Current Trends in ATRA Delivery for Cancer Therapy

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2020 Aug 1

PMID 32731612

Citations 32

Authors

Maria Valeria Giuli

Patrizia Nadia Hanieh

Eugenia Giuliani

Federica Rinaldi

Carlotta Marianecci

Isabella Screpanti

Saula Checquolo

Maria Carafa

Affiliations

Soon will be listed here.

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.

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References

Choi Y, Kim S, Kim S, Yang J, Park K, Byun Y . Inhibition of tumor growth by biodegradable microspheres containing all-trans-retinoic acid in a human head-and-neck cancer xenograft. Int J Cancer. 2003; 107(1):145-8. DOI: 10.1002/ijc.11354. View

Acharya S, Sahoo S . PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev. 2010; 63(3):170-83. DOI: 10.1016/j.addr.2010.10.008. View

Duester G . Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000; 267(14):4315-24. DOI: 10.1046/j.1432-1327.2000.01497.x. View

Szotek P, Pieretti-Vanmarcke R, Masiakos P, Dinulescu D, Connolly D, Foster R . Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A. 2006; 103(30):11154-9. PMC: 1544057. DOI: 10.1073/pnas.0603672103. View

Cheung B . Combination therapies improve the anticancer activities of retinoids in neuroblastoma. World J Clin Oncol. 2015; 6(6):212-5. PMC: 4675905. DOI: 10.5306/wjco.v6.i6.212. View

Whitlow J, Pacelli S, Paul A . Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions. J Control Release. 2017; 261:62-86. PMC: 5560434. DOI: 10.1016/j.jconrel.2017.05.033. View

Gudas L, Wagner J . Retinoids regulate stem cell differentiation. J Cell Physiol. 2010; 226(2):322-30. PMC: 3315372. DOI: 10.1002/jcp.22417. View

Ozpolat B, Lopez-Berestein G, Adamson P, Fu C, Williams A . Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. J Pharm Pharm Sci. 2003; 6(2):292-301. View

Alcalay M, Zangrilli D, Pandolfi P, Longo L, Mencarelli A, Giacomucci A . Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. Proc Natl Acad Sci U S A. 1991; 88(5):1977-81. PMC: 51149. DOI: 10.1073/pnas.88.5.1977. View

10.

Wang Q, Manmi K, Liu K . Cell mechanics in biomedical cavitation. Interface Focus. 2015; 5(5):20150018. PMC: 4549844. DOI: 10.1098/rsfs.2015.0018. View

11.

Takaishi S, Okumura T, Tu S, Wang S, Shibata W, Vigneshwaran R . Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009; 27(5):1006-20. PMC: 2746367. DOI: 10.1002/stem.30. View

12.

Kozono S, Lin Y, Seo H, Pinch B, Lian X, Qiu C . Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018; 9(1):3069. PMC: 6085299. DOI: 10.1038/s41467-018-05402-2. View

13.

Glass C, Rosenfeld M . The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000; 14(2):121-41. View

14.

Desai T, Finlay W . Nebulization of niosomal all-trans-retinoic acid: an inexpensive alternative to conventional liposomes. Int J Pharm. 2002; 241(2):311-7. DOI: 10.1016/s0378-5173(02)00245-4. View

15.

Campaner E, Rustighi A, Zannini A, Cristiani A, Piazza S, Ciani Y . A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nat Commun. 2017; 8:15772. PMC: 5472749. DOI: 10.1038/ncomms15772. View

16.

Grimwade D, Ivey A, Huntly B . Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2015; 127(1):29-41. PMC: 4705608. DOI: 10.1182/blood-2015-07-604496. View

17.

Liu H, Fan C, Ting C, Yeh C . Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. 2014; 4(4):432-44. PMC: 3936295. DOI: 10.7150/thno.8074. View

18.

Ma B, Xu W, Wei W, Wen D, Lu Z, Yang S . Clinicopathological and Survival Outcomes of Well-Differentiated Thyroid Carcinoma Undergoing Dedifferentiation: A Retrospective Study from FUSCC. Int J Endocrinol. 2018; 2018:2383715. PMC: 5987325. DOI: 10.1155/2018/2383715. View

19.

HEYMAN R, Mangelsdorf D, Dyck J, Stein R, Eichele G, Evans R . 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992; 68(2):397-406. DOI: 10.1016/0092-8674(92)90479-v. View

20.

Mu L, Feng S . A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. J Control Release. 2002; 86(1):33-48. DOI: 10.1016/s0168-3659(02)00320-6. View