pH-Responsive PEG-Shedding and Targeting Peptide-Modified Nanoparticles for Dual-Delivery of Irinotecan and microRNA to Enhance Tumor-Specific Therapy.

Autor: Juang V; Department and Institute of Pharmacology, National Yang-Ming University, Taipei, 112, Taiwan., Chang CH; Department and Institute of Pharmacology, National Yang-Ming University, Taipei, 112, Taiwan., Wang CS; Department and Institute of Pharmacology, National Yang-Ming University, Taipei, 112, Taiwan., Wang HE; Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 112, Taiwan., Lo YL; Department and Institute of Pharmacology, National Yang-Ming University, Taipei, 112, Taiwan.; Faculty of Pharmacy, National Yang-Ming University, Taipei, 112, Taiwan.; Center for Advanced Pharmaceutics and Drug Delivery Research, National Yang-Ming University, Taipei, 112, Taiwan.
Jazyk: angličtina
Zdroj: Small (Weinheim an der Bergstrasse, Germany) [Small] 2019 Dec; Vol. 15 (49), pp. e1903296. Date of Electronic Publication: 2019 Nov 11.
DOI: 10.1002/smll.201903296
Abstrakt: Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA-200 (miR-200) has been reported to inhibit metastasis in cancer cells. Herein, pH-sensitive and peptide-modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR-200, respectively. These peptides include one cell-penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria-targeting peptide. The peptide-modified nanoparticles are further coated with a pH-sensitive PEG-lipid derivative with an imine bond. These specially-designed nanoparticles exhibit pH-responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR-200 by SLN further increases the cytotoxicity of irinotecan-loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β-catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC-bearing mice, the in vivo results further indicate that irinotecan and miR-200 in pH-responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β-catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH-responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.
(© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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