Peptide-targeted, stimuli-responsive polymersomes for delivering a cancer stemness inhibitor to cancer stem cell microtumors.

Abstract

Often cancer relapses after an initial response to chemotherapy because of the tumor's heterogeneity and the presence of progenitor stem cells, which can renew. To overcome drug resistance, metastasis, and relapse in cancer, a promising approach is the inhibition of cancer stemness. In this study, the expression of the neuropilin-1 receptor in both pancreatic and prostate cancer stem cells was identified and targeted with a stimuli-responsive, polymeric nanocarrier to deliver a stemness inhibitor (napabucasin) to cancer stem cells. Reduction-sensitive amphiphilic block copolymers PEG1900-S-S-PLA6000 and the N3-PEG1900-PLA6000 were synthesized. The tumor penetrating iRGD peptide-hexynoic acid conjugate was linked to the N3-PEG1900-PLA6000 polymer via a Cu2+ catalyzed "Click" reaction. Subsequently, this peptide-polymer conjugate was incorporated into polymersomes for tumor targeting and tissue penetration. We prepared polymersomes containing 85% PEG1900-S-S-PLA6000, 10% iRGD-polymer conjugate, and 5% DPPE-lissamine rhodamine dye. The iRGD targeted polymersomes encapsulating the cancer stemness inhibitor napabucasin were internalized in both prostate and pancreatic cancer stem cells. The napabucasin encapsulated polymersomes significantly (p < .05) reduced the viability of both prostate and pancreatic cancer stem cells and decreased the stemness protein expression notch-1 and nanog compared to the control and vesicles without any drug. The napabucasin encapsulated polymersome formulations have the potential to lead to a new direction in prostate and pancreatic cancer therapy by penetrating deeply into the tumors, releasing the encapsulated stemness inhibitor, and killing cancer stem cells.

• Authors: Fataneh Karandish, James Froberg, Pawel Borowicz, John C Wilkinson, Yongki Choi, Sanku Mallik
• Journal: Colloids and surfaces. B, Biointerfaces (Colloids Surf B Biointerfaces) Vol. 163 Pg. 225-235 (Mar 01 2018) ISSN: 1873-4367 [Electronic] Netherlands
• PMID: 29304437 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Benzofurans
• N-end cysteine peptide tumor-homing peptide
• Naphthoquinones
• Oligopeptides
• Polymers
• napabucasin
• Neuropilin-1

Topics

• Apoptosis (drug effects)
• Benzofurans (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cycloaddition Reaction
• Endocytosis (drug effects)
• Flow Cytometry
• Humans
• Hydrodynamics
• Naphthoquinones (pharmacology)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Neuropilin-1 (metabolism)
• Oligopeptides (chemistry)
• Polymers (chemical synthesis, chemistry)