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

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A Correction to this article was published on 19 April 2022

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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 macrophage-targeting 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.

Table of contents: Macrophage-targeting and pH-sensitive solid lipid nanoparticles (SLN) were administrated to the lung via nebulization. Macrophage targeting was achieved by appropriate particle size and surface mannose modification with synthesized MAN-SA. After being swallowed by macrophages, the prodrug, Isonicotinic acid octylidene-hydrazide (INH-CHO), quickly released isoniazid, which was triggered by the intracellular acid environment. The SLNs exhibited higher intracellular antibiotic efficacy due to their macrophage-targeting and pH-sensitive properties.

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Abbreviations

MTB:

Mycobacterium tuberculosis

INH:

Isoniazid

MAN-SA:

6-octadecylimino-hexane-1,2,3,4,5-pentanol

INH-CHO:

Isonicotinic acid octylidene-hydrazide

H-NMR:

Hydrogen nuclear magnetic resonance

FTIR:

Fourier transform infrared spectroscopy

XPS:

X-ray photoelectron spectroscopy

MSG:

Mycobacterium smegmatis

WHO:

World Health Organization

ROS:

Reactive oxygen species

LTBI:

Latent tuberculosis infection

SLN:

Solid lipid nanoparticles

PP:

Palmityl palmitate

SA:

Stearyl amine

Leu:

Leucine

P-188:

Poloxamer188

NaH2PO4-2H2O:

Sodium dihydrogen phosphate dihydrate

NaOH:

Sodium hydroxide

MHB:

Mueller-Hinton Broth media

TLC:

Thin-layer chromatography

MAN:

Mannose

SDS:

Sodium dodecyl sulfate

DLS:

Dynamic light scattering method

TEM:

Transmission electron microscopy

XRD:

X-ray powder diffraction

DSC:

Differential scanning calorimetry analysis

TG:

Thermogravimetric analysis

EA:

Element analysis

TCD:

Thermal conductivity detector

NGI:

Next-generation impactor

CCK:

Cell counting kit-8

CLSM:

Confocal laser scanning microscope

C6:

Coumarin 6

PFA:

Paraformaldehyde

DAPI:

4′,6-diamidino-2-phenylindole

FC:

Flow Cytometry

MBC:

Minimum bactericidal concentration

IHC:

Immunohistochemistry staining

ALB:

Albumin

TB:

Total protein

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

HE staining:

Hematoxylin-eosin staining

References

  1. LoBue PA, Mermin JH. Latent tuberculosis infection: the final frontier of tuberculosis elimination in the USA. Lancet Infect Dis. 2017;17(10):e327–e33. https://doi.org/10.1016/s1473-3099(17)30248-7.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Organization WH. Global tuberculosis report 2019. 2019.

  3. Reuter A, Hughes J, Furin J. Challenges and controversies in childhood tuberculosis. Lancet. 2019;394(10202):967–78. https://doi.org/10.1016/s0140-6736(19)32045-8.

    Article  PubMed  Google Scholar 

  4. Reid MJA, Arinaminpathy N, Bloom A, Bloom BR, Boehme C, Chaisson R, et al. Building a tuberculosis-free world: the Lancet Commission on Tuberculosis. Lancet. 2019;393(10178):1331–84. https://doi.org/10.1016/s0140-6736(19)30024-8.

    Article  PubMed  Google Scholar 

  5. Fennelly KP, Jones-Lopez EC. Quantity and quality of inhaled dose predicts immunopathology in tuberculosis. Front Immunol. 2015;6:313. https://doi.org/10.3389/fimmu.2015.00313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Suarez I, Funger SM, Kroger S, Rademacher J, Fatkenheuer G, Rybniker J. The diagnosis and treatment of tuberculosis. Dtsch Arztebl Int. 2019;116(43):729–35. https://doi.org/10.3238/arztebl.2019.0729.

    Article  PubMed  Google Scholar 

  7. Fatmawati, Dyah Purwati U, Riyudha F, Tasman H. Optimal control of a discrete age-structured model for tuberculosis transmission. Heliyon. 2020;6(1):e03030. https://doi.org/10.1016/j.heliyon.2019.e03030.

    Article  CAS  PubMed  Google Scholar 

  8. Forman HJ, Torres M. Redox signaling in macrophages. Mol Asp Med. 2001;22(4–5):189–216. https://doi.org/10.1016/s0098-2997(01)00010-3.

    Article  CAS  Google Scholar 

  9. Voskuil MI, Bartek IL, Visconti K, Schoolnik GK. The response of Mycobacterium tuberculosis to reactive oxygen and nitrogen species. Front Microbiol. 2011;2:105. https://doi.org/10.3389/fmicb.2011.00105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khan SR, Manialawy Y, Siraki AG. Isoniazid and host immune system interactions: a proposal for a novel comprehensive mode of action. Br J Pharmacol. 2019;176:4599–608. https://doi.org/10.1111/bph.14867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium tuberculosis infection. N Engl J Med. 2015;372(22):2127–35. https://doi.org/10.1056/NEJMra1405427.

    Article  CAS  PubMed  Google Scholar 

  12. O'Connor G, Krishnan N, Fagan-Murphy A, Cassidy J, O'Leary S, Robertson BD, et al. Inhalable poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis infection. Eur J Pharm Biopharm. 2019;134:153–65. https://doi.org/10.1016/j.ejpb.2018.10.020.

    Article  CAS  PubMed  Google Scholar 

  13. Bussi C, Gutierrez MG. Mycobacterium tuberculosis infection of host cells in space and time. FEMS Microbiol Rev. 2019;43(4):341–61. https://doi.org/10.1093/femsre/fuz006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Salgame P, Geadas C, Collins L, Jones-Lopez E, Ellner JJ. Latent tuberculosis infection--revisiting and revising concepts. Tuberculosis. 2015;95(4):373–84. https://doi.org/10.1016/j.tube.2015.04.003.

    Article  PubMed  Google Scholar 

  15. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc. 1970;26:28–106.

    CAS  PubMed  Google Scholar 

  16. Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. N Engl J Med. 2002;347(23):1860–6. https://doi.org/10.1056/NEJMcp021045.

    Article  PubMed  Google Scholar 

  17. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;2:CD001363. https://doi.org/10.1002/14651858.CD001363.

    Article  Google Scholar 

  18. Society AT. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep. 2000;49(RR-6):1–51.

    Google Scholar 

  19. Horsburgh CR Jr, Goldberg S, Bethel J, Chen S, Colson PW, Hirsch-Moverman Y, et al. Latent TB infection treatment acceptance and completion in the United States and Canada. Chest. 2010;137(2):401–9. https://doi.org/10.1378/chest.09-0394.

    Article  PubMed  Google Scholar 

  20. Njie GJ, Morris SB, Woodruff RY, Moro RN, Vernon AA, Borisov AS. Isoniazid-rifapentine for latent tuberculosis infection: a systematic review and meta-analysis. Am J Prev Med. 2018;55(2):244–52. https://doi.org/10.1016/j.amepre.2018.04.030.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kumar Verma R, Mukker JK, Singh RS, Kumar K, Verma PR, Misra A. Partial biodistribution and pharmacokinetics of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to rhesus macaques. Mol Pharm. 2012;9(4):1011–6. https://doi.org/10.1021/mp300043f.

    Article  CAS  PubMed  Google Scholar 

  22. Jahagirdar PS, Gupta PK, Kulkarni SP, Devarajan PV. Polymeric curcumin nanoparticles by a facile in situ method for macrophage targeted delivery. Bioeng Transl Med. 2019;4(1):141–51. https://doi.org/10.1002/btm2.10112.

    Article  CAS  PubMed  Google Scholar 

  23. Ren H, He Y, Liang J, Cheng Z, Zhang M, Zhu Y, et al. Role of liposome size, surface charge, and PEGylation on rheumatoid arthritis targeting therapy. ACS Appl Mater Interfaces. 2019;11(22):20304–15. https://doi.org/10.1021/acsami.8b22693.

    Article  CAS  PubMed  Google Scholar 

  24. Cicuendez M, Fernandes M, Ayan-Varela M, Oliveira H, Feito MJ, Diez-Orejas R, et al. Macrophage inflammatory and metabolic responses to graphene-based nanomaterials differing in size and functionalization. Colloids Surf B: Biointerfaces. 2019;186:110709. https://doi.org/10.1016/j.colsurfb.2019.110709.

    Article  CAS  PubMed  Google Scholar 

  25. des Rieux A, Pourcelle V, Cani PD, Marchand-Brynaert J, Preat V. Targeted nanoparticles with novel non-peptidic ligands for oral delivery. Adv Drug Deliv Rev. 2013;65(6):833–44. https://doi.org/10.1016/j.addr.2013.01.002.

    Article  CAS  PubMed  Google Scholar 

  26. Loka RS, McConnell MS, Nguyen HM. Studies of highly-ordered heterodiantennary mannose/glucose-functionalized polymers and concanavalin a protein interactions using isothermal titration calorimetry. Biomacromolecules. 2015;16(12):4013–21. https://doi.org/10.1021/acs.biomac.5b01380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Verma RK, Kaur J, Kumar K, Yadav AB, Misra A. Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice. Antimicrob Agents Chemother. 2008;52(9):3195–201. https://doi.org/10.1128/AAC.00153-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pandey R, Khuller GK. Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis. Tuberculosis. 2005;85(4):227–34. https://doi.org/10.1016/j.tube.2004.11.003.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Y, Huang Z, Li J, Mo Z, Huang Y, Ma C, et al. PLGA porous microspheres dry powders for codelivery of afatinib-loaded solid lipid nanoparticles and paclitaxel: novel therapy for EGFR tyrosine kinase inhibitors resistant nonsmall cell lung cancer. Adv Healthc Mater. 2019;8(23):e1900965. https://doi.org/10.1002/adhm.201900965.

    Article  CAS  PubMed  Google Scholar 

  30. Marcianes P, Negro S, Barcia E, Montejo C, Fernandez-Carballido A. Potential active targeting of gatifloxacin to macrophages by means of surface-modified PLGA microparticles destined to treat tuberculosis. AAPS PharmSciTech. 2019;21(1):15. https://doi.org/10.1208/s12249-019-1552-3.

    Article  CAS  PubMed  Google Scholar 

  31. Pang L, Pei Y, Uzunalli G, Hyun H, Lyle LT, Yeo Y. Surface modification of polymeric nanoparticles with M2pep peptide for drug delivery to tumor-associated macrophages. Pharm Res. 2019;36(4):65. https://doi.org/10.1007/s11095-019-2596-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang C, Krishnamurthy S, Liu J, Liu S, Lu X, Coady DJ, et al. Broad-spectrum antimicrobial star polycarbonates functionalized with mannose for targeting bacteria residing inside immune cells. Adv Healthc Mater. 2016;5(11):1272–81. https://doi.org/10.1002/adhm.201600070.

    Article  CAS  PubMed  Google Scholar 

  33. Lin LC, Chattopadhyay S, Lin JC, Hu CJ. Advances and opportunities in nanoparticle- and nanomaterial-based vaccines against bacterial infections. Adv Healthc Mater. 2018;7(13):e1701395. https://doi.org/10.1002/adhm.201701395.

    Article  CAS  PubMed  Google Scholar 

  34. Tripodo G, Perteghella S, Grisoli P, Trapani A, Torre ML, Mandracchia D. Drug delivery of rifampicin by natural micelles based on inulin: physicochemical properties, antibacterial activity and human macrophages uptake. Eur J Pharm Biopharm. 2019;136:250–8. https://doi.org/10.1016/j.ejpb.2019.01.022.

    Article  CAS  PubMed  Google Scholar 

  35. Soni N, Soni N, Pandey H, Maheshwari R, Kesharwani P, Tekade RK. Augmented delivery of gemcitabine in lung cancer cells exploring mannose anchored solid lipid nanoparticles. J Colloid Interface Sci. 2016;481:107–16. https://doi.org/10.1016/j.jcis.2016.07.020.

    Article  CAS  PubMed  Google Scholar 

  36. Truzzi E, Nascimento TL, Iannuccelli V, Costantino L, Lima EM, Leo E, et al. In vivo biodistribution of respirable solid lipid nanoparticles surface-decorated with a mannose-based surfactant: a promising tool for pulmonary tuberculosis treatment? Nanomaterials (Basel). 2020;10:3. https://doi.org/10.3390/nano10030568.

    Article  CAS  Google Scholar 

  37. Yu W, Liu C, Liu Y, Zhang N, Xu W. Mannan-modified solid lipid nanoparticles for targeted gene delivery to alveolar macrophages. Pharm Res. 2010;27(8):1584–96. https://doi.org/10.1007/s11095-010-0149-z.

    Article  CAS  PubMed  Google Scholar 

  38. Sahu PK, Mishra DK, Jain N, Rajoriya V, Jain AK. Mannosylated solid lipid nanoparticles for lung-targeted delivery of paclitaxel. Drug Dev Ind Pharm. 2015;41(4):640–9. https://doi.org/10.3109/03639045.2014.891130.

    Article  CAS  PubMed  Google Scholar 

  39. Costa A, Sarmento B, Seabra V. Mannose-functionalized solid lipid nanoparticles are effective in targeting alveolar macrophages. Eur J Pharm Sci. 2018;114:103–13. https://doi.org/10.1016/j.ejps.2017.12.006.

    Article  CAS  PubMed  Google Scholar 

  40. Vieira ACC, Chaves LL, Pinheiro M, Lima SAC, Ferreira D, Sarmento B, et al. Mannosylated solid lipid nanoparticles for the selective delivery of rifampicin to macrophages. Artif Cells Nanomed Biotechnol. 2018;46(sup1):653–63. https://doi.org/10.1080/21691401.2018.1434186.

    Article  CAS  PubMed  Google Scholar 

  41. Singh I, Swami R, Jeengar MK, Khan W, Sistla R. p-Aminophenyl-alpha-D-mannopyranoside engineered lipidic nanoparticles for effective delivery of docetaxel to brain. Chem Phys Lipids. 2015;188:1–9. https://doi.org/10.1016/j.chemphyslip.2015.03.003.

    Article  CAS  PubMed  Google Scholar 

  42. Yang R, Xu J, Xu L, Sun X, Chen Q, Zhao Y, et al. Cancer cell membrane-coated adjuvant nanoparticles with mannose modification for effective anticancer vaccination. ACS Nano. 2018;12(6):5121–9. https://doi.org/10.1021/acsnano.7b09041.

    Article  CAS  PubMed  Google Scholar 

  43. Ke X, Yang C, Cheng W, Yang YY. Delivery of NF-kappaB shRNA using carbamate-mannose modified PEI for eliminating cancer stem cells. Nanomedicine. 2018;14(2):405–14. https://doi.org/10.1016/j.nano.2017.11.015.

    Article  CAS  PubMed  Google Scholar 

  44. Cui Z, Han D, Sun X, Zhang M, Feng X, Sun C, et al. Mannose-modified chitosan microspheres enhance OprF-OprI-mediated protection of mice against Pseudomonas aeruginosa infection via induction of mucosal immunity. Appl Microbiol Biotechnol. 2015;99(2):667–80. https://doi.org/10.1007/s00253-014-6147-z.

    Article  CAS  PubMed  Google Scholar 

  45. Bernardo J, Billingslea AM, Blumenthal RL, Seetoo KF, Simons ER, Fenton MJ. Differential responses of human mononuclear phagocytes to mycobacterial lipoarabinomannans: role of CD14 and the mannose receptor. Infect Immun. 1998;66(1):28–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Takata I, Chida K, Gordon MR, Myrvik QN, Ricardo MJ Jr, Kucera LS. L-fucose, D-mannose, L-galactose, and their BSA conjugates stimulate macrophage migration. J Leukoc Biol. 1987;41(3):248–56. https://doi.org/10.1002/jlb.41.3.248.

    Article  CAS  PubMed  Google Scholar 

  47. Gordon MR, Chida K, Takata I, Myrvik QN. Macrophage migration inhibition induced by MDP, LPS, PMA, and MIF/MAF: reversal by macrophage migration enhancement factor (MEF), L-fucose, L-fucosyl BSA, D-mannose, and D-mannosyl BSA. J Leukoc Biol. 1987;42(3):197–203. https://doi.org/10.1002/jlb.42.3.197.

    Article  CAS  PubMed  Google Scholar 

  48. Sturge J, Todd SK, Kogianni G, McCarthy A, Isacke CM. Mannose receptor regulation of macrophage cell migration. J Leukoc Biol. 2007;82(3):585–93. https://doi.org/10.1189/jlb.0107053.

    Article  CAS  PubMed  Google Scholar 

  49. Misra A, Hickey AJ, Rossi C, Borchard G, Terada H, Makino K, et al. Inhaled drug therapy for treatment of tuberculosis. Tuberculosis (Edinb). 2011;91(1):71–81. https://doi.org/10.1016/j.tube.2010.08.009.

    Article  CAS  Google Scholar 

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Acknowledgments

Thanks for the assistance of Hangzhou Yuhao Chemical Technology Co., Ltd. (Hangzhou, China) in synthesis isonicotinic acid octylene-hydrazide (INH-CHO) and the help of Xi’an Ruixi Biological Technology Co. Ltd. (Xi’an, China) in the synthesis of 6-octadecylimino-hexane-1,2,3,4,5-pentanol (MAN-SA).

Availability of data and material

All authors make sure that all data and materials and software applications support their published claims and comply with field standards.

Funding

This work was supported by the National Science Foundation of China [grant numbers 81703431, 81673375].

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Authors and Affiliations

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

    Cheng Ma, Mingjun Wu, Weifen Ye, Zhengwei Huang, Wenhao Wang, Wenhua Wang, Xin Pan & Chuanbin Wu

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

    Xiangyu Ma

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

    Ying Huang & Chuanbin Wu

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  1. Cheng Ma
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  2. Mingjun Wu
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Contributions

Cheng Ma designed and completed the study and the manuscript. Mingjun Wu and Weifen Ye participated in the in vitro evaluation tests. Wenhao Wang and Wenhua Wang assisted in the in vivo tests. Thanks for the guidance for the study and the revision of the manuscript by Zhengwei Huang, Xiangyu Ma and Ying Huang. The study was performed under the supervision by Xin Pan and Chuanbin Wu.

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Correspondence to Ying Huang or Xin Pan.

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All authors declare the experiments comply with the current laws of China. The in vivo tests were assessed based on Wistar rats, which were purchased from Southern Medical University Laboratory Animal Center. The in vivo animal tests were approved by the institutional animal care and use committee of Sun Yat-sen University (No. SYSU-IACUC-2019-000308).

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Ma, C., Wu, M., Ye, W. et al. Inhalable solid lipid nanoparticles for intracellular tuberculosis infection therapy: macrophage-targeting and pH-sensitive properties. Drug Deliv. and Transl. Res. 11, 1218–1235 (2021). https://doi.org/10.1007/s13346-020-00849-7

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