymers were fluorescently labeled and used to determine macrophage-specific targeting both in vitro and in vivo. Mannose- and N-acetylglucosamine-containing glycopolymers were shown to specifically target mouse bone marrow-derived macrophages (BMDMs) in vitro in a dose-dependent manner as compared to a galactose-containing glycopolymer (30- and 19-fold higher uptake, respectively). In addition, upon macrophage differentiation, the mannose glycopolymer exhibited enhanced uptake in M2-polarized macrophages, an anti-inflammatory macrophage phenotype prevalent in injured tissue. This carbohydrate-specific uptake was retained in vivo, as alveolar macrophages demonstrated 6-fold higher internalization of mannose glycopolymer, as compared to galactose, following intratracheal administration in mice. We have shown the successful synthesis of a class of functional RAFT glycopolymers capable of macrophage-type specific uptake both in vitro and in vivo, with significant implications for the design of future targeted drug delivery systems.

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

“…[16][17][18][19][20][21][22] Furthermore, ligating immune-stimulatory small molecules to supramolecular structures should reduce systemic levels and confine the inflammatory activity to lymphatic tissues. 23,24 Although, the synthesis of mannosylated polymers and nanoparticle derived thereof has been extensively reported 7,[25][26][27] and explored for DC targeting 28,29 , the efficacy of unambiguously targeting the mannose receptor CD206 on DCs remains elusive. This can be attributed to the use of immortalized DC cell lines 30 that only show low expression of the mannose receptor or the use of controls that could exhibit inherent fewer cell interaction.…”

Facile and Efficient Preparation of Tri-component Fluorescent Glycopolymers via RAFT-controlled Polymerization

“…Characterizing the distribution of different monomers within the polymer is still very challenging. The post-modification method, presented here, is both simpler and more amenable to the use of a wider selection of fluorescent labels, compared to other protocols applied to label glycopolymers 2,11 . These would include many of the water-soluble amine-reactive fluorophores, quantum dots, biotins, and others.…”

“…In the past two decades, investigations with synthetic glycopolymers have undergone slow but continual development, demonstrating significant potential in examining infectious mechanisms that include research which focuses on lectin recognition processes [1][2][3] . Since synthetic glycopolymers possessing multivalent sugar moieties exhibit much higher lectin-binding efficacies, as compared to monovalent carbohydrates, they are of great demand in the glycobiology field 3 .…”

Synthesis of Glycopolymer Architectures by Reversible-Deactivation Radical Polymerization

“…Table 3 summarizes the reults obtained for the synthesis of glycopolymers by RAFT polymerization [12,. In their study on thermoresponsive glycopolymers, Voit et al [161] described both the RAFT homopolymerization of glucofuranose methacrylamides M48 and M49 bearing a hydrophobic linker and their copolymerization with NIPAAm M42 (Entry 145-149, Table 3).…”

“…This is due to the expectation that polymers displaying carbohydrate functionalities, similar to those of natural glycoconjugates, might be able to mimic, or even exceed, their performance in specific applications (biomimetic approach). More in general, studies have been published on their use of as macromolecular drugs [2][3][4][5][6][7][8], drug delivery systems [9][10][11][12], cell culture substrates [13,14], stationary phase in separation problems [15,16] and bioassays [17]; responsive [18] and catalytic [19] hydrogels, surface modifiers [20][21][22][23], artificial tissues and artificial organ substrates [13].…”