title: Engineering of caveolae-specific self-micellizing anticancer lipid nanoparticles to enhance the chemotherapeutic efficacy of oxaliplatin in colorectal cancer cells.
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.
  
  
  
  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.
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Pasupathi
authors.initials: P
authors.lastname: Sundaramoorthy
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors.forename: Thiruganesh
authors.initials: T
authors.lastname: Ramasamy
authors.affiliation: Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University, Sagar 470003, India.
authors.forename: Siddhartha Kumar
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Keun-Yeong
authors.initials: KY
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea. Electronic address: hwanmook@gachon.ac.kr.
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008055:Lipids / Q000494:pharmacology / Q000627:therapeutic use*; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D036103:Nanotechnology / Q000379:methods*; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D008823:Micelles; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D010743:Phospholipids; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Caveolae-mediated endocytosis (CvME); Colorectal cancers; Nanoparticles; Oxaliplatin; Self-micellizing anticancer lipid (SMAL)