Nanoparticles based on polyferylic and polygentisic acids as new carriers of anticancer drugs

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Lignin polymers and their derivatives are actively used in various fields of biomedicine to create biocompatible materials, as medications, and to form nanoparticles. However, natural polymeric compounds derived from plant materials or monomers are defined as a mixture of compounds having a high heterogeneity in chemical structure, which greatly complicates the determination of their biological activity. This paper describes a new method of controlled synthesis using the enzyme laccase, which can be applied to obtain polymers with a specific structure. Based on enzymatically synthesized lignin-like polymers from ferulic and gentisiс phenolic monomers, nanoparticles with stable properties under physiological conditions were formed. The nanoparticles can differ in morphology from globular to fibrillar structures, depending on monomers used in the enzymatic reaction and the method of their formation. Nanoparticles obtained from lignin-like polymers of ferulic and gentisic acids can be loaded with low molecular weight hydrophobic compounds, including the anticancer drug doxorubicin. It has been shown that polyferulic nanoparticles are actively penetrate in tumor cells growing both in a monolayer culture and as part of spheroids, and, compared with a free compound, doxorubicin in the composition of nanoparticles has a greater cytotoxic effect on breast cancer cells. These data indicate the possibility of effective use of these carriers as passive targeted drug delivery in the treatment of tumors.

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作者简介

I. Smirnov

Skolkovo Institute of Science and Technology

编辑信件的主要联系方式.
Email: ivan_cmirnov_98@mail.ru
俄罗斯联邦, Moscow, 121205

A. Lisov

G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences

Email: ivan_cmirnov_98@mail.ru
俄罗斯联邦, 142290, Pushchino, prosp. Nauki, 5

A. Kazakov

Institute of Biological Instrumentation, Russian Academy of Sciences

Email: ivan_cmirnov_98@mail.ru
俄罗斯联邦, 142290, Pushchino, prosp. Nauki, 7

A. Zvonarev

G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences

Email: ivan_cmirnov_98@mail.ru
俄罗斯联邦, 142290, Pushchino, prosp. Nauki, 5

N. Suzina

G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences

Email: ivan_cmirnov_98@mail.ru
俄罗斯联邦, 142290, Pushchino, prosp. Nauki, 5

M. Zemskova

G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences

Email: marinazemskova9@gmail.com
俄罗斯联邦, 142290, Pushchino, prosp. Nauki, 5

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2. Fig. 1. IR-Fourier spectra of polymers (lower graphs) and monomers (upper graphs): (a) spectra of polyferule polymers and ferulic acid monomers; (b) spectra of polygentisine polymers and gentisic acid monomers.

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3. Fig. 2. Spectra of 1H-NMR polymers: (a) – spectra of polyferule polymers; (b) – the condensation reaction of monomers to obtain a dominant dimer; (c) – the polymerization reaction of ferulic acid; (d) – the spectra of polygentisine polymers; (e) – the proposed polymerization reaction of gentisic acid.

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4. Fig. 3. Micrographs of transmission electron microscopy (TEM): (a) – polyferule LF pFA/0.22. In the right corner, a micrograph of the woofers at magnification (scale 100 nm) shows their heterogeneous structure; (b) – LPS fractionated from a colloidal mixture by low–speed centrifugation (pFA/NC); (c, d) – polygentizine LPS obtained using filtration (pGA/0.22) (c) and low-speed centrifugation (pGA/NC) (d). Scale segments: 500 nm (a-c) and 1 micron (g).

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5. Fig. 4. 1H-NMR spectra of gentisic acid polymers obtained from LF pGA/0.22.

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6. Fig. 5. The results of the analysis of the obtained nanoparticles by dynamic light scattering (DLS). (a) is a graph of the size distribution of nanoparticles, where pGA/0.22 are polygentisine NPS, pFA/0.22 are polyferule NPS, pDMF/0.22 are polydimethoxyphenolic NPS obtained by filtering dialized polymers through a membrane with a pore size of 0.22 microns; (b) is the stability of the NPS determined by a change in the hydrodynamic radius (histogram) and polydispersity index (PDI, dots) in the PBS buffer (pH 7.2); (c) is the size distribution of pFA/NC polyferule particles obtained after low–speed centrifugation. The presence of only one peak indicates the homogeneity of the suspension; (d) – the size distribution of polyferule particles pFA/0.22 after incubation in a solution of bovine serum albumin (BSA) of different concentrations. Major peaks (~100 nm) show intact woofers. The presence of minor peaks (<100 nm) indicates a partial violation of the LF structure, peaks in the region of 4-10 nm are characteristic of the light scattering of BSA molecules in solution, peaks >100 nm determine the aggregation of LF; (e) – the size distribution of polygentizine particles pGA/0.22 after incubation in BSA solutions of various concentrations.

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7. Fig. 6. The yield of doxorubicin (Dox) from nanoparticles under various environmental conditions. (a) – Dox output from the LF in a phosphate buffer containing 5% BSA for 24 hours; (b–d) – Dox output (%) from the LF after 3 and 24 hours of incubation under conditions of different acidity: for polyferule LF pFA/0.22 – 27% after 3 hours and 65% after 24 hours at pH 5.5–6.8 vs. 9 and 41% at pH 7.2–7.4 (b); for polyferule pFA/NC – 6% after 3 hours and 18% after 24 hours at pH 5.5–6.8 vs. 1 and 2% at pH 7.2–7.4 (c); – for polygentisine LPS pGA/0.22 – 44% after 3 hours and 65% after 24 hours at pH 5.5–6.8 versus 17 and 42% at pH 7.2–7.4 (g).

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8. Fig. 7. Absorption of nanoparticles by cultured human cells. (a–c) – Fluorescence micrographs of Vibrant fluorochrome: (a) – untreated MDA-MB-231 cells; (b) – MDA-MB-231 cells after incubation with Vibrant fluorochrome (green); (c) – MDA-MB-231 cells incubated with LF pFA/0.22, uploaded by Vybrant. In samples (a) and (c), the nuclei were stained with DAPI-405 (blue), scale segments – 10 microns; (d–e) – histograms of the results of flow cytometry: (d) – dependence of the absorption by cells of MDA-MB-231 of Dox-loaded particles pFA/0.22 and pGA/0.22 (100 NM per 1 cell) from the incubation time; (e) – pFA/NC internalization graph for MDA-MB-231 cells; (e) – pFA/NC internalization graph for MCF-7 cells.

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9. Fig. 8. Analysis of cytotoxicity of free Dox and doxorubicin in nanoparticles. (a) – MTT test of cell lines MDA-MB-231 and MCF-7 after 15 minutes of treatment followed by washing of samples from the compound. Incubation time after treatment is 48 hours; (b) – the results of flow cytometry show the number of annexin V–FITC-positive, apoptotic MCF-7 cells in the composition of spheroids 48 hours after treatment with either free Dox or a compound in the composition of polyferule nPS pFA/NC in the constant presence of Dox (left panel) or its removal from the medium after 15 minutes of incubation (right panel).

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