Protein nanocages that penetrate airway mucus and tumor tissue
Open accessAbstract
Reports on drug delivery systems capable of overcoming multiple biological barriers are rare. We introduce a nanoparticle-based drug delivery technology capable of rapidly penetrating both lung tumor tissue and the mucus layer that protects airway tissues from nanoscale objects. Specifically, human ferritin heavy-chain nanocages (FTn) were functionalized with polyethylene glycol (PEG) in a unique manner that allows robust control over PEG location (nanoparticle surface only) and surface density. We varied PEG surface density and molecular weight to discover PEGylated FTn that rapidly penetrated both mucus barriers and tumor tissues in vitro and in vivo. Upon inhalation in mice, PEGylated FTn with optimized PEGylation rapidly penetrated the mucus gel layer and thus provided a uniform distribution throughout the airways. Subsequently, PEGylated FTn preferentially penetrated and distributed within orthotopic lung tumor tissue, and selectively entered cancer cells, in a transferrin receptor 1-dependent manner, which is up-regulated in most cancers. To test the potential therapeutic benefits, doxorubicin (DOX) was conjugated to PEGylated FTn via an acid-labile linker to facilitate intracellular release of DOX after cell entry. Inhalation of DOX-loaded PEGylated FTn led to 60% survival, compared with 10% survival in the group that inhaled DOX in solution at the maximally tolerated dose, in a murine model of malignant airway lung cancer. This approach may provide benefits as an adjuvant therapy combined with systemic chemo- or immunotherapy or as a stand-alone therapy for patients with tumors confined to the airways.
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BLI is used to assess nanodrug efficiency based on endogenic luminescence of tumors to confirm NPs diagnostics or theranostic prospects and to integrate with other imaging modalities.
“BLI is used to assess nanodrug efficiency based on the endogenic luminescence of tumors to confirm NPs diagnostics or theranostic prospects and to integrate with other imaging modalities [19,134,135,136].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [135]
The Results (page not provided) use bioluminescence imaging to monitor tumor growth and assess the efficacy of drug-loaded nanocages in mice. But Materials and Methods (page not provided) show that the signal came from engineered luciferase-expressing tumor cells after d-luciferin administration, not endogenous tumor luminescence. The paper does not establish the claimed diagnostic or theranostic prospects or integration of BLI with other imaging modalities. (LLM, conf=0.88)
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- Authors
- Huang, X., Chisholm, J., Zhuang, J., Xiao, Y., Duncan, G., Chen, X., Suk, J. S., & Hanes, J.
- Affiliations
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-07-24
- Volume
- 114
- Issue
- 32
- Pages
- E6595-E6602
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5559033
- OpenAlex
- W2740024147
- Cited by
- 131
- References
- 51
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 8 · 2023: 20 · 2022: 19 · 2021: 18 · 2020: 17 · 2019: 13 · 2018: 12 · 2017: 1
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (U54CA151838, R01HL127413, R01HL136617)
- Cystic Fibrosis Foundation (HANES07XX0, HANES15G0)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- protein nanocages, FTH1, PEGylation, pulmonary drug delivery, transferrin receptor 1, doxorubicin, acid-labile linker, anticancer drug delivery, nanoparticle functionalization
- MeSH terms
- Animals, Apoferritins, Doxorubicin, Humans, Lung Neoplasms, Neoplasms, Experimental, Polyethylene Glycols, Respiratory Mucosa, Nanostructures, Mice
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