Protein nanocages that penetrate airway mucus and tumor tissue

Xinglu Huang, Jane Chisholm, Jie Zhuang, Yanyu Xiao, Gregg Duncan, Xiaoyuan Chen, Jung Soo Suk, Justin S Hanes

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E6595-E6602
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number32
DOIs
StatePublished - Aug 8 2017

Fingerprint

Mucus
Doxorubicin
Neoplasms
Proteins
Nanoparticles
Inhalation
Apoferritins
Lung
Transferrin Receptors
Survival
Maximum Tolerated Dose
Drug Delivery Systems
Immunotherapy
Lung Neoplasms
Therapeutics
Molecular Weight
Gels
Technology
Drug Therapy
Acids

Keywords

  • Biological barriers
  • Human ferritin
  • Lung cancer
  • Nanoparticle
  • PEG

ASJC Scopus subject areas

  • General

Cite this

Protein nanocages that penetrate airway mucus and tumor tissue. / Huang, Xinglu; Chisholm, Jane; Zhuang, Jie; Xiao, Yanyu; Duncan, Gregg; Chen, Xiaoyuan; Suk, Jung Soo; Hanes, Justin S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 32, 08.08.2017, p. E6595-E6602.

Research output: Contribution to journalArticle

Huang, Xinglu ; Chisholm, Jane ; Zhuang, Jie ; Xiao, Yanyu ; Duncan, Gregg ; Chen, Xiaoyuan ; Suk, Jung Soo ; Hanes, Justin S. / Protein nanocages that penetrate airway mucus and tumor tissue. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 32. pp. E6595-E6602.
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