Inhalable solid lipid nanoparticles for intracellular tuberculosis infection therapy: macrophage-targeting and pH-sensit

  • PDF / 8,067,110 Bytes
  • 18 Pages / 595.276 x 790.866 pts Page_size
  • 25 Downloads / 179 Views

DOWNLOAD

REPORT


ORIGINAL ARTICLE

Inhalable solid lipid nanoparticles for intracellular tuberculosis infection therapy: macrophage-targeting and pH-sensitive properties Cheng Ma 1 & Mingjun Wu 1 & Weifen Ye 1 & Zhengwei Huang 1 & Xiangyu Ma 2 & Wenhao Wang 1 & Wenhua Wang 1 & Ying Huang 3 & Xin Pan 1 & Chuanbin Wu 1,3 Accepted: 28 August 2020 # Controlled Release Society 2020

Abstract Mycobacterium tuberculosis (MTB) is one of the most threatening pathogens for its latent infection in macrophages. The intracellular MTB isolated itself from drugs and could spread via macrophages. Therefore, a mannose-modified macrophagetargeting solid lipid nanoparticle, MAN-IC-SLN, loading the pH-sensitive prodrug of isoniazid (INH), was designed to treat the latent tuberculosis infection. The surface of SLNs was modified by a synthesized 6-octadecylimino-hexane-1,2,3,4,5-pentanol (MAN-SA) to target macrophages, and the modified SLNs showed a higher cell uptake in macrophages (97.2%) than unmodified SLNs (42.4%). The prodrug, isonicotinic acid octylidene-hydrazide (INH-CHO), was synthesized to achieve the pH-sensitive release of INH in macrophages. The INH-CHO-loaded SLNs exhibited a pH-sensitive release profile and accomplished a higher accumulated release in pH 5.5 media (82.63 ± 2.12%) compared with the release in pH 7.4 media (58.83 ± 3.84%). Mycobacterium smegmatis was used as a substitute for MTB, and the MAN-IC-SLNs showed a fourfold increase of intracellular antibiotic efficacy and enhanced macrophage uptake because of the pH-sensitive degradation of INH-CHO and MAN-SA in SLNs, respectively. For the in vivo antibiotic efficacy test, the SLNs group displayed an 83% decrease of the colony-forming unit while the free INH group only showed a 60% decrease. The study demonstrates that macrophage targeting and pH-sensitive SLNs can be used as a promising platform for the latent tuberculosis infection. Keywords Latent tuberculosis infection . Targeting macrophages . Mannose modification . Prodrug . pH-sensitive release profile

Abbreviations MTB INH MAN-SA

Mycobacterium tuberculosis Isoniazid 6-octadecylimino-hexane1,2,3,4,5-pentanol

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-020-00849-7) contains supplementary material, which is available to authorized users. * Ying Huang [email protected] * Xin Pan [email protected] 1

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

2

College of Pharmacy, Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin, Austin, TX, USA

3

School of Pharmacy, Jinan University, Guangzhou 510632, People’s Republic of China

INH-CHO H-NMR FTIR XPS MSG WHO ROS LTBI SLN PP SA Leu P-188 NaH2PO4-2H2O NaOH MHB TLC MAN SDS

Isonicotinic acid octylidene-hydrazide Hydrogen nuclear magnetic resonance Fourier transform infrared spectroscopy X-ray photoelectron spectroscopy Mycobacterium smegmatis World Health Organization Reactive oxygen species Latent tuberculosis infection Solid lipid nanoparticles Palmityl