Journal
SMALL
Volume 15, Issue 49, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/smll.201903296
Keywords
chemotherapy; cleavable PEG shedding; colorectal cancer; combination therapy; microRNA; pH-sensitive targeting nanoparticles
Categories
Funding
- Ministry of Science and Technology of Taiwan [MOST 106-2320-B-010-005, MOST 107-2320-B-010-015-MY3]
- Veterans General Hospitals and University System of Taiwan [VGHUST106-G7-7-3, VGHUST108-G2-1-2]
- National Yang-Ming University and Cheng Hsin General Hospital [CY10726, CY10839]
- Center for Advanced Pharmaceutics and Drug Delivery Research, School of Medicine (Development and Construction Plan), National Yang-Ming University, Ministry of Education of Taiwan (Aiming for the Top University Plan)
- Taiwan Animal Consortium [MOST 107-2319-B-001-002]
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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/beta-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 beta-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.
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