All-trans retinoic acid in anticancer therapy: how nanotechnology can enhance its efficacy and resolve its drawbacks

ABSTRACT

Introduction: All-trans retinoic acid (ATRA, tretinoin) is the main drug used in the treatment of acute promyelocytic leukemia (APL). Despite its impressive activity against APL, the same could not be clinically observed in other types of cancer. Nanotechnology can be a tool to enhance ATRA anticancer efficacy and resolve its drawbacks in APL as well as in other malignancies.

Areas covered: This review covers ATRA use in APL and non-APL cancers, the problems that were found in ATRA therapy and how nanoencapsulation can aid to circumvent them. Pre-clinical results obtained with nanoencapsulated ATRA are shown as well as the two ATRA products based on nanotechnology that were clinically tested: ATRA-IV® and Apealea®.

Expert opinion: ATRA presents interesting properties to be used in anticancer therapy with a notorious differentiation and antimetastatic activity. Bioavailability and resistance limitations impair the use of ATRA in non-APL cancers. Nanotechnology can circumvent these issues and provide tools to enhance its anticancer activities, such as co-loading of multiple drug and active targeting to tumor site.

KEYWORDS:

• Tretinoin
• all-trans retinoic acid
• nanotechnology
• cancer
• acute promyelocytic leukemia
• drug delivery
• self-assembly
• drug combination
• nano-conjugates

Article highlights

• All-trans retinoic acid (ATRA, tretinoin) is the drug of choice for acute promyelocytic leukemia (APL) but, so far, has not proven to be effective in non-APL cancers;

• Nanoencapsulation can increase the efficacy of ATRA in APL and non-APL cancers by enhancing ATRA bioavailability, circumventing intrinsic and acquired resistance, allowing co-encapsulation with other drugs, improving physicochemical stability, and reducing side effects;

• Co-encapsulation of ATRA with other bioactive molecules in a same nanocarrier can provide powerful synergic combinations that have shown good efficacy in animal studies against non-APL cancers;

• ATRA can react with other molecules, mainly polyethylene glycol (PEG), to form nano-conjugates that can produce micelles in aqueous environment and load other drugs within their core;

• Favorable differentiation and antimetastatic characteristics of nanoencapsulated ATRA can be satisfactorily combined with pro-apoptotic chemotherapeutics, producing a potent treatment for different types of cancer.

• Strategies as pH-sensibility and active targeting can be additional tools to enhance the efficacy of ATRA-loaded nanocarriers against many types of cancers.

This box summarizes key points contained in the article.

Acknowledgments

GSM Borges would like to thank CAPES for the PhD scholarship. LAM Ferreira, G Carneiro, and GAC Goulart would like to thank CAPES, CNPq, and FAPEMIG for the grants.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).