A. Kiselev

V. A. Maslova, O. I. Ivankov - FLNP

E. V. Zemlyanaya - MLIT

The development of drug delivery systems can significantly increase the efficiency of the use of the latter. To date, a range of finished dosage forms based on various delivery systems have already been implemented in medicine. These drugs are highly effective and are in high demand in the pharmaceutical market. In this regard, phospholipid-based carriers as biodegradable, biologically inactive systems with no allergic, antigenic and pyrogenic reactions are of sufficient interest. In recent years, at the V. N. Orekhovich Research Institute of Biomedical Chemistry (Moscow, Russia) a technology for obtaining drug delivery systems based on small-diameter vesicles from soybean phosphatidylcholine has been developed. It has already been discovered that reducing the size of the particles used as vehicles for drug compounds increases the therapeutic efficacy of embedded drugs. The YuMO small-angle neutron spectrometer positioned at beamline 4 of the high-flux pulsed reactor IBR-2 at FLNP JINR is perfect for determining the structural characteristics of nanoparticles, such as size and shape.

Fig. 1. Schematic of the YuMO small-angle neutron scattering spectrometer (1 – double reflector, 2 – reactor core with a moderator, 3 – chopper, 4 – first collimator, 5 – vacuum tube, 6 – second collimator, 7 – thermostat, 8 – rack for samples, 9 - goniometer, 10-11 - vanadium (Vd) standard, 12 - ring-wire detector, 13 - position-sensitive detector "Volga", 14 - direct beam detector.)

The small-angle neutron scattering is an efficient experimental technique for investigation of the supraatomic structure of matter and is widely used to study the structure of vesicular systems. Due to the contrast variation technique, it is possible to obtain information about the distribution of lipid molecules in the vesicle. Complexes of phospholipid transport nanosystems, as well as finished preparations embedded in phospholipid transport nanosystems were investigated using small-angle neutron scattering. From the data obtained, it can be concluded that the system as a whole is stable. It is important that the vesicular morphology of the system is preserved at all concentrations and the parameters vary only slightly (the radius does not exceed 1.4%, the thickness by no more 3.6%). When processing data from SANS, a uniform approximation of the scattering length distribution density (SLDD) was sufficient, this is due to the high contrast.

Information on the thickness of the lipid bilayer was obtained.

Fig. 2. Small-angle neutron scattering spectra (dots) and calculated curves from PTNS vesicles with concentrations: a-5%, b-10%, c-25%; T=20 ̊ C

Investigation of the structure of phospholipid nanodrugs is crucial for understanding the kinematics of these medical compounds in the human body. Also, this research has allowed to describe more precisely the characteristics of drugs that can be further included in nanosystems of such a small size. The data obtained can be used for the future production of drugs and drug compounds that will have fewer side effects on the human body. In order to have complete information, the small-angle neutron scattering can be complemented with small-angle X-ray scattering, reflectometry, dynamic light scattering and atomic force microscopy.

Thus, we can conclude that the SANS technique is excellent for the investigation of the main structural parameters of polydisperse vesicular nanosystems. This technique can be an essential step for the development of new drug delivery systems, as well as for enhancing the efficacy of current drugs.

Publications:

1. Lombardo D., Calandra P., Kiselev M. A. Nanostructures in Nanomedicine: Critical Issues and Perspectives. Proceedings of the 7th World Congress on New Technologies (2021). Doi:10.11159/icnfa21.122
2. Kiselev M.A., Zemlyanaya E.V., Aswal V.K., et al., What can we learn about the lipid vesicle structure from the small-angle neutron scattering experiment? European Biophysics Journal 35(6) 477-493 (2006). Doi:10.1007/s00249-006-0055-9
3. Zemlyanaya E.V., Kiselev M.A., Zhabitskaya E.I., et al., The small-angle neutron scattering data analysis of the phospholipid transport nanosystem structure. In Journal of Physics: Conference Series 1023(1), 012017 (2018). Doi:10.1088/1742-6596/1023/1/012017
4. Bashashin M., Zemlyanaya E., Kiselev M., Parallel SFF-SANS study of structure of polydispersed vesicular systems. In International Conference on Numerical Methods and Applications, Springer, Cham. 309-317 (2018). Doi:10.1007/978-3-030-10692-8_34
5. Kiselev M.A., Selyakov D.N., Gapon I.V., et al., Investigation of Nanodrug Phospholipovit by Small-Angle Neutron Scattering. Crystallography Reports, 64(4), 656-661 (2019). Doi:10.1134/S1063774519040114
6. Lombardo D., Calandra P., Kiselev M.A., Structural characterization of biomaterials by means of small angle X-rays and neutron scattering (saxs and sans), and light scattering experiments. Molecules, 25(23), 5624 (2020). Doi:10.3390/molecules25235624