1. Engineering of caveolae-specific self-micellizing anticancer lipid nanoparticles to enhance the chemotherapeutic efficacy of oxaliplatin in colorectal cancer cells
- Author
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Chul Soon Yong, Keun-Yeong Jeong, Siddhartha Kumar Mishra, Pasupathi Sundaramoorthy, Jong Oh Kim, Thiruganesh Ramasamy, and Hwan Mook Kim
- Subjects
Organoplatinum Compounds ,Blotting, Western ,Biomedical Engineering ,Antineoplastic Agents ,Apoptosis ,02 engineering and technology ,Pharmacology ,Biology ,Endocytosis ,Caveolae ,Biochemistry ,Biomaterials ,03 medical and health sciences ,HT29 Cells ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Humans ,Nanotechnology ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Micelles ,Phospholipids ,Cell Proliferation ,TOR Serine-Threonine Kinases ,Cell Cycle ,Drug Synergism ,General Medicine ,021001 nanoscience & nanotechnology ,HCT116 Cells ,Lipids ,Oxaliplatin ,Intrinsic apoptotic signaling pathway ,030220 oncology & carcinogenesis ,Cancer cell ,Drug delivery ,Cancer research ,Nanoparticles ,Nanocarriers ,0210 nano-technology ,Colorectal Neoplasms ,Proto-Oncogene Proteins c-akt ,Biotechnology ,Signal Transduction - Abstract
Novel nanomaterials for the intracellular transport of therapeutic cargos have been actively sought to effectively breach cell-membrane barriers. In this study we developed novel self-micellizing anticancer lipid (SMAL)-based pro-apoptotic nanoparticles (NPs) that enhance the accumulation and chemotherapeutic efficacy of oxaliplatin (OL) in colorectal cancer cells (CRCs). We demonstrated that NPs with special affinity to caveolae could be designed and based on this specificity, NPs effectively differentiated between endothelial cells (tumor cells) and epithelial cells, without the need for a cell-specific targeting moiety. We demonstrated a remarkable uptake of OL-loaded SMAL NPs (SMAL-OL) in HCT116 and HT-29 cells via the caveolae-mediated endocytosis (CvME) pathway. The higher accumulation of SMAL-OL in the intracellular environment resulted in a significantly elevated anticancer effect compared to that of free OL. Cell cycle analysis proved G2/M phase arrest, along with substantial presence of cells in the sub-G1 phase. An immunoblot analysis indicated an upregulation of pro-apoptotic markers (Bax; caspase-3; caspase-9; and PARP1) and downregulation of Bcl-xl and the PI3K/AKT/mTOR complex, indicating a possible intrinsic apoptotic signaling pathway. Overall, the ability of SMAL NPs to confer preferential specificity towards the cell surface domain could offer an exciting means of targeted delivery without the need for receptor-ligand-type strategies. Statement of Significance In this work, we developed a novel self-micellizing anticancer lipid (SMAL)-based pro-apoptotic nanoparticles (NPs) that enhance the accumulation and chemotherapeutic efficacy of oxaliplatin (OL) in colorectal cancer cells. We demonstrated that NPs with special affinity to caveolae could be realized and based on this specificity, NPs effectively differentiated between endothelial cells (tumor cells) and epithelial cells, without the need for a cell-specific targeting moiety. In addition, oxaliplatin-loaded SMAL were efficiently endocytosed by the cancer cells and represent a significant breakthrough as an effective drug delivery system with promising potential in cancer therapy. We believe this work holds promising potential for the development of next generation of multifunctional nanocarriers for an exciting means of targeted delivery without the need for receptor-ligand-type strategies.
- Published
- 2016