Theranostics 2020; 10(15):6695-6714. doi:10.7150/thno.45164
PEG-coated nanoparticles detachable in acidic microenvironments for the tumor-directed delivery of chemo- and gene therapies for head and neck cancer
1. Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan.
2. Faculty of Pharmacy, National Yang-Ming University, Taipei 11221, Taiwan.
3. Center for Advanced Pharmaceutics and Drug Delivery Research, National Yang-Ming University, Taipei 11221, Taiwan.
4. Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
5. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
6. Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Lo YL, Chang CH, Wang CS, Yang MH, Lin AMY, Hong CJ, Tseng WH. PEG-coated nanoparticles detachable in acidic microenvironments for the tumor-directed delivery of chemo- and gene therapies for head and neck cancer. Theranostics 2020; 10(15):6695-6714. doi:10.7150/thno.45164. Available from https://www.thno.org/v10p6695.htm
Background: Head and neck cancer (HNC) is a major cause of morbidity and mortality and has a poor treatment outcome. Irinotecan, a topoisomerase-I inhibitor, induces cell death by decreasing the religation of double-strand DNA. However, epithelial-mesenchymal transition (EMT), therapy resistance, and systemic toxicity caused by available antineoplastic agents hinder the efficacy and safety of HNC treatment. Chemotherapy combined with gene therapy shows potential application in circumventing therapy resistance and EMT. miR-200 exerts a remarkable suppressing effect on EMT-associated genes. Herein, liposomes and solid lipid nanoparticles (SLNs) modified with a pH-sensitive, self-destructive polyethylene glycol (PEG) shell and different peptides were designed as irinotecan and miR-200 nanovectors to enhance tumor-specific accumulation. These peptides included one ligand targeting the angiogenic tumor neovasculature, one mitochondrion-directed apoptosis-inducing peptide, and one cell-penetrating peptide (CPP) with high potency and selectivity toward cancer cells.
Methods: Physicochemical characterization, cytotoxicity analysis, cellular uptake, regulation mechanisms, and in vivo studies on miR-200- and irinotecan-incorporated nanoparticles were performed to identify the potential antitumor efficacy and biosafety issues involved in HNC treatment and to elucidate the underlying signaling pathways.
Results: We found that the cleavable PEG layer responded to low extracellular pH, and that the CPP and targeting peptides were exposed to improve the uptake and release of miR-200 and irinotecan into HNC human tongue squamous carcinoma (SAS) cells. The apoptosis of SAS cells treated with the combinatorial therapy was significantly induced by regulating various pathways, such as the Wnt/β-catenin, MDR, and EMT pathways. The therapeutic efficacy and safety of the proposed co-treatment outperformed the commercially available Onivyde and other formulations used in a SAS tumor-bearing mouse model in this study.
Conclusion: Chemotherapy and gene therapy co-treatment involving pH-sensitive and targeting peptide-modified nanoparticles may be an innovative strategy for HNC treatment.
Keywords: head and neck cancer, self-cleavable PEG-shell, combinatorial therapy, microRNA, pH-sensitive targeting nanoparticles