TY - JOUR
T1 - Codelivery of 1α,25-Dihydroxyvitamin D3and CYP24A1 Inhibitor VID400 by Nanofiber Dressings Promotes Endogenous Antimicrobial Peptide LL-37 Induction
AU - Su, Yajuan
AU - Ganguli-Indra, Gitali
AU - Bhattacharya, Nilika
AU - Logan, Isabelle E.
AU - Indra, Arup K.
AU - Gombart, Adrian F.
AU - Wong, Shannon L.
AU - Xie, Jingwei
N1 - Funding Information:
This work was partially supported by startup funds from the University of Nebraska Medical Center (UNMC), the National Institute of General Medical Science (NIGMS) of the National Institutes of Health under Award Numbers R01GM123081 and R01GM138552, UNMC Regenerative Medicine Program pilot grant, Nebraska Research Initiative grant, and NE LB606. I.E.L. was supported by the 2019 Audrey and George Varsevelt LPI Graduate Fellowship, the 2019–20 Mark Spoonenburgh LPI Graduate Fellowship, and the 2020–21 P.F. and Nellie Buck Yerex Graduate Scholarship from OSU.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/7
Y1 - 2022/3/7
N2 - Surgical site infections represent a significant clinical problem. Herein, we report a nanofiber dressing for topical codelivery of immunomodulating compounds including 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) and VID400, a CYP24A1 inhibitor in a sustained manner, for inducing the expression of the endogenous cathelicidin antimicrobial peptide (CAMP) gene encoding the hCAP18 protein, which is processed into the LL-37 peptide. Nanofiber wound dressings with coencapsulation of 1,25(OH)2D3and VID400 were generated by electrospinning. Both 1,25(OH)2D3and VID400 were coencapsulated into nanofibers with loading efficiencies higher than 90% and exhibited a prolonged release from nanofiber membranes longer than 28 days. Incubation with 1,25(OH)2D3/VID400-coencapsulated poly(μ-caprolactone) nanofiber membranes greatly induced the hCAP18/LL-37 gene expression in monocytes, neutrophils, and keratinocytes in vitro. Moreover, the administration of 1,25(OH)2D3/VID400-coencapsulated nanofiber membranes dramatically promoted the hCAP18/LL-37 expression in dermal wounds created in both human CAMP transgenic mice and human skin tissues. The 1,25(OH)2D3- and VID400-coencapsulated nanofiber dressings enhanced innate immunity via the more effective induction of antimicrobial peptide than the free drug alone or 1,25(OH)2D3-loaded nanofibers. Together, 1,25(OH)2D3/VID400-embedded nanofiber dressings presented in this study show potential in preventing surgical site infections.
AB - Surgical site infections represent a significant clinical problem. Herein, we report a nanofiber dressing for topical codelivery of immunomodulating compounds including 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) and VID400, a CYP24A1 inhibitor in a sustained manner, for inducing the expression of the endogenous cathelicidin antimicrobial peptide (CAMP) gene encoding the hCAP18 protein, which is processed into the LL-37 peptide. Nanofiber wound dressings with coencapsulation of 1,25(OH)2D3and VID400 were generated by electrospinning. Both 1,25(OH)2D3and VID400 were coencapsulated into nanofibers with loading efficiencies higher than 90% and exhibited a prolonged release from nanofiber membranes longer than 28 days. Incubation with 1,25(OH)2D3/VID400-coencapsulated poly(μ-caprolactone) nanofiber membranes greatly induced the hCAP18/LL-37 gene expression in monocytes, neutrophils, and keratinocytes in vitro. Moreover, the administration of 1,25(OH)2D3/VID400-coencapsulated nanofiber membranes dramatically promoted the hCAP18/LL-37 expression in dermal wounds created in both human CAMP transgenic mice and human skin tissues. The 1,25(OH)2D3- and VID400-coencapsulated nanofiber dressings enhanced innate immunity via the more effective induction of antimicrobial peptide than the free drug alone or 1,25(OH)2D3-loaded nanofibers. Together, 1,25(OH)2D3/VID400-embedded nanofiber dressings presented in this study show potential in preventing surgical site infections.
KW - 1α,25-dihydroxyvitamin D3
KW - CYP24A1 inhibitor
KW - antimicrobial peptide LL-37
KW - codelivery
KW - nanofiber dressings
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U2 - 10.1021/acs.molpharmaceut.1c00944
DO - 10.1021/acs.molpharmaceut.1c00944
M3 - Article
C2 - 35179903
AN - SCOPUS:85125416442
SN - 1543-8384
VL - 19
SP - 974
EP - 984
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 3
ER -