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Bacterial infections and especially resistant strains of pathogens localized in macrophages and granulomas are intractable diseases that pose a threat to millions of people. In this paper, the theoretical and experimental foundations for solving this problem are proposed due to two key aspects. The first is the use of a three-component polymer system for delivering fluoroquinolones to macrophages due to high-affinity interaction with mannose receptors (CD206). Cytometry assay determined that 95.5% macrophage-like cells were FITC-positive after adding high-affine to CD206 trimannoside conjugate HPCD-PEI1.8-triMan, and 61.7% were FITC-positive after adding medium-affine ligand with linear mannose label HPCD-PEI1.8-Man. The second aspect is the use of adjuvants, which are synergists for antibiotics. Using FTIR and NMR spectroscopy, it was shown that molecular containers, namely mannosylated polyethyleneimines (PEIs) and cyclodextrins (CDs), load moxifloxacin (MF) with dissociation constants of the order of 10−4–10−6 M; moreover, due to prolonged release and adsorption on the cell membrane, they enhance the effect of MF. Using CLSM, it was shown that eugenol (EG) increases the penetration of doxorubicin (Dox) into cells by an order of magnitude due to the creation of defects in the bacterial wall and the inhibition of efflux proteins. Fluorescence spectroscopy showed that 0.5% EG penetrates into bacteria and inhibits efflux proteins, which makes it possible to increase the maximum concentration of the antibiotic by 60% and maintain it for several hours until the pathogens are completely neutralized. Regulation of efflux is a possible way to overcome multiple drug resistance of both pathogens and cancer cells.

In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21–75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20–35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.

A strategy for stereoselective synthesis of molecular platform for targeted delivery of bimodal therapeutic or theranostic agents to the prostate-specific membrane antigen (PSMA) receptor was developed. The proposed platform contains a urea-based, PSMA-targeting Glu-Urea-Lys (EuK) fragment as a vector moiety and tripeptide linker with terminal amide and azide groups for subsequent addition of two different therapeutic and diagnostic agents. The optimal method for this molecular platform synthesis includes (a) solid-phase assembly of the polypeptide linker, (b) coupling of this linker with the vector fragment, (c) attachment of 3-aminopropylazide, and (d) amide and carboxylic groups deprotection. A bimodal theranostic conjugate of the proposed platform with a cytostatic drug (docetaxel) and a fluorescent label (Sulfo-Cy5) was synthesized to demonstrate its possible sequential conjugation with different functional molecules.

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