title: Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.
abstract: Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions.
authors.forename: Prajakta
authors.initials: P
authors.lastname: Kulkarni
authors.forename: Manas K
authors.initials: MK
authors.lastname: Haldar
authors.affiliation: Davies High School , Fargo, North Dakota 58104, United States.
authors.forename: Preeya
authors.initials: P
authors.lastname: Katti
authors.affiliation: Valley City High School , Valley City, North Dakota 58072, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Dawes
authors.forename: Seungyong
authors.initials: S
authors.lastname: You
authors.forename: Yongki
authors.initials: Y
authors.lastname: Choi
authors.forename: Sanku
authors.initials: S
authors.lastname: Mallik
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001391:Azo Compounds / Q000737:chemistry; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D065546:Drug Liberation; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D018874:Spheroids, Cellular / Q000378:metabolism*; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D004337:Drug Carriers; D009842:Oligopeptides; D010743:Phospholipids; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; C009850:azobenzene