Vol 52, No 8 (2018)

Targeted radioimmunotherapy is a promising approach to radiotherapy. Tumor-specific compounds were synthesized using monoclonal antibodies anti-ICO-25 (MUC1) and anti-ICO-80 (CD5) labeled with the therapeutic radioisotope ¹⁸⁸Re. The specificity of the conjugates was demonstrated in vitro using SKOV-3 (ovary cancer) and Jurkat tumor cell lines (T-lymphoblastic lymphoma), which are known to have membrane surface receptors specific for the corresponding antibodies. Short-term survival tests revealed 90-93% death of tumor cells, indicating the proposed conjugates were promising for targeted delivery of diagnostic and therapeutic cancer drugs.

Proteolysis of 5-oxo-Pro-Arg-Pro, 5-oxo-Pro-His-Pro-Gly-ProNH₂, and Phe-Pro-Leu-Pro-Ala in the presence of leucine aminopeptidase and carboxypeptidases Y and B was compared. It was found that 5-oxo-Pro-Arg-Pro was stable in the presence of the peptidases. This peptide was hydrolyzed only by carboxypeptidase Y and by ~50% over 26 h. 5-Oxo-Pro-His-Pro-Gly-ProNH₂ was stable in the presence of leucine aminopeptidase and carboxypeptidase Y whereas Phe-Pro-Leu-Pro-Ala was stable only in the presence of carboxypeptidase B. 5-Oxo-Pro-Arg-Pro was the most stable peptide in the presence of nasal mucus, blood, and the rat-brain microsomal fraction. The blood enzyme system was most effective for hydrolysis of all three peptides. Several metabolites of the aforementioned peptides were detected and identified. Conclusions about the main hydrolysis pathways of 5-oxo-Pro-His-Pro-Gly-ProNH₂ and Phe-Pro-Leu-Pro-Ala were made and suggested a set of peptides that could be formed in experiments in vivo.

Dosage forms intended for ophthalmic use with declared and potential antioxidant properties were investigated. Antioxidant activity was determined using potentiometry with potassium hexacyanoferrate (III) as the oxidant. Antiradical activity was studied using the stable radical 2,2-diphenyl-1-picrylhydrazyl. The reaction half-lives of the investigated dosage forms were determined. Ratios of the experimental antioxidant activity to the content of main active ingredient were assessed.

5-(Amino- and 2-pyridylmethylamino)-1-alkylbenzimidazoles treated sequentially with butyllithium and benzophenone synthesized [5-(amino- and 2-pyridylmethylamino)-1-alkylbenzimidazol-2-yl]diphenylmethanols. (5-Amino-1-methylbenzimidazol-2-yl)diphenylmethanol was converted by acyl chlorides into (5-acylamino-1-methylbenzimidazol-2-yl)diphenylmethanols. The products were shown to possess bacteriostatic activity against Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Escherichia coli), antiprotozoal activity against the ciliate Colpoda steinii, and fungicidal activity against Penicillium italicum.

Triblock poly(ε-caprolactone) – poly(ethylene glycol) – poly(ε-caprolactone) (PCL-PEG-PCL) copolymers were synthesized and used to prepare polymersomes for controlled release of lovastatin (LOV) as hydrophobic drug. Biodegradable PCL-PEG-PCL copolymer nanoparticles were prepared and the drug loading, release, release kinetics, and anti-cancer activity of these drugs was investigated. The PCL-PEG-PCL copolymer was synthesized by ring-opening polymerization of e-caprolactone in the presence of mPEG as the initiator and Sn(Oct)₂ as the catalyst. The synthesized copolymers and nanoparticles were characterized by FTIR, ¹H NMR, DLS, and AFM techniques. The efficiency of drug loading and release from nanoparticles in vitro was studied by UV-Vis spectrophotometry. Additionally, MTT assays on HFF-2 cell lines were performed for determining the biocompatibility of polymersomes. Finally, the antiproliferative activity of polymersomes was examined on MCF-7 breast cancer cell line. The obtained results showed that the average diameter of nanoparticles was less than 57 nm. The loading capacity and encapsulation efficiency of LOV was 16.1 ± 0.36% and 59.01 ± 0.78%, respectively. In vitro release study showed that the release rate of polymersomes depended on pH and was higher at lower pH than under neutral condition. The result of cell viability assay on the MCF-7 line proved that bare nanoparticles showed little inherent cytotoxicity whereas the LOV-loaded nanoparticles were cytotoxic.

Drugs based on recombinant interferons β are in high demand in clinical practice for first-line therapy of multiple sclerosis. Drugs based on recombinant interferons β-1a and β-1b are registered in the Russian Federation. These proteins have different production technologies and, hence, structures. Recombinant interferon β-1a is a glycosylated protein with a structure close to that of endogenous human interferon. Recombinant interferon β-1b is a non-glycosylated protein that differs by two amino-acid residues from interferon β-1a. These structural features influence the biological properties of drugs based on interferons β-1a and β-1b, in particular, their clinical efficacy, side effects, and induction intensity of neutralizing antibodies. For this reason, a laboratory pharmaceutical examination of the drug quality of interferons β should include confirmation of the specific biological activity and the correspondence of the target protein to the claimed structure. However, domestic and international pharmacopoeial requirements for quality assessment of interferon-β-based drugs are not currently fully adequate. Formulation of unified domestic requirements would allow the registration process to be optimized and provide a basis for harmonization of domestic and international requirements.

Previously, a dimeric dipeptide mimetic bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2) based on the β-turn of the fourth loop of nerve growth factor was prepared by us, activated TrkA, and exhibited neuroprotective activity in vitro (10^–5 – 10^–9 M) and in vivo (0.05 – 5 mg/kg i.p.). The present work reports the synthesis of two of its diastereomers, bis-(N-monosuccinyl-L-glutamyl-D-lysine) (GK-2LD) and bis-(N-monosuccinyl-D-glutamyl-L-lysine) hexamethylenediamides (GK-2DL). Studies of their neuroprotective activities using HT-22 neuronal culture under oxidative stress showed that switching L-lysine to D-lysine led to a significant activity decrease whereas switching L-glutamic acid to the D-stereoisomer caused it to disappear completely. Both dipeptide residues were concluded to be involved in interactions with the TrkA receptor.

Automated technology for synthesizing [¹⁸F]fluoromethylcholine, a radiopharmaceutical for diagnostic positron-emission-tomography tumor imaging, was developed. A TRACERlab FX_FN synthesis module (GE Healthcare) used the combined technology of on-line alkylation and solid-phase extraction. The synthesis module was modified to allow operation at various He flow rates in critical process steps. The radiochemical yield of [¹⁸F]fluoromethylcholine was >10%, which was sufficient to produce several clinical doses. The quality control parameters of the produced [¹⁸F]fluoromethylcholine met the requirements of the RF Pharmacopoeia.

The current classification of impurities in chemical and mineral drug substances is presented. General approaches to standardization of chemical and mineral drug substances according to the Purity section are given depending on their origin and production technology and considering requirements of international and domestic pharmacopoeial practice