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Cited by 138Retinoids in leukemia and cellular processesAdvanced Drug Delivery SystemsAdvancements in Transdermal Drug Delivery

Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine

Open access
Ferreira, Raquel, Napoli, Joseph, Enver, Tariq, Bernardino, Liliana, Ferreira, Lino·2020·Nature Communications
DOI 10.1038/s41467-020-18042-2PMC PMC7450074
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Abstract

Retinoids regulate a wide spectrum of cellular functions from the embryo throughout adulthood, including cell differentiation, metabolic regulation, and inflammation. These traits make retinoids very attractive molecules for medical purposes. In light of some of the physicochemical limitations of retinoids, the development of drug delivery systems offers several advantages for clinical translation of retinoid-based therapies, including improved solubilization, prolonged circulation, reduced toxicity, sustained release, and improved efficacy. In this Review, we discuss advances in preclinical and clinical tests regarding retinoid formulations, specifically the ones based in natural retinoids, evaluated in the context of regenerative medicine, brain, cancer, skin, and immune diseases. Advantages and limitations of retinoid formulations, as well as prospects to push the field forward, will be presented.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes advances and challenges in natural retinoid delivery systems for regenerative and therapeutic medicine, covering regenerative medicine, brain, skin, cancer, and immune applications. It reports improved solubilization, stability, circulation, targeting, and efficacy in preclinical and some clinical settings, but notes limited clinical translation due to targeting, scale-up, regulatory, and combination-release barriers.

Key findings

  • Retinoid delivery systems—including liposomes, polymeric and inorganic nanoparticles, microparticles, micelles, scaffolds, and electrospun meshes—improve solubilization, prolong circulation, reduce toxicity, provide sustained release, and improve efficacy; more than 50 active clinical trials evaluate RA, including 28 in cancer (16 hematological, 8 brain tumors), 5 in skin pathologies, and others in inflammation, olfactory loss, and neuropsychiatric diseases.
  • Formulations show varied loading and release: high loading above 100 μg/mg, medium 25–100 μg/mg, and low below 25 μg/mg; sustained release can exceed 1 month, with examples of 80% cumulative RA release in 3.5 months and light-activatable nanoparticles disassembling in minutes after 405 nm blue laser activation.
  • In preclinical tests, ATRA-containing liposomes or polymeric nanoparticles were 100–1000 times more active than soluble ATRA in cultured tumor cells or neural stem cells; liposomal ATRA maintained plasma ATRA levels in rats and humans, whereas oral nonliposomal ATRA caused significant plasma decreases.
  • Clinical examples include a liposomal RA formulation in refractory hematological malignancies with 67% clinical remission versus 77% for ATRA plus idarubicin combination therapy, and a collagen sponge delivering ∼0.4% RA for cervical intraepithelial neoplasia with 50% total regression in phase II.

Methods

  • Design: narrative review of preclinical and clinical tests of natural retinoid formulations in regenerative medicine, brain, cancer, skin, and immune diseases; the authors state they focused only on natural retinoids.
  • Data: literature on retinoid chemistry, RA signaling, delivery formulations, marketed products, and clinical trials, including more than 50 active trials according to ClinicalTrials.gov and tables of RA formulations and synthetic retinoids.
  • Analysis: qualitative synthesis of formulation strategies, biological barriers, preclinical/clinical outcomes, advantages, limitations, and future prospects; no systematic review, meta-analysis, or primary experimental study is reported.

Limitations

  • The paper states that clinical translation remains relatively low because of delivery issues (limited cell targeting, limited capacity to cross biological barriers), technical issues (scale-up), and regulatory aspects (study design and approval challenges); most preclinical nanoparticles/microparticles were prepared in small batches.
  • The paper states that the capacity of RA-containing formulations to cross the blood-brain barrier is largely unexplored, most brain formulations were administered by stereotaxic rather than intravenous injection, and most RA formulations for blood cancers have not explored simultaneous controlled release of RA and other agents.
  • Evident from the text: this is a narrative review without a stated systematic search strategy or meta-analysis, and it reports no primary experimental data of its own.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-020-18042-2

Cites

142 of 142 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 198 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    The most common strategy for RA delivery has been based on liposomal or polymeric nanoparticles formed by polyesters, polyimines, polysaccharides, and proteins.

    “Despite several reports on RA delivery systems based on polymeric scaffolds or electrospun fibrous meshes, the most common strategy has been based on liposomal or polymeric nanoparticles formed by polyesters, polyimines, polysaccharides, and proteins (Table 3).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    A significant number of formulations have allowed RA encapsulation in the core of nanoparticles.

    “A significant number of formulations have allowed the RA encapsulation in the core of the nanoparticles.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    For topical administration, seven RA-containing formulations have reached the market for the treatment of skin-related diseases.

    “For topical administration, seven RA-containing formulations have reached the market for the treatment of skin-related diseases (Table 4).”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Systemic delivery of RA causes side effects because RA is involved in many biological processes.

    “Lastly, RA is involved in many biological processes and thus the systemic delivery of RA causes side effects.”
    Quote in the paperSubstantial claim
  • Premisecitation

    High levels of serum aminotransferase and liver injury have been reported with bexarotene.

    “However, high levels of serum aminotransferase and liver injury have been reported32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Huen, A. O. & Kim, E. J. The role of systemic retinoids in the treatment of cutaneous T-cell lymphoma. Dermatol. Clin. 33, 715–729 (2015). source

      Not checked in the free run.

  • May combine two claims. 47
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingcitation

    More than 50 active clinical trials are evaluating the effect of RA in cancer (28 trials), mostly in hematological (16 trials) and brain tumors (8 trials), skin pathologies (5 trials), and other conditions such as inflammation, olfactory loss, and neuropsychiatric diseases.

    “This interest is confirmed by more than 50 active clinical trials (according to ClinicalTrials.gov) evaluating the effect of RA in cancer (28 trials), mostly in hematological (16 trials) and brain tumors (8 trials), skin pathologies (e.g., acne, photoaging, eczema) (5 trials), and in other conditions such as inflammation, olfactory loss, and neuropsychiatric diseases (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    For oral administration, four formulations containing RA have reached the market, particularly for the treatment of skin diseases (three of them) and cancer (only one).

    “For oral administration, four formulations containing RA have reached the market, particularly for the treatment of skin diseases (three of them) and cancer (only one) (Table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The mechanisms underlying paracrine signaling remain unclear, while autocrine signaling requires CRABP2 for nuclear entry.

    “The mechanisms underlying paracrine signaling remain unclear while autocrine signaling requires CRABP2 for nuclear entry28,34.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008). source

      Not checked in the free run.

    • cites [34] Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8, 755–765 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA induces irritation when applied onto the skin and increases its catabolism when administered intravenously, reducing its therapeutic efficacy.

    “Secondly, RA induces irritation when applied onto the skin and increases its catabolism, when it is administered intravenously, reducing its therapeutic efficacy20.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Adamson, P. C. Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia. Semin. Hematol. 31, 14–17 (1994).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    At least four molecules have reached phase 4 clinical trials: bexarotene, tazarotene, adapalene, and trifarotene.

    “At least four molecules have reached phase 4 clinical trials: bexarotene, tazarotene, adapalene, and trifarotene29–31.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Altucci, L., Leibowitz, M. D., Ogilvie, K. M., de Lera, A. R. & Gronemeyer, H. RAR and RXR modulation in cancer and metabolic disease. Nat. Rev. Drug Discov. 6, 793–810 (2007). source

      Not checked in the free run.

    • cites [30] di Masi, A. et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol. Asp. Med. 41, 1–115 (2015). source

      Not checked in the free run.

    • cites [31] Wagner, N., Benkali, K., Alio Saenz, A., Poncet, M. & Graeber, M. Clinical pharmacology and safety of trifarotene, a first-in-class RARgamma-selective topical retinoid. J. Clin. Pharmacol. 60, 660–668 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RA binds to cellular retinoic acid-binding proteins (CRABP), assisting autocrine and paracrine signaling.

    “RA binds to cellular retinoic acid-binding proteins (CRABP), assisting autocrine and paracrine signaling34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8, 755–765 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tazarotene and adapalene formulations have high affinity and selectivity for RARβ and RARγ, although tazarotene showed more toxicity than adapalene in dermatological applications.

    “Tazarotene and adapalene formulations have high affinity and selectivity for RARβ and RARγ, although the first one showed more toxicity than the second in dermatological applications33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Gaikwad, J., Sharma, S. & Hatware, K. V. Review on characteristics and analytical methods of tazarotene: an update. Crit. Rev. Anal. Chem. 50, 90–96 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trifarotene is a selective RAR-γ agonist, approved in late 2019 in the USA, for the topical treatment of acne in patients as young as 9 years old.

    “Trifarotene is a selective RAR-γ agonist, approved in late 2019 in the USA, for the topical treatment of acne in patients as young as 9 years old31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Wagner, N., Benkali, K., Alio Saenz, A., Poncet, M. & Graeber, M. Clinical pharmacology and safety of trifarotene, a first-in-class RARgamma-selective topical retinoid. J. Clin. Pharmacol. 60, 660–668 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA is poorly soluble in aqueous solutions and photosensitive, which makes its administration challenging.

    “First, RA is poorly soluble in aqueous solutions18 and photosensitive19, which makes its administration challenging.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Szuts, E. Z. & Harosi, F. I. Solubility of retinoids in water. Arch. Biochem. Biophys. 287, 297–304 (1991). source

      Not checked in the free run.

    • cites [19] Ourique, A. F. et al. Improved photostability and reduced skin permeation of tretinoin: development of a semisolid nanomedicine. Eur. J. Pharm. Biopharm. 79, 95–101 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The continued scrutiny of natural retinoids is likely because RA is a natural drug, blocks multiple disease signaling pathways, is less selective than some synthetic retinoids, and has long been used in combinatorial therapy and is well known by clinicians.

    “The reasons are likely combinatorial: RA is a natural drug, blocks multiple disease signaling pathways12, in opposition to some synthetic retinoids that are very selective to a single receptor-mediated signaling pathway, and it has been used for many years in combinatorial therapy and thus well known by clinicians.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Wei, S. et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat. Med. 21, 457–U230 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several semi-synthetic and synthetic retinoids have been developed to decrease the toxicity of natural retinoids and to increase their stability and selectivity against a specific RAR subtype.

    “To decrease the toxicity of the natural retinoids as well as to increase their stability and selectivity against a specific RAR subtype, several semi-synthetic and synthetic retinoids (including “atypical retinoids”) have been developed29,30.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Altucci, L., Leibowitz, M. D., Ogilvie, K. M., de Lera, A. R. & Gronemeyer, H. RAR and RXR modulation in cancer and metabolic disease. Nat. Rev. Drug Discov. 6, 793–810 (2007). source

      Not checked in the free run.

    • cites [30] di Masi, A. et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol. Asp. Med. 41, 1–115 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RA is the main biologically active metabolite of vitamin A.

    “RA is the main biologically active metabolite of vitamin A28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA has very low solubility in aqueous solution (0.21 μM at pH 7.3) and thus requires specific binding proteins (e.g., CRABPs) to be transported within cells to act at nuclear receptors.

    “RA has very low solubility in aqueous solution (0.21 μM at pH 7.3)18 and thus requires specific binding proteins (e.g., CRABPs) to be transported within cells to act at nuclear receptors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Szuts, E. Z. & Harosi, F. I. Solubility of retinoids in water. Arch. Biochem. Biophys. 287, 297–304 (1991). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RAR also regulates nonnuclear and nontranscriptional effects, namely activation of kinase signaling pathways.

    “Importantly, RAR also regulates nonnuclear and nontranscriptional effects, namely the activation of kinase signaling pathways38 (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Al Tanoury, Z., Piskunov, A. & Rochette-Egly, C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J. Lipid Res. 54, 1761–1775 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In physical entrapment, RA is captured during nanoparticle formation or in the pores of the nanoparticles.

    “Concerning physical entrapment, RA is captured during nanoparticle formation57,58 or in the pores of the nanoparticles59.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [57] Cho, C. S. et al. Receptor-mediated delivery of all trans-retinoic acid to hepatocyte using poly(L-lactic acid) nanoparticles coated with galactose-carrying polystyrene. J. Control. Release 77, 7–15 (2001). source

      Not checked in the free run.

    • cites [58] Almouazen, E. et al. Development of a nanoparticle-based system for the delivery of retinoic acid into macrophages. Int J. Pharm. 430, 207–215 (2012). source

      Not checked in the free run.

    • cites [59] Park, S. J. et al. Highly efficient and rapid neural differentiation of mouse embryonic stem cells based on retinoic acid encapsulated porous nanoparticle. ACS Appl. Mater. Interfaces 9, 34634–34640 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA delivery systems have been prepared by complexation of RA with proteins or cationic polymers, by physical encapsulation in polymeric or inorganic nanoparticles, microparticles, micelles, liposomes, or films, by covalent attachment of RA to a carrier, or by immobilization of RA on surfaces of nanoparticles.

    “Several strategies have been used to prepare RA delivery systems: namely, by complexation of RA with proteins (e.g., transthyretin)42 or cationic polymers (e.g., poly(ethyleneimine) (PEI))43,44, by physical encapsulation in polymeric25,44 or inorganic45 nanoparticles, microparticles46, micelles47,48, liposomes49, or films43, by covalent attachment of RA to a carrier50, or by immobilization of RA”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Zanotti, G., Dacunto, M. R., Malpeli, G., Folli, C. & Berni, R. Crystal-structure of the transthyretin retinoic-acid complex. Eur. J. Biochem. 234, 563–569 (1995). source

      Not checked in the free run.

    • cites [43] Thunemann, A. F. & Beyermann, J. Polyethylenimine complexes with retinoic acid: structure, release profiles, and nanoparticles. Macromolecules 33, 6878–6885 (2000). source

      Not checked in the free run.

    • cites [44] Maia, J. et al. Controlling the neuronal differentiation of stem cells by the intracellular delivery of retinoic acid-loaded nanoparticles. ACS Nano 5, 97–106 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These bonds are susceptible to degradation during specific pH conditions, in the presence of proteases, or reducing agents that lead to RA release.

    “These bonds are susceptible to degradation during specific pH conditions, in the presence of proteases, or reducing agents that lead to RA release.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In physical interaction, RA is complexed with positively charged polymers such as chitosan or PEI; the carboxylic acid of RA interacts electrostatically with the amine group located in the polymer, forming a complex that can be stabilized by addition of a polyanion and divalent ions.

    “Regarding physical interaction, RA is complexed with positively charged polymers such as chitosan, or PEI43,51. The carboxylic acid of RA interacts electrostatically with the amine group located in the polymer, forming a complex that can be stabilized by addition of a polyanion and divalent ions43,44.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Thunemann, A. F. & Beyermann, J. Polyethylenimine complexes with retinoic acid: structure, release profiles, and nanoparticles. Macromolecules 33, 6878–6885 (2000). source

      Not checked in the free run.

    • cites [51] Kim, D. G. et al. All-trans retinoic acid-associated low molecular weight water-soluble chitosan nanoparticles based on ion complex. Macromol. Res. 14, 66–72 (2006). source

      Not checked in the free run.

    • cites [44] Maia, J. et al. Controlling the neuronal differentiation of stem cells by the intracellular delivery of retinoic acid-loaded nanoparticles. ACS Nano 5, 97–106 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RAR-RXR heterodimers interact with a DNA sequence known as the retinoic acid-response element, which facilitates binding of co-activators to histone acetylase, leading to transcription of target genes.

    “RAR–RXR heterodimers interact with a deoxyribonucleic acid sequence known as the retinoic acid-response element35, which facilitates the binding of co-activators to histone acetylase, ultimately leading to the transcription of target genes (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Schenk, T., Stengel, S. & Zelent, A. Unlocking the potential of retinoic acid in anticancer therapy. Br. J. Cancer 111, 2039–2045 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sustained release of RA for more than 1 month can be accomplished by encapsulating it into biodegradable microspheres and tuning release rate by adjusting polymer composition, by encapsulation in polyion complex micelles and adjusting polymer composition or drug content, or by encapsulation in liposomes.

    “The sustained release of RA for more than 1 month can be accomplished by encapsulating it into biodegradable microspheres and tuning the release rate by adjusting polymer composition in the formulation61, by the encapsulation in polyion complex micelles62 and adjusting polymer composition or drug content, or by the encapsulation in liposomes49.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Choi, Y. et al. Long-term delivery of all-trans-retinoic acid using biodegradable PLLA/PEG-PLLA blended microspheres. Int. J. Pharm. 215, 67–81 (2001). source

      Not checked in the free run.

    • cites [62] Jeong, Y. I. et al. Polyion complex micelles composed of all-trans retinoic acid and poly (ethylene glycol)-grafted-chitosan. J. Pharm. Sci. 95, 2348–2360 (2006). source

      Not checked in the free run.

    • cites [49] Mehta, K., Sadeghi, T., Mcqueen, T. & Lopezberestein, G. Liposome encapsulation circumvents the hepatic-clearance mechanisms of all-trans-retinoic acid. Leuk. Res. 18, 587–596 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a relatively low number of formulations, RA was immobilized on the surface of the nanoparticle; the concentration of RA immobilized on the surface is lower than in the core.

    “In a relatively low number of formulations, RA was immobilized not in the core but on the surface of the nanoparticle22; however, the concentration of RA immobilized on the surface is lower than in the core.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Han, X. X. et al. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem. Nat. Commun. 9, 3390 https://doi.org/10.1038/s41467-018-05906-x (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RXRα homodimers can also regulate gene transcription.

    “Recent data showed that RXRα homodimers can also regulate gene transcription36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Nunez, V. et al. Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression. Proc. Natl Acad. Sci. USA 107, 10626–10631 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    For more than 35 years, several groups have developed different RA delivery systems to overcome the limitations of RA.

    “Therefore, for more than 35 years, several groups have developed different RA delivery systems to overcome these limitations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the nucleus, RA triggers gene transcription by binding to heterodimers formed by RA receptors (RARα, RARβ, RARγ) and retinoid X receptors (RXRα, RXRβ, RXRγ).

    “In the nucleus, RA triggers gene transcription by binding to heterodimers formed by RA receptors (RARα, RARβ, and RARγ) and retinoid X receptors (RXRα, RXRβ, and RXRγ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Schenk, T., Stengel, S. & Zelent, A. Unlocking the potential of retinoic acid in anticancer therapy. Br. J. Cancer 111, 2039–2045 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RA is catabolized by monooxygenases of the cytochrome P450 superfamily.

    “Finally, RA is catabolized by monooxygenases of the cytochrome P450 superfamily34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8, 755–765 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo tests showed that rats or human patients treated with ATRA-containing liposomes by intravenous administration had no decrease in plasma ATRA levels while animals/humans treated with oral formulation of ATRA (nonliposomal) had a significant decrease in plasma ATRA levels.

    “In vivo tests showed that rats49 or human patients70 treated with ATRA-containing liposomes by intravenous administration had no decrease in plasma ATRA levels while animals/humans treated with oral formulation of ATRA (nonliposomal) had a significant decrease in plasma ATRA levels41,49.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Muindi, J. et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 79, 299–303 (1992). source

      Not checked in the free run.

    • cites [49] Mehta, K., Sadeghi, T., Mcqueen, T. & Lopezberestein, G. Liposome encapsulation circumvents the hepatic-clearance mechanisms of all-trans-retinoic acid. Leuk. Res. 18, 587–596 (1994). source

      Not checked in the free run.

    • cites [70] Estey, E. et al. Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood 87, 3650–3654 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Electrospun poly(ε-caprolactone) fibers loaded with ATRA led to extremely high local concentrations of this agent and the differentiation of murine embryonic cells within multilayered scaffolds.

    “Electrospun poly(ε-caprolactone) fibers were loaded with ATRA, which led to extremely high local concentrations of this agent and the differentiation of murine embryonic cells, within the multilayered scaffolds73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Tzezana, R., Reznik, S., Blumenthal, J., Zussman, E. & Levenberg, S. Regulation of stem cell differentiation by control of retinoic acid gradients in hydrospun 3D scaffold. Macromol. Biosci. 12, 598–607 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both ATRA-containing liposomes and oral ATRA formulations were safe in human trials.

    “Both formulations were safe in human trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Estey, E. et al. Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood 87, 3650–3654 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    RA downregulates expressions of geminin and zinc finger protein Zic2, SoxB1 (Sox-1, Sox-2, Sox-3), and Notch-1, which maintain neural progenitor cell proliferation; by halting proliferation, RA shifts signaling toward differentiation.

    “RA downregulates expressions of geminin and zinc finger protein Zic2, SoxB1 (Sox-1, Sox-2, Sox-3), and Notch-1, which maintain neural progenitor cell proliferation. By halting proliferation, RA shifts signaling toward differentiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When mice were fed a vitamin A-free diet to deplete the RA reservoir, animals suffered functional impairment of hematopoietic stem cells and their numbers were unable to recover even after injection with an immunostimulant.

    “When mice were fed a vitamin A-free diet to deplete the RA reservoir, animals suffered, among other effects, functional impairment of hematopoietic stem cells and their numbers were unable to recover even after injection with an immunostimulant8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Cabezas-Wallscheid, N. et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell 169, 807–823.e19 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In refractory hematological malignancies, the remission rate with liposomal RA (67% clinical remission) was lower than that obtained using a combinatorial therapy (77% clinical remission) including oral ATRA plus idarubicin, and thus the liposomal formulation was not further evaluated.

    “In the last application, the remission rate (67% clinical remission) was lower than that obtained using a combinatorial therapy (77% clinical remission), which included oral administration of ATRA plus idarubicin and thus the liposomal formulation was not further evaluated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Estey, E. et al. Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood 87, 3650–3654 (1996). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    9-cis-RA encapsulated in a gel is an FDA-approved topical agent for cutaneous Kaposi's sarcoma.

    “9-cis-RA encapsulated in a gel is an FDA-approved topical agent for cutaneous Kaposi’s sarcoma75.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Sardana, K. & Sehgal, V. N. Retinoids: fascinating up-and-coming scenario. J. Dermatol. 30, 355–380 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In experimental models of AD, RA inhibited oxidative damage and mitochondrial dysfunction; increased ApoE expression and suppressed inflammation; and improved learning and memory.

    “In experimental models of AD, RA: (1) inhibited oxidative damage and mitochondrial dysfunction; (2) increased ApoE expression and suppressed inflammation; and (3) improved learning and memory84,85.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Ding, Y. et al. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J. Neurosci. 28, 11622–11634 (2008). source

      Not checked in the free run.

    • cites [85] Chakrabarti, M. et al. Molecular signaling mechanisms of natural and synthetic retinoids for inhibition of pathogenesis in Alzheimer’s disease. J. Alzheimers Dis. 50, 335–352 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATRA-containing nanoparticles enhanced endothelial cell proliferation and tubule network formation and protected against ischemia-induced death in endothelial cell lines and endothelial progenitor cells isolated from ischemic stroke patients.

    “The formulation enhanced endothelial cell proliferation and tubule network formation and protected against ischemia-induced death in endothelial cell lines and endothelial progenitor cells isolated from ischemic stroke patients24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Ferreira, R. et al. Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia. Nanoscale 8, 8126–8137 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single short pulse of light prompted β-catenin-dependent neuronal differentiation and RARα upregulation.

    “A single short pulse of light prompted β-catenin-dependent neuronal differentiation and RARα upregulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Santos, T. et al. Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles. Acta Biomater. 59, 293–302 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some formulations (e.g., ATRA-containing liposomes) improve the local effect of RA in the skin and decrease systemic adsorption.

    “some formulations (e.g., ATRA-containing liposomes) improve the local effect of RA in the skin and decrease systemic adsorption78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Masini, V., Bonte, F., Meybeck, A. & Wepierre, J. Cutaneous bioavailability in hairless rats of tretinoin in liposomes or gel. J. Pharm. Sci. 82, 17–21 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The biological effect of ATRA includes modulation of proliferation and differentiation of skin cells and anti-inflammatory activity.

    “the biological effect of ATRA includes: (1) modulation of proliferation and differentiation of skin cells; (2) anti-inflammatory activity75.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Sardana, K. & Sehgal, V. N. Retinoids: fascinating up-and-coming scenario. J. Dermatol. 30, 355–380 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA promoted terminal differentiation of leukemic cells while reducing their proliferation.

    “RA promoted terminal differentiation of leukemic cells while reducing their proliferation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Kozono, S. et al. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat. Commun. 9, 3069 (2018). source

      Not checked in the free run.

    • cites [12] Wei, S. et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat. Med. 21, 457–U230 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Although formulations having affinity ligands in their surface have increased retention in the brain, only a minor fraction of the injected formulation reaches the brain and crosses the BBB.

    “Although the formulations having affinity ligands in their surface have increased retention in the brain, only a minor fraction of the injected formulation reaches the brain and crosses the BBB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ATRA induces skin angiogenesis and collagen deposition, increases mitotic activity of inter- and follicular epithelium, and reduces melanin production.

    “ATRA also induces skin angiogenesis and collagen deposition, increases the mitotic activity of inter- and follicular epithelium, and reduces melanin production75.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Sardana, K. & Sehgal, V. N. Retinoids: fascinating up-and-coming scenario. J. Dermatol. 30, 355–380 (2003). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATRA was approved for acne vulgaris treatment in 1971.

    “ATRA was approved for acne vulgaris treatment in 19712”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Raza, K. et al. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Int J. Pharm. 456, 65–72 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The formulation was highly internalized by leukemia-initiating cells and accumulated in the cell cytoplasm.

    “The formulation was highly internalized by leukemia-initiating cells and accumulated in the cell cytoplasm.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Boto, C. et al. Prolonged intracellular accumulation of light-inducible nanoparticles in leukemia cells allows their remote activation. Nat. Commun. 8, 15204 (2017). source

      Not checked in the free run.

    • cites [26] Jimenez-Balsa, A. et al. Nanoparticles conjugated with photocleavable linkers for the intracellular delivery of biomolecules. Bioconjug. Chem. 29, 1485–1489 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATRA was effective in differentiating myeloid-derived suppressor cells, and in synergy with doxorubicin, contributed to increase the number of dendritic cells at the tumor site; IL-2 facilitated the proliferation of CD8+ T cells at the tumor site to promote effective tumor killing.

    “ATRA was effective in differentiating myeloid-derived suppressor cells, and in synergy with doxorubicin, contributed to increase the number of dendritic cells at the tumor site; IL-2 facilitated the proliferation of CD8+ T cells at the tumor site to promote effective tumor killing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Kong, M. et al. Biodegradable hollow mesoporous silica nanoparticles for regulating tumor microenvironment and enhancing antitumor efficiency. Theranostics 7, 3276–3292 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These altered cells are difficult to eliminate by conventional antitumoral agents because drugs do not reach the bone marrow at the required concentration, and because the stem cell niche changes/adapts after chemotherapy, protecting altered cells.

    “These altered cells are difficult to eliminate by conventional antitumoral agents because drugs do not reach the bone marrow at the required concentration, and because the stem cell niche (a physical and functional entity that supports the self-renewal and differentiation of stem cells) changes/adapts after chemotherapy, protecting altered cells97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Duan, C. W. et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell 25, 778–793 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATRA inhibits proliferation of glioblastoma cells in vitro and in vivo, while promoting their differentiation.

    “ATRA inhibits proliferation of glioblastoma cells in vitro and in vivo, while promoting their differentiation117,118.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Ying, M. et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 30, 3454–3467 (2011). source

      Not checked in the free run.

    • cites [118] Niu, C. S. et al. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. J. Exp. Clin. Cancer Res. 29, 113 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animals treated with formulations containing doxorubicin, ATRA, and IL-2 were the ones with the most effective tumor growth inhibition and decreased metastasis.

    “Animals treated with formulations containing the three agents were the ones with the most effective tumor growth inhibition and decreased metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Kong, M. et al. Biodegradable hollow mesoporous silica nanoparticles for regulating tumor microenvironment and enhancing antitumor efficiency. Theranostics 7, 3276–3292 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The formulation did not reach the market, likely because it was not sufficient to reverse or suppress more advanced dysplasia with acceptable local side effects in phase III clinical trial.

    “the formulation did not reach the market, likely because it was not sufficient to reverse or suppress more advanced dysplasia with acceptable local side effects in phase III clinical trial107.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Meyskens, F. L. et al. Enhancement of regression of cervical intraepithelial neoplasia-ii (moderate dysplasia) with topically applied all-trans-retinoic acid—a randomized trial. J. Natl. Cancer Inst. 86, 539–543 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Irradiation of bone marrow with a blue light induced photo-disassembly of the nanoparticles within the cells and consequently their differentiation.

    “The irradiation of bone marrow with a blue light induced photo-disassembly of the nanoparticles within the cells and consequently their differentiation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Boto, C. et al. Prolonged intracellular accumulation of light-inducible nanoparticles in leukemia cells allows their remote activation. Nat. Commun. 8, 15204 (2017). source

      Not checked in the free run.

    • cites [26] Jimenez-Balsa, A. et al. Nanoparticles conjugated with photocleavable linkers for the intracellular delivery of biomolecules. Bioconjug. Chem. 29, 1485–1489 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATRA liposomes and nanoparticles encapsulating simultaneously ATRA and doxorubicin have been used successfully to arrest the proliferation of breast cancer-initiating cells and to differentiate them.

    “ATRA liposomes and nanoparticles encapsulating simultaneously ATRA and doxorubicin have been used successfully to arrest the proliferation of breast cancer-initiating cells and to differentiate them113,114.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [113] Li, R. J. et al. All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. J. Control. Release 149, 281–291 (2011). source

      Not checked in the free run.

    • cites [114] Sun, R. et al. Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells. Biomaterials 37, 405–414 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to free drugs, the nanoparticle formulation increased the accumulation of all-trans-retinal and doxorubicin at the tumor site and induced higher levels of cell senescence and antitumoral activity.

    “Compared to free drugs, the nanoparticle formulation increased the accumulation of the all-trans-retinal and doxorubicin at the tumor site and induced higher levels of cell senescence and antitumoral activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Zhang, Y. et al. Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy. Biomaterials 83, 219–232 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of vitamin A, in the adult, led to a decrease of Th1, Th17, and ILC3 responses, an effect which is counteracted through time.

    “the depletion of vitamin A, in the adult, led to a decrease of Th1, Th17, and ILC3 responses (a synonym of lowered immunity to bacterial infection), an effect which is counteracted through time127.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA formulations are taken up by macrophages and induce anti-inflammatory responses by suppressing NF-kB signaling and increasing bone morphogenetic protein 2 signaling, as well as by enhancing the production of anti-inflammatory cytokines (e.g., IL-10).

    “RA formulations are taken up by macrophages and induce anti-inflammatory responses by suppressing NF-kB signaling and increasing bone morphogenetic protein 2 signaling (pivotal for bone and cartilage development), as well as by enhancing the production of anti-inflammatory cytokines (e.g., IL-10)58,124.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Almouazen, E. et al. Development of a nanoparticle-based system for the delivery of retinoic acid into macrophages. Int J. Pharm. 430, 207–215 (2012). source

      Not checked in the free run.

    • cites [124] Zai, K. et al. Regulation of inflammatory response of macrophages and induction of regulatory T cells by using retinoic acid-loaded nanostructured lipid carrier. J. Biomater. Sci. Polym. Ed. 30, 1–11 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The concept of stimuli-responsive RA formulations is that the systems retain the drug and release it only after a specific trigger, enhancing its therapeutic efficacy and minimizing systemic toxicity.

    “The concept here is that the systems retain the drug and release it only after a specific trigger, enhancing its therapeutic efficacy and minimizing systemic toxicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RA inhibited IL-6-driven induction of proinflammatory Th17 cells and promoted the differentiation of Treg cells.

    “RA inhibited IL-6-driven induction of proinflammatory Th17 cells and promoted the differentiation of Treg cells, which are important to suppress excessive immune responses125.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Mucida, D. et al. Reciprocal T(H)17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Development of stimuli-responsive RA formulations requires the use of linkers susceptible to pH or enzymes present in the targeted cell or tissue.

    “Development of these formulations requires the use of linkers susceptible to pH or enzymes present in the targeted cell/tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The advantages of RA-containing nanoparticles versus free RA were demonstrated by inhibiting expression of IL-6 and IL-8 in alveolar epithelial cells, but were not demonstrated in the induction of immune cell differentiation.

    “The advantages of RA-containing nanoparticles versus free RA were demonstrated by inhibiting expression of IL-6 and IL-8 in alveolar epithelial cells74, but were not demonstrated in the induction of immune cell differentiation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Payne, C. M. et al. Evaluation of the immunomodulatory effects of all-trans retinoic acid solid lipid nanoparticles and human mesenchymal stem cells in an A549 epithelial cell line model. Pharm. Res. 36, 50 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The advantages of RA formulations have been demonstrated in preclinical (in all applications described in this review) and clinical trials (cancer and skin applications).

    “The advantages of RA formulations have been demonstrated in preclinical (in all applications described in this review) and clinical trials (cancer and skin applications)71,129.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Rahman, S. A. et al. Tretinoin-loaded liposomal formulations: from lab to comparative clinical study in acne patients. Drug Deliv. 23, 1184–1193 (2016). source

      Not checked in the free run.

    • cites [129] Jain, P. et al. Single-agent liposomal all-trans-retinoic acid as initial therapy for acute promyelocytic leukemia: 13-year follow-up data. Clin. Lymphoma Myeloma Leuk. 14, e47–e49 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Levels of retinoids obtained from the maternal diet increase the size of secondary lymphoid organs and the efficacy of adult immune responses.

    “the levels of retinoids obtained from the maternal diet increase the size of secondary lymphoid organs and the efficacy of adult immune responses13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The advantages of RA formulations include increased cell targeting and capacity to cross biological barriers.

    “(5) increased cell targeting and capacity to cross biological barriers.”
    Quote in the paperSubstantial claim
59 of 59

  • The paper relies on this without support.

    Nanoparticles and microparticles used in most preclinical studies have been prepared in small batches.

    “nanoparticles/microparticles used in most preclinical studies have been prepared in small batches”

  • The paper relies on this without support.

    Pathologies discussed in this review (neurologic diseases, cancer, immune diseases) are multifactorial and display complex signaling pathways and symptoms.

    “Pathologies discussed in this review (neurologic diseases, cancer, immune diseases) are multifactorial and display complex signaling pathways and symptoms.”

  • The paper relies on this without support.

    RA is an evolutionarily ancient and conserved molecule with overlapping and pleiotropic effects.

    “RA is an evolutionarily ancient and conserved molecule with overlapping and pleiotropic effects.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • After penetrating the epidermis, retinoids play a role in the release of transcription and growth factors.

    “After penetrating the epidermis, retinoids play a role in the release of transcription and growth factors.”

    From Bioactive Compounds for Skin Health: A Review (2021) · cites this paper as [35]

  • Retinoids affect the thickness and color of the skin, regulate sebaceous gland function, limit sebum production, are responsible for hair and nail growth, and influence melanin distribution in the skin.

    “Retinoids also affect the thickness and color of the skin, regulate the function of the sebaceous glands, and limit sebum production, as well as being responsible for hair and nail growth, and also influencing the distribution of melanin in the skin [27,30,35].”

    From Bioactive Compounds for Skin Health: A Review (2021) · cites this paper as [35]

  • Retinoids and all biologically active forms of vitamin A promote remodeling of reticulin fibers and synthesis of a new capillary network in the dermis.

    “Retinoids and all biologically active forms of vitamin A also promote the remodeling of reticulin fibers and synthesis of a new capillary network in the dermis.”

    From Bioactive Compounds for Skin Health: A Review (2021) · cites this paper as [35]

  • Retinoids reduce transepidermal water loss by strengthening the epidermal barrier.

    “Retinoids also reduce transepidermal water loss (TEWL) by strengthening the epidermal barrier [28,34,35].”

    From Bioactive Compounds for Skin Health: A Review (2021) · cites this paper as [35]

  • Topically applied retinoids penetrate the keratinized epidermis and, to a lesser extent, the dermis and subcutaneous tissue.

    “Topically applied retinoids penetrate the keratinized epidermis and, to a lesser extent, the dermis and subcutaneous tissue [27,30,35].”

    From Bioactive Compounds for Skin Health: A Review (2021) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table 4 lists only two oral formulations for skin diseases

    Minor

    The text says three of the four marketed oral formulations treat skin diseases. Table 4 lists two skin indications, one leukemia indication, and one indication for preventing or treating vitamin A deficiency.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Karrer, P., Morf, R. & Schopp, K. Information on vitamine A from train-oil. Helv. Chim. Acta 14, 1035–1040 (1931).
  2. Levin, A. A., B. T., KazmerS. & Grippo, J. F. 13-cis retinoic acid does not bind to retinoic acid receptors alpha, beta and gamma. Toxicologist 12, 181 (1992).
  3. Jeong, Y. I. et al. Polyion complex micelles composed of all-trans retinoic acid and poly (ethylene glycol)-grafted-chitosan. J. Pharm. Sci. 95, 2348–2360 (2006). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Ferreira, R., Napoli, J., Enver, T., Bernardino, L., & Ferreira, L.
Affiliations
  • University of Beira Interior (PT)
  • University of California, Berkeley (US)
  • University College London (GB)
  • Centro de Neurociências e Biologia Celular (PT)
Corresponding author
  • Bernardino, Liliana
  • Ferreira, Lino
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-08-26
Volume
11
Issue
1
Pages
4265-4265
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-18042-2
PMC
PMC7450074
OpenAlex
W3080707378
Semantic Scholar
01a0c2b8608e246e19036f546426348623c486cd
Cited by
138
References
142
Citations by year
2026: 24 · 2025: 28 · 2024: 23 · 2023: 22 · 2022: 24 · 2021: 16 · 2020: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • L'Oreal USA
  • Programa Operacional Regional do Centro (CENTRO-01-0145-FEDER-000013)
  • Medical Research Council (MR/N000838/1)
  • Fundação para a Ciência e a Tecnologia (01-0145, POCI-01-0145, 0624_2IQBIONEURO_6_E, CENTRO-01-0145-FEDER, 00709/2013, POCI-01-0145-FEDER-, POCI-01-0145- FEDER-016390, POCI-01-, 669088, SFRH/BPD/102103/2014, CENTRO-01-0145-FEDER-000013, IF/00178/2015/CP1300/CT0001, CT0001, EXPL/BIM-MED/0822/2013, 00709, POCI-01-0145-FEDER-029414)
  • Interreg (0624_2IQBIONEURO_6_E, EAPA_791/2018)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
Keywords
retinoids, drug delivery systems, regenerative medicine, brain disorders, cancer, skin diseases, immune disorders, sustained drug release, drug solubilization, toxicity reduction
MeSH terms
Animals, Brain Diseases, Cell Differentiation, Clinical Trials as Topic, Drug Compounding, Humans, Immune System Diseases, Neoplasms, Retinoids, Skin Diseases, Signal Transduction, Drug Delivery Systems, Regenerative Medicine, Embryonic Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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