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. 2019 May 9;24(9):1793.
doi: 10.3390/molecules24091793.

Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

Silvia Tampucci  1   2 , Sara Carpi  3   4 , Maria Digiacomo  5   6 , Beatrice Polini  7 , Stefano Fogli  8 , Susi Burgalassi  9 , Marco Macchia  10   11 , Paola Nieri  12   13 , Clementina Manera  14   15 , Daniela Monti  16
Affiliations

Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

Silvia Tampucci et al. Molecules. .

Abstract

In this work, hybrid compounds 1-4 obtained by conjugation of the non-steroidal anti-inflammatory drug diclofenac, with natural molecules endowed with antioxidant and antiproliferative activity were prepared. The antiproliferative activity of these hybrids was evaluated on immortalized human keratinocyte (HaCaT) cells stimulated with epidermal growth factor (EGF), an actinic keratosis (AK) model, and on human squamous cell carcinoma (SCC) cells (A431). Hybrid 1 presented the best activity in both cell models. Self-assembling surfactant nanomicelles have been chosen as the carrier to drive the hybrid 1 into the skin; the in vitro permeation through and penetration into pig ear skin have been evaluated. Among the nanostructured formulations tested, Nano3Hybrid20 showed a higher tendency of the hybrid 1 to be retained in the skin rather than permeating it, with a desirable topical and non-systemic action. On these bases, hybrid 1 may represent an attractive lead scaffold for the development of new treatments for AK and SCC.

Keywords: actinic keratosis; antiproliferative activity; diclofenac; hybrid; in vitro skin permeation/penetration; nanomicelles; squamous cell carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of synthesized hybrids (1–4).
Scheme 1
Scheme 1
Reagents and conditions: (a) DCC, DMAP, THF, rt, 12 h.
Scheme 2
Scheme 2
Reagents and conditions: (a) pyridine, toluene, rt, 20 h; (b) DMF, 110 °C, 3 h; (c) H2, Pd/C, EtOH, rt, 3 h; (d) DCC, THF, refluxed, 3 h.
Figure 2
Figure 2
Effects induced by test compounds on cell viability of HaCaT cells after stimulation with 5 ng/mL EGF (A, B) and A431 cells (C, D). Cells were exposed to compounds for 72 h and cell viability assessed by neutral red assay. Data are expressed as means ± SEM of three independent experiments, each performed in triplicate. Each hybrid was compared to single agents. D: diclofenac, HT: hydroxytyrosol, T: tyrosol.
Figure 3
Figure 3
Drug recovered in the pig ear skin after application of the formulation under study (nanomols/g of skin, mean ± SEM, n = 6).
Figure 4
Figure 4
Efficacy of the drug retained in the skin related to its capacity to hinder the growth of EGF-stimulated HaCaT cells.
See this image and copyright information in PMC

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