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. 2022 Jan 14;23(2):915.
doi: 10.3390/ijms23020915.

Lignin Nanoparticles Deliver Novel Thymine Biomimetic Photo-Adducts with Antimelanoma Activity

Sofia Gabellone  1 , Davide Piccinino  1 , Silvia Filippi  1 , Tiziana Castrignanò  1 , Claudio Zippilli  1 , Davide Del Buono  1 , Raffaele Saladino  1
Affiliations

Lignin Nanoparticles Deliver Novel Thymine Biomimetic Photo-Adducts with Antimelanoma Activity

Sofia Gabellone et al. Int J Mol Sci. .

Abstract

We report here the synthesis of novel thymine biomimetic photo-adducts bearing an alkane spacer between nucleobases and characterized by antimelanoma activity against two mutated cancer cell lines overexpressing human Topoisomerase 1 (TOP1), namely SKMEL28 and RPMI7951. Among them, Dewar Valence photo-adducts showed a selectivity index higher than the corresponding pyrimidine-(6-4)-pyrimidone and cyclobutane counterpart and were characterized by the highest affinity towards TOP1/DNA complex as evaluated by molecular docking analysis. The antimelanoma activity of novel photo-adducts was retained after loading into UV photo-protective lignin nanoparticles as stabilizing agent and efficient drug delivery system. Overall, these results support a combined antimelanoma and UV sunscreen strategy involving the use of photo-protective lignin nanoparticles for the controlled release of thymine dimers on the skin followed by their sacrificial transformation into photo-adducts and successive inhibition of melanoma and alert of cellular UV machinery repair pathways.

Keywords: antimelanoma activity; drug delivery; lignin nanoparticles; pyrimidine photo-adducts biomimetic approach.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Experimental workflow. Panel (A): Synthesis of biomimetic compound and preparation of photo-adducts; panel (B): loading of biomimetic compound into LNPs and characterization. Panel (C): Biological assay of loaded-LNPs on melanoma cell lines. Panel (D): molecular docking of most active biomimetic compound.
Scheme 2
Scheme 2
Synthesis of biomimetic thymine dimers 4a-d.
Scheme 3
Scheme 3
Synthesis of CPD, (6-4)PP, and DV photo-adducts by UV-irradiation of biomimetic thymine dimers 4a-d.
Figure 1
Figure 1
LNPs obtained during the nanoprecipitation process. (A) Stable colloidal LNPs (30 days at 25 °C). (B) Low stable colloidal LNPs (1–2 days at 25 °C). (C) Aggregates of LNPs. (D) Formation of a precipitate. (E) Absence of LNPs.
Figure 2
Figure 2
Morphological analysis of loaded and unloaded nanoparticles. Panel (A): Scanning electron microscopy of empty LNPs, and loaded LNPs/4a, LNPs/6a, and LNPs/8a. Panel (B): Dynamic light scattering analysis.
Figure 3
Figure 3
UV shielding capacity of LNPs. The photo-protective effect is expressed as the amount of residual 4a, 6a, 7a, and 8a recovered after UV treatment of LNPs/4a, LNPs/6a, LNPs/7a, and LNPs/8a.
Figure 4
Figure 4
The cumulative releasing property of biomimetic thymine dimers 4a-d (A) and photo-adducts 6a-d (B) and 8a-d (C).
Figure 5
Figure 5
Panel (A): Binding mode of compound 8b. H-bond interactions are shown with continuous blue lines, and salt bridges are reported as dashed magenta lines. Panel (B): Binding mode of compound 8a. H-bond interactions are shown with continuous blue lines, and pi–cation interactions are reported as dashed red lines. Panel (C): Binding mode of compound 4b. H-bond interactions are shown with continuous blue lines. Panel (D): Binding mode of compound 4a. H-bond interactions are shown with continuous blue lines, hydrophobic interactions with dashed green lines, and pi-stacking interactions with dashed orange lines.
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