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)

Research output: Contribution to journalArticleAcademicpeer-review

3 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

Fingerprint

Granzymes
Lung
Neoplasms
Fluorescein-5-isothiocyanate
Cytochromes
Proteins
Lung Neoplasms
Cell-Penetrating Peptides
Therapeutic Uses
Nude Mice
Inhibitory Concentration 50
Weight Loss
Permeability
Body Weight

Keywords

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

Cite this

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title = "Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo",
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.",
keywords = "UT-Hybrid-D, Lung cancer, Polymersomes, Protein delivery, Reduction-sensitive, Cell penetrating peptide",
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Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo. / Yang, Weijing; Wei, Yaohua; Yang, Liang; Zhang, Jian; Zhong, Zhiyuan (Corresponding Author); Storm, Gert; Meng, Fenghua (Corresponding Author).

In: Journal of controlled release, Vol. 290, 28.11.2018, p. 141-149.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo

AU - Yang, Weijing

AU - Wei, Yaohua

AU - Yang, Liang

AU - Zhang, Jian

AU - Zhong, Zhiyuan

AU - Storm, Gert

AU - Meng, Fenghua

N1 - Elsevier deal

PY - 2018/11/28

Y1 - 2018/11/28

N2 - 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.

AB - 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.

KW - UT-Hybrid-D

KW - Lung cancer

KW - Polymersomes

KW - Protein delivery

KW - Reduction-sensitive

KW - Cell penetrating peptide

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DO - 10.1016/j.jconrel.2018.10.013

M3 - Article

VL - 290

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EP - 149

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

ER -