Mannosylated Cationic Copolymers for Gene Delivery to Macrophages

Abstract

Macrophages are desirable targets for gene therapy of cancer and other diseases. Cationic diblock copolymers of polyethylene glycol (PEG) and poly‐L‐lysine (PLL) or poly{N‐[N‐(2‐aminoethyl)‐2‐aminoethyl]aspartamide} (pAsp(DET)) are synthesized and used to form polyplexes with a plasmid DNA (pDNA) that are decorated with mannose moieties, serving as the targeting ligands for the C type lectin receptors displayed at the surface of macrophages. The PEG‐b‐PLL copolymers are known for its cytotoxicity, so PEG‐b‐PLL‐based polyplexes are cross‐linked using reducible reagent dithiobis(succinimidyl propionate) (DSP). The cross‐linked polyplexes display low toxicity to both mouse embryonic fibroblasts NIH/3T3 cell line and mouse bone marrow‐derived macrophages (BMMΦ). In macrophages mannose‐decorated polyplexes demonstrate an ≈8 times higher transfection efficiency. The cross‐linking of the polyplexes decrease the toxicity, but the transfection enhancement is moderate. The PEG‐b‐pAsp(DET) copolymers display low toxicity with respect to the IC‐21 murine macrophage cell line and are used for the production of non‐cross‐linked pDNA‐contained polyplexes. The obtained mannose modified polyplexes exhibit ca. 500‐times greater transfection activity in IC‐21 macrophages compared to the mannose‐free polyplexes. This result greatly exceeds the targeting gene transfer effects previously described using mannose receptor targeted non‐viral gene delivery systems. These results suggest that Man‐PEG‐b‐pAsp(DET)/pDNA polyplex is a potential vector for immune cells‐based gene therapy.

Spectroscopy Approach for Highly-Efficient Screening of Lectin-Ligand Interactions in Application for Mannose Receptor and Molecular Containers for Antibacterial Drugs

“…At the same time, cyclodextrins protect them from oxidation, hydrolysis, enzymatic destruction, excessive hygroscopicity [ 36 ], and, in addition, cause increased penetration of drugs through biological membranes, which is extremely important in the field of drug delivery [ 37 ]. To achieve an additional effect, cyclodextrins were modified with spermine molecules or attached to the polymer chain of PEI, which is often used for targeted delivery [ 38 , 39 ]. This brings the positive charge of the conjugate, and the ability to hold the therapeutic agent more firmly and release it in a prolonged manner due to the polymer mesh [ 40 ].…”

Mannosylated Polymeric Ligands for Targeted Delivery of Antibacterials and Their Adjuvants to Macrophages for the Enhancement of the Drug Efficiency

“…The effect of enhancing drug penetration due to delivery systems adsorbed on bacterial wall surfaces was demonstrated [ 25 , 52 ]. The literature describes molecular containers based on liposomes [ 53 , 54 ], cyclodextrins [ 55 , 56 ], oligo- and polyamines [ 25 , 57 ], polyglycols [ 58 , 59 , 60 ], chitosan [ 44 , 61 ], and mannan [ 45 , 60 , 61 ]. Synthesis of molecular containers includes two main parts: container synthesis (carrier molecule) and mannosylation (introduction of a mannose label).…”

Mannosylated Systems for Targeted Delivery of Antibacterial Drugs to Activated Macrophages

“…Earlier, we outlined the problem of the emergence of resistant and intractable strains of pathogens [25]. The two main vectors of the fight against this kind of infection are as follows: (i) the use of adjuvants (eugenol, apiol, other terpenoids), antibiotic enhancers that inhibit efflux and increase the permeability of the bacterial membrane [26][27][28][29][30][31][32][33][34][35]; (ii) the use of targeted drug delivery systems to macrophages in order to increase their local content and circulation time [9,10,14,[16][17][18]22,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53].…”