Targeted Intracellular Delivery of Antituberculosis Drugs to Mycobacterium tuberculosis-Infected Macrophages via Functionalized Mesoporous Silica Nanoparticles
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Delivery of antituberculosis drugs by nanoparticles offers potential advantages over free drug, including the potential to target specifically the tissues and cells that are infected by Mycobacterium tuberculosis , thereby simultaneously increasing therapeutic efficacy and decreasing systemic toxicity, and the capacity for prolonged release of drug, thereby allowing less-frequent dosing. We have employed mesoporous silica nanoparticle (MSNP) drug delivery systems either equipped with a polyethyleneimine (PEI) coating to release rifampin or equipped with cyclodextrin-based pH-operated valves that open only at acidic pH to release isoniazid (INH) into M. tuberculosis -infected macrophages. The MSNP are internalized efficiently by human macrophages, traffic to acidified endosomes, and release high concentrations of antituberculosis drugs intracellularly. PEI-coated MSNP show much greater loading of rifampin than uncoated MSNP and much greater efficacy against M. tuberculosis- infected macrophages. MSNP were devoid of cytotoxicity at the particle doses employed for drug delivery. Similarly, we have demonstrated that the isoniazid delivered by MSNP equipped with pH-operated nanovalves kill M. tuberculosis within macrophages significantly more effectively than an equivalent amount of free drug. These data demonstrate that MSNP provide a versatile platform that can be functionalized to optimize the loading and intracellular release of specific drugs for the treatment of tuberculosis.
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Approximately 90% of MSNP was intracellularly colocalized with CD63 after 3 h of incubation.
“Approximately 90% of MSNP was intracellularly colocalized with CD63 after 3 h of incubation.204”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [204]
The majority of macrophages incubated with RITC-labeled NP-RIF internalized the fluorescent nanoparticles and exhibited 10-fold higher fluorescence intensity than untreated control macrophages.
“The majority of the macrophages that were incubated with RITC-labeled NP-RIF internalized the fluorescent nanoparticles and exhibited 10-fold higher fluorescence intensity than the untreated control macrophages.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [204]
Drug-specific surface functionalization has been employed for rifampicin, and further functionalization with poly(ethylene imine) yields high loading and controlled drug delivery to MTB-infected macrophages compared to uncoated MSNP.
“Drug-specific surface functionalization has been employed for RIF, and further functionalization with poly(ethylene imine) (PEI) yields high loading and controlled drug delivery to MTB-infected macrophages compared to uncoated MSNP.204”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [204]
For isoniazid, MSNP decorated with pH-operated nanovalves has been designed to open after endocytosis and endosome acidification to deliver the drug directly to MTB-infected macrophages.
“On the other hand, in the case of INH, MSNP decorated with pH-operated nanovalves has been designed to open after endocytosis and endosome acidification to deliver the drug directly to MTB-infected macrophages.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [204]
Functionalized MSNP can be internalized efficiently by human macrophages such as THP-1 cells.
“Functionalized MSNP can be internalized efficiently, as confirmed by using human macrophages such as THP-1 cells.”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [204]
At acidic pH, the β-cyclodextrin plug is lost, resulting in drug release from mesoporous silica nanoparticles loaded with isoniazid.
“at an acidic pH, the plug is lost, resulting in drug release.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [66]
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- Authors
- Clemens, D. L., Lee, B.-Y., Xue, M., Thomas, C. R., Meng, H., Ferris, D., Nel, A. E., Zink, J. I., & Horwitz, M. A.
- Affiliations
- University of California, Los Angeles (US)
- Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, California, USA
- California NanoSystems Institute (US)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-05
- Volume
- 56
- Issue
- 5
- Pages
- 2535-2545
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3346638
- OpenAlex
- W2021068830
- Cited by
- 260
- References
- 49
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 17 · 2023: 24 · 2022: 24 · 2021: 29 · 2020: 24 · 2019: 22 · 2018: 14 · 2017: 16 · 2016: 15 · 2015: 21 · 2014: 21 · 2013: 8 · 2012: 2
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Foundation for the National Institutes of Health
- Bill and Melinda Gates Foundation
- National Cancer Institute (R01CA133697, CA 133697)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Physical Sciences › Materials Science › Materials Chemistry › Mesoporous Materials and Catalysis
- Keywords
- mesoporous silica nanoparticles, Mycobacterium tuberculosis, infected macrophages, rifampicin, isoniazid, polyethyleneimine coating, intracellular drug release, endosomal acidification, tuberculosis treatment
- MeSH terms
- Antitubercular Agents, Cell Line, Cell Survival, Cyclodextrins, Drug Compounding, Humans, Hydrogen-Ion Concentration, Isoniazid, Macrophages, Mycobacterium tuberculosis, Phagocytosis, Polyethyleneimine, Rifampin, Silicon Dioxide, Colony Count, Microbial, Porosity, Drug Delivery Systems, Microscopy, Electron, Transmission, Microbial Viability, Nanoparticles
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