Drach, J., Lopezberestein, G., Mcqueen, T., Andreeff, M. & Mehta, K. Induction of differentiation in myeloid-leukemia cell-lines and acute promyelocytic leukemia-cells by liposomal all-trans-retinoic acid. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neurosci. To obtain Control. Clinical applications of RA have highlighted three main limitations of its pharmacological use. Kim, D. G., Jeong, Y. I. Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. 17, 265276 (2016). Raza, K. et al. The capacity of RA-containing formulations to cross biological barriers such as the blood-brain barrier (BBB) (relevance for the treatment of brain cancer and neurodegenerative disorders) is a topic largely unexplored. Pharm. Despite the progress made in the last years in the synthesis of novel retinoids to increase natural retinoid efficacy while reducing their toxicity, it is evident that natural retinoids are still under intense scrutiny as demonstrated by a considerable number of clinical trials (Table1). J. Appl. Castro, G. A. et al. Schug, T. T., Berry, D. C., Shaw, N. S., Travis, S. N. & Noy, N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. 50, 9096 (2020). In the last 10 years, a new therapeutic paradigm has emerged based on the targeted delivery of formulations to bone marrow96. Dermatol. J. Dermatol. Russo, D. et al. Med. In general, formulations with high RA loading show a slower release profile of the drug51. Kligman, A. M. The growing importance of topical retinoids in clinical dermatology: a retrospective and prospective analysis. Neurosci. PubMed 33, 715729 (2015). Challenges include: a crossing endothelial barriers for extravasation of RA-containing formulations into a specific body region; b targeting of RA-containing formulations to specific cells; c development of formulations that combine RA with other pharmacological agents, able to release each agent with a specific release kinetics. Leukemia 12, 449454 (1998). The reasons behind the development of retinoid formulations in each application will be presented, along with their benefits and limitations, considering retinoid solubility, photostability, biocompatibility, release profile, tissue/cell availability and targeting, and therapeutic efficacy. Han, X. X. et al. All these limitations motivated researchers to synthesize novel and better tolerated synthetic retinoid compounds and to develop retinoid delivery formulations based on gels, liposomes, microparticles, nanoparticles, and micro-/nanofibers, which in some cases have been modified to target-specific tissues and cells of interest21. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Huen, A. O. J. Pharm. RA/RAR signaling is critical for BBB differentiation and integrity90. In general, RA formulations showed sustained intracellular RA delivery for a few days58,74. In this study, the transplantation of nanoparticle-treated NSCs in AD mice improved cognition and memory. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa. At a cellular level, 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. Theranostic RA formulations are particularly relevant if they are injected intravenously. Front. Experimental data in humans indicate that ATRA administered orally is not able to accumulate in the cerebrospinal fluid67. 8, 29062912 (2008). Current challenges for using RA formulations for immune diseases are related to the in vivo demonstration of RA effects. Machado-Pereira, M., Santos, T., Ferreira, L., Bernardino, L. & Ferreira, R. Intravenous administration of retinoic acid-loaded polymeric nanoparticles prevents ischemic injury in the immature brain. 72, 15591576 (2015). 352, 14 (2008). 27, 10071013 (2009). The transport of these retinoids to cells occurs when blood-circulating retinol is bound to retinol-binding protein (RBP) 4 (Fig. CAS Therefore, for more than 35 years, several groups have developed different RA delivery systems to overcome these limitations. The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. It should be noted that a liposomal formulation having two agents (non-RA drugs) has been approved recently for AML106. Targeted drug delivery for tumor therapy inside the bone marrow. Cell 129, 723733 (2007). Google Scholar. Commun. Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer. Li, R. J. et al. RA-coated solid lipid nanoparticles showed higher in vitro toxicity relatively to glioblastoma cells than the parent drug120. Chronopoulos, A. et al. Although many of these formulations have been tested in preclinical models, the clinical translation is still relatively low. 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. A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression. Farinello, D. et al. Cite this article. Nat. Mukherjee, S. et al. The protective effect of these formulations was linked to their ability to reflect and scatter UV radiation80. 119, 272279 (2006). With the exception of some formulations for parenteral administration63 or for intracellular delivery in ex vivo conditions25,26, most RA-containing formulations have been developed for intravenous delivery. Yao, J., Zhang, L., Zhou, J. P., Liu, H. P. & Zhang, Q. Dermatol. RA has been tested in several clinical trials and the results showed that RA alone did not present significant antitumoral activity against breast cancer109; however, when RA was combined with tamoxifen or paclitaxel it showed moderate antitumoral activity110,111. ADS Improved photostability and reduced skin permeation of tretinoin: development of a semisolid nanomedicine. All-trans retinoic acid-associated low molecular weight water-soluble chitosan nanoparticles based on ion complex. Receptor-mediated delivery of all trans-retinoic acid to hepatocyte using poly(L-lactic acid) nanoparticles coated with galactose-carrying polystyrene. Why topical retinoids are mainstay of therapy for acne. 6, 12581268 (2010). 64, 83101 (2012). Therefore, a combination of chemotherapy with immunotherapy might be a better strategy to fight tumor biology. Zuccari, G., Carosio, R., Fini, A., Montaldo, P. G. & Orienti, I. Kozono, S. et al. RARalpha supports the development of Langerhans cells and langerin-expressing conventional dendritic cells. Biomaterials 31, 36573666 (2010). Nat Commun 11, 4265 (2020). Jeong, Y. I. et al. 41, 1115 (2015). Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Budd, G. T. et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. 12, 598607 (2012). Initial studies have used RA as a potent regulator of neural differentiation72. Moreover, further formulations should be developed with the capacity to release multiple drugs in combination with RA. Rev. Commun. By submitting a comment you agree to abide by our Terms and Community Guidelines. van de Pavert, S. A. et al. 91, 77727776 (1994). of retinoids-encapsulating liposomes have been testing against several types of cancer, including lung, thyroid, and liver cancers, as well as on neuroectodermal-derived tumors such as melanoma . In addition, pH-sensitive nanoparticles have been designed to release all-trans retinal and doxorubicin in weakly acidic tumors (pH 6.5) or acidic intracellular environments such as endosomes/lysosomes (pH 4.55.5)112. RA formulations have some limitations that preclude a more significant translation to the clinic. Liposomes are a suitable choice for retinoids' encapsulation, as the active ingredients can be incorporated into the membrane of the particles, ending in skin penetration and enhanced stability. Fifty percent of the patients showed a total regression of the disease4,5. These bonds are susceptible to degradation during specific pH conditions, in the presence of proteases, or reducing agents that lead to RA release. Cell. Formulations such as micro- and nanoparticles might have the capacity to target particular cells by specificities in their physicochemical properties or by incorporating in their surface peptides, proteins, or aptamers that recognize specific cell receptors. Res. Clin. Rev. However, 13-cis RA may be converted into molecules that act as agonists for nuclear RAR and RXR. 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. Mol. The cellular uptake of some RA-containing nanoparticles has been demonstrated to take <12h44 by clathrin-mediated endocytosis and macropinocytosis25. In the case of cancer, recent studies indicate that the antitumoral activity of RA might be greatly enhanced with formulations that extend the in vivo half-life of RA12. CAS The advantages of RA formulations compared to free RA have been demonstrated in various biomedical applications. USA 111, 1028710292 (2014). Several ATRA delivery systems showed relative success in reducing the induction of ATRA catabolism and thus maintaining RA for longer periods in blood plasma. Karnik, R. et al. Engineered nanomedicine for myeloma and bone microenvironment targeting. Biosci. Oncol. Development of a nanoparticle-based system for the delivery of retinoic acid into macrophages. J. Others were tested in clinical trials but did not reach the market. Med. Rahman, S. A. et al. J. Natl. At least four molecules have reached phase 4 clinical trials: bexarotene, tazarotene, adapalene, and trifarotene29,30,31. Nat. RA is the main biologically active metabolite of vitamin A28. All-trans-retinoic acid (ATRA)-grafted polymeric gene carriers for nuclear translocation and cell growth control. Chim. First, RA is poorly soluble in aqueous solutions18 and photosensitive19, which makes its administration challenging. Acta Biomater. 95, 23482360 (2006). In that sense, light-activatable nanoparticles containing RA that disassemble in minutes after activation by a blue laser at 405nm have been prepared25,26,60. Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer. 40, 335341 (1997). Eur. Dermatol. Zhang, R. et al. Zhang, Y. et al. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. RA is an evolutionarily ancient and conserved molecule with overlapping and pleiotropic effects. Hou, L., Yao, J., Zhou, J. P. & Zhang, Q. Pharmacokinetics of a paclitaxel-loaded low molecular weight heparin-all-trans-retinoid acid conjugate ternary nanoparticulate drug delivery system. Several RA formulations have been developed to target immune cells and induce an immunomodulatory response, such as solid lipid nanoparticles74, polymeric nanoparticles58, nanostructured lipid carriers124, among others. Nam, Y. S. et al. Thus, further investigation is needed to address this issue. 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. Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules. 6, 253258 (2004). Moreover, when intravenously injected, RA formulations restored neuronal and vascular functions in a prenatal model of brain ischemia91. Modified polyvinylalcohol for encapsulation of all-trans-retinoic acid in polymeric micelles. Google Scholar. Research is also being done into their ability to treat skin cancers. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. 7, 293304 (2017). CAS 2014).New functional food components promoted, require unique encapsulation technologies with low reactive activity . Acad. Thunemann, A. F. & Beyermann, J. Polyethylenimine complexes with retinoic acid: structure, release profiles, and nanoparticles. In addition, the recent FDA approval of gemtuzumab ozogamicin (an antibodydrug conjugate in which the anti-CD33 antibody is linked to a cytotoxic agent)106 or daratumumab (anti-CD38 antibody)132 might accelerate clinical testing and the approval of other formulations conjugated with antibodies. The efficiency of combination therapies is likely ascribed to several factors: (1) a combination of drugs may act at different sites of the antiproliferative signaling pathway and thus be more effective in the inhibition process; (2) combination therapies may decrease the probability of cancer resistance; (3) synergies between the drugs reduces the dose necessary for therapy, as well as their toxicity and treatment time. Smits, S. M., Ponnio, T., Conneely, O. M., Burbach, J. P. H. & Smidt, M. P. Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Macromol. Nanomedicine 10, 253269 (2015). Estey, E. H. et al. Retinoic acid induces blood-brain barrier development. Ourique, A. F., Pohlmann, A. R., Guterres, S. S. & Beck, R. C. R. Tretinoin-loaded nanocapsules: preparation, physicochemical characterization, and photostability study. Bioconjug. Retinoic acid (RA) signaling is one of the most important biological pathways in nature, triggered by RA interaction with nuclear receptors that control gene expression. Given the diverse pharmacological activities of RA, there is ample potential for developing therapeutic applications. Cancer Chemother. Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression. ATRA is used clinically for treating photoaging, acne, and psoriasis. 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. Increased in vitro antiproliferative effects on neoplastic cells. Niu, C. S. et al. 9, 3390 https://doi.org/10.1038/s41467-018-05906-x (2018). Nat. and JavaScript. Lapteva, M., Moller, M., Gurny, R. & Kalia, Y. N. Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle. Nat. Google Scholar. 6, 793810 (2007). Treatment of early AIDS-related Kaposis sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Muindi, J. et al. Erkelens, M. N. & Mebius, R. E. Retinoic acid and immune homeostasis: a balancing act. The spatiotemporal release of RA by polymeric microparticles incorporated within embryonic bodies, derived from human embryonic stem cells, was reported to induce cell differentiation and tissue formation resembling the phenotype and structure of early human embryos7. The role of RA in the gastrointestinal tract is particularly relevant since it is produced and metabolized in the intestine, where it regulates the differentiation and function of diverse immune cells and supports mucosal barrier immunity126. RA has very low solubility in aqueous solution (0.21M at pH 7.3)18 and thus requires specific binding proteins (e.g., CRABPs) to be transported within cells to act at nuclear receptors. 34, 27432751 (1993). Dermatol. The carriers presented a particle size between 100 and 400nm, a range of zeta potential from neutral (liposomes) to negative (polymeric nanoparticles, ethosomes, solid lipid nanoparticles, and nanostructured lipidic carriers), high entrapment efficiency (above 65%), high photostability (between two- and threefold higher than commercial tretinoin dissolved in ethanol), moderate to high skin permeation, high skin tolerance, and moderate to high antipsoriatic activity. In most cases, ATRA was encapsulated in the formulation49,70, or chemically conjugated to the carrier50. Severe psoriasisoral therapy with a new retinoid. Am. 16, 17651772 (2017). 50, 335352 (2016). In addition, some formulations (e.g., ATRA-containing liposomes) improve the local effect of RA in the skin and decrease systemic adsorption78. Stereotaxic injection of ATRA-containing nanoparticles in the striatum protected nigral dopaminergic neurons in an in vivo PD model68. Recently, we have developed a new platform to target bone marrow, based on light-activatable nanoparticle formulations containing ATRA25,26. & Moroni, L. Enhancement of synthesis of extracellular matrix proteins on retinoic acid loaded electrospun scaffolds. Liposome encapsulated surfactant abetted copper nanoparticles - Nature the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Correspondence to Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. Currently, several clinical trials are investigating the combination of ATRA with arsenic trioxide, with arsenic trioxide and gemtuzumab ozogamicin (a monoclonal antibody against CD33 conjugated with ozogamicin, a cytotoxic agent), with epigenetic regulators such as tranylcypromine, with decitabine, cytarabine and granulocyte-stimulating factor, among others, in the context of AML (Table1). Polyion complex micelles composed of all-trans retinoic acid and poly (ethylene glycol)-grafted-citosan. It is possible that some of the RA delivery systems developed so far may be used for embryonic immune and hematopoietic stem cell development studies. Therefore, several formulations have been developed to improve the long-term effect of ATRA, to reduce side effects like desquamation and erythema, skin irritation, and to increase the stability of RA to light19 (Fig. Estey, E. et al. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. 269, 1053810544 (1994). Bexarotene has optimal RXR binding, which effectively causes cancer cell death, particularly in cutaneous T-cell lymphoma. ); Cerebrovascular Disease Society Research Grant (R.F.) Ten days later, rats were intravitreally injected with saline, tacrolimus, tacrolimus-loaded liposomes, or unloaded liposomes. Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation . J. Preclinical and clinical applications: most RA-containing formulations are under clinical evaluation for the treatment of blood tumors (Table1). Importantly, these formulations presented higher activity than formulations in which RA was released by passive diffusion (not light triggered) because they rapidly saturated nuclear receptors. Once leukemia-initiating cells transfected with light-activatable nanoparticles containing RA were administered intravenously in leukemic mice they tend to home in the bone marrow, in the proximity of other leukemia cells. The authors would like to thank Andreia Vilaa for the illustrations and the financial support of ERA Chair project (ERA@UC, reference: 669088) through EU Horizon 2020 program; the POCI-01-0145-FEDER-016390 (acronym: CANCEL STEM) and POCI-01-0145-FEDER-029414 (acronym: LIghtBRARY) projects, through Compete 2020 and FCT programs; projects 2IQBIONEURO (reference: 0624_2IQBIONEURO_6_E) and NEUROATLANTIC (reference: EAPA_791/2018), co-funded by INTERREG (Atlantic program or V-A Spain-Portugal) and European fund for Regional Development (FEDER), FCT (Portugal, SFRH/BPD/102103/2014); national funds by FCT (reference: UID/Multi/00709/2013); Programa Operacional do Centro, Centro 2020 through the funding of the ICON project (Interdisciplinary Challenges On Neurodegeneration; reference: CENTRO-01-0145-FEDER-000013); EXPL/BIM-MED/0822/2013 (L.B. Google Scholar. 21, 457U230 (2015). Another important challenge in clinical translation of RA formulations is targeting. & Nah, J. W. All-trans retinoic acid release from polyion-complex micelles of methoxy poly(ethylene glycol) grafted chitosan. For each application, the pathological context will be briefly presented as well as the effect of retinoid that was administered without any controlled release system. The decrease was attributed to an induction of ATRA catabolism and increased levels of RA-binding protein20. Graham, V., Surwit, E. S., Weiner, S. & Meyskens, F. L. Jr Phase II trial of beta-all-trans-retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap. 39, S2S7 (1998). Recently, a chemo-immunotherapy approach for melanoma was developed based on biodegradable hollow mesoporous nanoparticles containing three drugs: doxorubicin, ATRA, and interleukin (IL)-223. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Acta Biomater. Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. McCaffery, P. & Drger, U. Retinoids are a class of compounds composed of three regions: a hydrophobic, a central polyene, and a polar (usually a carboxyl group)29. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. 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. Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Hashimoto-Hill, S. et al. PubMed 7, 20 (2015). 54, 17611775 (2013). Control. The antitumoral activity of RA is linked to its differentiation and cell growth arrest properties108. Another isomer of RA, isomer 9-cis RA (alitretinoin), binds to retinoid X receptors28,35, while 13-cis RA (isotretinoin), has negligible affinity for retinoic acid receptors (RAR or RXR) or cellular RBP37. High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Wang, W. et al. Although some progress has been made in the last 5 years regarding formulations with the ability to release RA in combination with other agents54,112, further effort is needed to better control the half-life of each drug in vivo to match clinical dosage programs. Regenacalm Serum S1 Pro with 3% Encapsulated Retinoid and Liquorice Eur. Cell 155, 215227 (2013). J. Ezpeleta, I. et al. ); SFRH/BPD/94228/2013 and IF/00178/2015/CP1300/CT0001 (R.F. Use of antibodies, peptides, aptamers immobilized in the surface of nanoparticles to target-specific cellular receptors may accelerate clinical translation of RA formulations. It is expected that the knowledge gathered in the development of retinoid formulations inspires others to generate delivery systems based on different drugs thus expanding the field of regenerative and therapeutic medicine. Targeted delivery can be achieved by surface modification of nanoparticles with bisphosphonate to promote binding to bone100, by surface modification of liposomes with folate to target the folate receptor, which is highly expressed by AML cells21,101, by the conjugation of nanoparticles with the surface of hematopoietic stem cells102, or by surface modification of nanoparticles with antibodies (e.g., CD45.1, CD117)103,104 or aptamers (E-selectin thioaptamer)105. Commun. Rev. J. Clin. Chem. Park, S. J. et al. Trifarotene is a selective RAR- agonist, approved in late 2019 in the USA, for the topical treatment of acne in patients as young as 9 years old31. 8, 15204 (2017). J. Neurosci. Abdel-Wahab, O. One of the initial applications of RA for regenerative medicine was as a differentiation agent during embryogenesis. Conversely, RA pathway shutdown terminated this process9. Release 103, 369380 (2005). The intracellular concentration of formulations containing RA was dependent on the initial formulation loading, type of formulation, and type of cell25,45. Ourique, A. F. et al. J. Clin. In addition, RA formulations have the capacity to enhance the differentiation of nave T cells to regulatory T cells124. Enhancement of regression of cervical intraepithelial neoplasia-ii (moderate dysplasia) with topically applied all-trans-retinoic acida randomized trial. Mol. Lu, Y. et al. 71, 904907 (1982). In this review, the role of retinoid formulations in the context of the brain, skin, immune system, and cancer applications will be discussed. For example, uptake is higher in nanoparticles with high negative or positive surface charges128. Treatment of experimental autoimmune uveoretinitis with intravitreal 10, 10801091 (2013). 2). The use of RA for skin disorders2 and cancer treatment (acute myeloid leukemia (AML)3 and cervical neoplasia4,5) started in the 1960s and 1980s (Fig. Ther. Nat. Masini, V., Bonte, F., Meybeck, A. Goldberg et al. Cho, C. S. et al. Am. Recent data showed that RXR homodimers can also regulate gene transcription36. Recent developments in the use of retinoid for cancer treatment22,23 and differentiation studies using stem/progenitor cells8,24, as well as the development of more advanced formulations to control retinoid bioactivity25,26, make this review timely. Release 149, 281291 (2011). 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. Shelley, R. S., Jun, H. W., Price, J. C. & Cadwallader, D. E. Blood level studies of all-trans-retinoic and 13-Cis-retinoic acids in rats using different formulations. Lymphoma Myeloma Leuk. Interv. Cancer Res. RA binds to cellular retinoic acid-binding proteins (CRABP), assisting autocrine and paracrine signaling34. Sci. Damanik, F. F. R., van Blitterswijk, C., Rotmans, J. Neurosci. ATRA also induces skin angiogenesis and collagen deposition, increases the mitotic activity of inter- and follicular epithelium, and reduces melanin production75.
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