Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo

Weijing Yang, Yaohua Wei, Liang Yang, Jian Zhang, Zhiyuan Zhong* (Corresponding Author), Gert Storm, Fenghua Meng (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)

Abstract

The clinical use of protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell-selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high-efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82–90 nm, reduction-responsive protein release, as well as greatly enhanced internalization and cytoplasmic protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB-loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC50) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non-targeted and non-treated controls. These cell-selective penetrating and reduction-responsive polymersomes provide a targeted protein therapy for cancers.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalJournal of controlled release
Volume290
DOIs
Publication statusPublished - 28 Nov 2018

Keywords

  • UT-Hybrid-D
  • Lung cancer
  • Polymersomes
  • Protein delivery
  • Reduction-sensitive
  • Cell penetrating peptide

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