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Review
. 2020 Jul 28;12(8):707.
doi: 10.3390/pharmaceutics12080707.

Current Trends in ATRA Delivery for Cancer Therapy

Maria Valeria Giuli  1 , Patrizia Nadia Hanieh  2 , Eugenia Giuliani  1 , Federica Rinaldi  2 , Carlotta Marianecci  2 , Isabella Screpanti  1 , Saula Checquolo  3 , Maria Carafa  2
Affiliations
Review

Current Trends in ATRA Delivery for Cancer Therapy

Maria Valeria Giuli et al. Pharmaceutics. .

Abstract

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer.

Keywords: ATRA; DDSs; cancer; delivery; targeting.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Total number of analyzed research papers and patents relative to this topic in the last 6 years until July 2020. Histograms: light blue, research paper; dark blue, patents.
Figure 2
Figure 2
Retinoids metabolism in humans from food intake to ATRA. Graphical representation of the metabolism, transport and fate of derivatives of Vitamin A in: (A) gut and bloodstream, (B) cytoplasm, and (C) nucleus. Retinoids: atRAL, all-trans RetinALdehyde; atROL, all-trans RetinOL; ATRA, All-Trans Retinoic Acid. Proteins: RBP, Retinol Binding Protein; STRA6, STimulated by Retinoic Acid 6; CRABP, Cellular Retinoic Acid BP; RAR, Retinoic Acid Receptor; RXR, Retinoid X Receptor. Enzymes: BCMO1, β-carotene MonoOxigenase 1; REH, Retinyl Ester Hydrolase; RALR, RetinAL Reductase; LRAT, Lecithin Retinol AcetylTransferase; RDH, Retinol DeHydrogenase; ALDH1, ALdehyde DeHydrogenase 1.
Figure 3
Figure 3
Pleiotropic effects of ATRA in cancer. The image schematically represents how ATRA affects multiple processes by genomic (orange) and non-genomic pathways (pink). Moreover, the image highlights the therapeutic targets for each process.
Figure 4
Figure 4
Targeting strategies of ATRA-loaded DDSs. Graphical representation according to targeting strategies: (A) passive targeting, (B) active targeting, and (C) responsiveness to endogenous and/or exogenous stimuli.
See this image and copyright information in PMC

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