title: Development of drug loaded nanoparticles for tumor targeting. Part 2: Enhancement of tumor penetration through receptor mediated transcytosis in 3D tumor models.
abstract: We report that receptor mediated transcytosis can be utilized to facilitate tumor penetration by drug loaded nanoparticles (NPs). We synthesized hyaluronan (HA) coated silica nanoparticles (SNPs) containing a highly fluorescent core to target CD44 expressed on the cancer cell surface. Although prior studies have primarily focused on CD44 mediated endocytosis to facilitate cellular uptake of HA-NPs by cancer cells, we discovered that, once internalized, the HA-SNPs could be transported out of the cells with their cargo. The exported NPs could be taken up by neighboring cells. This enabled the HA-SNPs to penetrate deeper inside tumors and reach a much greater number of tumor cells in 3D tumor models, presumably through tandem cycles of CD44 mediated endocytosis and exocytosis. When doxorubicin (DOX) was loaded onto the NPs, better penetration of multilayered tumor cells was observed with much improved cytotoxicities against both drug sensitive and drug resistant cancer spheroids compared to the free drug. Thus, targeting receptors such as CD44 that can readily undergo recycling between the cell surface and interior of the cells can become a useful strategy to enhance the tumor penetration potential of NPs and the efficiency of drug delivery through receptor mediated transcytosis.
authors.affiliation: Department of Chemistry, Michigan State University, Chemistry Building, Room 426, 578 S. Shaw Lane, East Lansing, MI 48824, USA.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: El-Dakdouki
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Xuefei
authors.initials: X
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry; D018613:Microscopy, Confocal; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D012822:Silicon Dioxide / Q000737:chemistry; D057900:Transcytosis
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D012822:Silicon Dioxide; D004317:Doxorubicin; D006820:Hyaluronic Acid; D017239:Paclitaxel
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