To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

Chinese Herbal Medicine Research Team Healthy Aging Research Center Chang Gung University Kweishan Taoyuan Taiwan

Department of Anesthesiology Chang Gung Memorial Hospital Kweishan Taoyuan Taiwan

Department of Chemical Engineering Ming Chi University of Technology New Taipei City Taiwan

Department of Traditional Chinese Medicine Chang Gung Memorial Hospital Keelung Taiwan

Graduate Institute of Biomedical Sciences Chang Gung University Kweishan Taoyuan Taiwan

Graduate Institute of Natural Products Chang Gung University Kweishan Taoyuan Taiwan

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic

Laboratory of Pharmaceutical Engineering Gifu Pharmaceutical University Gifu Japan

Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine Chang Gung University of Science and Technology Kweishan Taoyuan Taiwan

School of Nursing National Taipei University of Nursing and Health Sciences Taipei Taiwan

School of Traditional Chinese Medicine Chang Gung University Kweishan Taoyuan Taiwan

See more in PubMed

Huang TH, Lin CF, Alalaiwe A, Yang SC, Fang JY. Apoptotic or antiproliferative activity of natural products against keratinocytes for the treatment of psoriasis. Int J Mol Sci. 2019;20:2558. PubMed PMC

Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, Psoriasis, Nat Rev Dis Primers. 2016; 2: 1-17. PubMed

Shao S, Gudjonsson JE. Epigenetics of psoriasis. Adv Exp Med Biol. 2020;1253:209–21. PubMed

Boehncke WH, Schön MP. Psoriasis. Lancet. 2015;386:983–94. PubMed

Damiani G, Pacifico A, Linder DM, Pigatto PDM, Conic R, Grada A. et al. Nanodermatology-based solutions for psoriasis: state-of-the art and future prospects. Dermatol Ther. 2019;32:e13113. PubMed

Richards DA, Maruani A, Chudasama V. Antibody fragments as nanoparticle targeting ligands: a step in the right direction. Chem Sci. 2017;8:63–77. PubMed PMC

Yamamoto Y, Aoyama Y, Shu E, Tsunoda K, Amagai M, Kitajima Y. No activation of urokinase plasminogen activator by anti-desmoglein 3 monoclonal IgG antibodies in cultured human keratinocytes. J Dermatol Sci. 2007;47:119–25. PubMed

Kouno M, Lin C, Schechter NM, Siegel D, Yang X, Seykora JT, Stanley JR. Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with apemphigus mAb. J Invest Dermatol. 2013;133:2212–20. PubMed PMC

Ross K. Towards topical microRNA-directed therapy for epidermal disorders. J Control Release. 2018;269:136–47. PubMed

Simpson E.L, Paller A.S, Boguniewicz M, Eichenfield L.F, Feldman S.R, Silverberg J.I. et al. Crisaborole ointment improves quality of life of patients with mild to moderate atopic dermatitis and their families. Dermatol Ther. (Heidelb) 2018;8:605–19. PubMed PMC

Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V. et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett. 2009;19:2129–32. PubMed

Psomadakis CE, Han G. New and emerging topical therapies for psoriasis and atopic dermatitis. J Clin Aesthet Dermatol. 2019;12:28–34. PubMed PMC

Wcisło-Dziadecka D, Zbiciak-Nylec M, Brzezińska-Wcisło L, Bebenek K, Kaźmierczak A. Newer treatments of psoriasis regarding IL-23 inhibitors, phosphodiesterase 4 inhibitors, and Janus kinase inhibitors. Dermatol Ther. 2017;30:e12555. PubMed

Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast. Drug Des Develop Ther. 2013;7:201–10. PubMed PMC

Date T, Nimbalkar V, Kamat J, Mittal A, Mahato RI, Chitkara D. Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics. J Control Release. 2018;271:60–73. PubMed

Xu C, Chen X, Yang M, Yuan X, Zhao A, Bao H. Simple strategy for single-chain fragment antibody-conjugated probe construction. Life Sci. 2019;239:117052. PubMed

Jeong S, Park J.Y, Cha M.G, Chang H, Kim Y.I, Kim H.M. et al. Highly robust and optimized conjugation of antibodies to nanoparticles using quantitatively validated protocols. Nanoscale. 2017;9:2548. PubMed

Sharma H, Mutharasan R. Half antibody fragments improve biosensor sensitivity without loss of selectivity. Anal Chem. 2013;85:2472–7. PubMed

Makaraviciute A, Jackson CD, Millner PA, Ramanaviciene A. Considerations in producing preferentially reduced half-antibody fragments. J Immunol Methods. 2016;429:50–6. PubMed

Vij N, Min T, Bodas M, Gorde A, Roy I. Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases. Nanomed Nanotechnol Biol Med. 2016;12:2415–27. PubMed

Yu HP, Hsieh PW, Chang YJ, Chung PJ, Kuo LM, Hwang TL, 2-(2-Fluorobenzamido)benzoate ethyl ester (EFB-1) inhibits superoxide production by human neutrophils, attenuates hemorrhagic shock-induced organ dysfunction in rats. Free Radic Biol Med. 2011; 50: 1737-48. PubMed

van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182:5836–45. PubMed

Sumida H, Yanagida K, Kita Y, Abe J, Matsushima K, Nakamura M. et al. Interplay between CXCR2 and BLT1 facilitates neutrophil infiltration and resultant keratinocyte activation in a murine model of imiquimod-induced psoriasis. J Immunol. 2014;192:4361–9. PubMed

Lin ZC, Hsieh PW, Hwang TL, Chen CY, Sung CT, Fang JY. Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration. FASEB J. 2018;32:6783–95. PubMed

Marques DR, Dos Santos L, O'Brien MA, Cartmell SH, Gough JE. In vitro evaluation of poly (lactic-co-glycolic acid)/polyisoprene fibers for soft tissue engineering J Biomed Mater Res B Appl Biomater. 2017; 105: 2581-91. PubMed

Lu B, Lv X, Le Y. Chitosan-modified PLGA nanoparticles for control-released drug delivery. Polymers. 2019;11:304. PubMed PMC

Esfandyari-Manesh M, Abdi M, Talasaz AH, Ebrahimi SM, Atyabi F, Dinarvand R. S2P peptide-conjugated PLGA-Maleimide-PEG nanoparticles containing Imatinib for targeting drug delivery to atherosclerotic plaques. Daru J Pharm Sci. 2020;28:131–8. PubMed PMC

Saei A, Asfia S, Kouchakzadeh H, Rahmandoust M. Antibody-modified magnetic nanoparticles as specific high-efficient cell-separation agents. J Biomed Mater Res B Appl Biomater. 2020;108:2633–42. PubMed

Hartlieb E, Kempf B, Partilla M, Vigh B, Spindler V, Waschke J. Desmoglein 2 is less important than desmoglein 3 for keratinocyte cohesion. PloS ONE. 2013;8:e53739. PubMed PMC

Uttagomol J, Ahmed US, Rehman A, Huang Y, Laly AC, Kang A. et al. Evidence for the desmosomal cadherin desmoglein-3 in regulating YAP and phosphor-YAP in keratinocyte responses to mechanical forces. Int J Mol Sci. 2019;20:6221. PubMed PMC

Marques AC, Costa PJ, Velho S, Amaral MH. Functionalizing nanoparticles with cancer-targeting antibodies: a comparison of strategies. J Control Release. 2020;320:180–200. PubMed

Zhao P, Wang H, Yu M, Cao S, Zhang F, Chang J. et al. Paclitaxel-loaded, folic-acid-targeted and TAT-peptide-conjugated polymeric liposomes: in vitro and in vivo evaluation. Pharm Res. 2010;27:1914–26. PubMed

Li J, Ghatak S, El Masry MS, Das A, Liu Y, Roy S. et al. Topical lyophilized targeted lipid nanoparticles in the restoration of skin barrier function following burn wound. Mol Ther. 2018;26:2178–88. PubMed PMC

Yu HP, Liu FC, Umoro A, Lin ZC, Elzoghby AO, Hwang TL. et al. Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency. J Nanobiotechnol. 2020;18:25. PubMed PMC

Monteleone G, Pallone F, MacDonald TT, Chimenti S, Costanzo A. Psoriasis: from pathogenesis to novel therapeutic approaches. Clin Sci. 2011;120:1–11. PubMed

Yang YSS, Moynihan KD, Bekdemir A, Dichwalkar TM, Noh MM, Watson N. et al. Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles. Biomater Sci. 2019;7:113. PubMed PMC

Albanesi C, Madonna S, Gisondi P, Girolomoni G, The interplay between keratinocytes, immune cells in the pathogenesis of psoriasis. Front Immunol. 2018; 9: 1549. PubMed PMC

Bäumer W, Kietzmann M. Effect of cyclosporin A and cilomilast on activated canine, murine and human keratinocytes. Vet Dermatol. 2007;18:107–14. PubMed

Jarnagin K, Chanda S, Coronado D, Ciaravino V, Zane LT, Guttman-Yassky E. et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiestease 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol. 2016;15:390–6. PubMed

Lin CY, Hsu CY, Elzoghby AO, Alalaiwe A, Hwang TL, Fang JY. Oleic acid as the active agent and lipid matrix in cilomilast-loaded nanocarriers to assist PDE4 inhibition of activated neutrophils for mitigating psoriasis-like lesions. Acta Biomater. 2019;90:350–61. PubMed

Hoshyar N, Gray S, Han H, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine. 2016;11:673–92. PubMed PMC

Boraschi D, Italiani P, Palomba R, Decuzzi P, Duschl A, Fadeel B. et al. Nanoparticles and innate immunity: new perspectives on host defense. Semin Immunol. 2017;34:33–51. PubMed

Mao X, Cho MJT, Ellebrecht CT, Mukherjee EM, Payne AS. Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes. JCI Insight. 2017;2:e92253. PubMed PMC

Wu H, Stanley JR, Cotsarelis G. Desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation. J Invest Dermatol. 2003;120:1052–7. PubMed

Silva E, Barreiros L, Segundo MA, Costa Lima SA, Reis S. Cellular interactions of a lipid-based nanocarrier model with human keratinocytes: unraveling transport mechanisms. Acta Biomater. 2017;53:439–49. PubMed

Frombach J, Unbehauen M, Kurniasih IN, Schumacher F, Volz P, Hadam S. et al. Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin. J Control Release. 2019;299:138–48. PubMed

Hsu CY, Yang SC, Sung CT, Weng YH, Fang JY. Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting. Int J Nanomed. 2017;12:8227–38. PubMed PMC

Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin. 2015;33:13–23. PubMed

Yoshiki R, Kabashima K, Honda T, Nakamizo S, Sawada Y, Sugita K. et al. IL-23 from Langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing γδ T cells. J Invest Dermatol. 2014;134:1912–21. PubMed

Leys J, Wang Y, Paulsboe S, Edelmayer R, Salte K, Wetter J. et al. Characterization of psoriasiform dermatitis induced by systemic injection of interleukin-23 minicircles in mice. J Dermatol. 2019;46:482–97. PubMed

Boehncke WH, Brembilla NC. Unmet needs in the field of psoriasis: pathogenesis and treatment. Clin Rev Allergy Immunol. 2018;55:295–311. PubMed

Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Ann Rev Immunol. 2014;32:227–55. PubMed PMC

Van Belle AB, de Heusch M, Lemaire MM, Hendrickx E, Warnier G, Dunussi-Joannopoulos K, IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice, J Immunol. 2012; 188: 462-9. PubMed

Jiang M, Fang H, Shao S, Dang E, Zhang J, Qiao P. et al. Keratinocyte exosomes activate neutrophils and enhance skin inflammation in psoriasis. FASEB J. 2019;33:13241–53. PubMed

Chiang CC, Cheng WJ, Korinek M, Lin CY, Hwang TL. Neutrophils in psoriasis. Front Immunol. 2019;10:2376. PubMed PMC

Senra L, Mylonas A, Kavanagh R, Fallon PG, Conrad C, Borowczyk-Michalowska J. et al. IL-17E (IL-25) enhances innate immune responses during skin inflammation. J Invest Dermatol. 2019;139:1732–42. PubMed

Li L, Cataisson C, Flowers B, Fraser E, Sanchez V, Day CP. et al. Topical application of a dual ABC transporter substrate and NF-κB inhibitor blocks multiple sources of cutaneous inflammation in mouse skin. J Invest Dermatol. 2019;139:1506–15. PubMed PMC

Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell. 2017;168:37–57. PubMed PMC