title: Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors.
abstract: Current tumor targeted drug and diagnostic delivery systems suffer from a lack of selectivity for tumor cells. Here, we propose a two-step tumor targeting strategy based on mesenchymal stem cells (MSCs), which actively traffic to tumors. We developed glycoengineering protocols to induce expression of non-natural azide groups on the surface of MSCs without affecting their viability or tumor homing properties. Glycoengineered MSCs demonstrated active tumor homing in subcutaneous and orthotopic lung and ovarian tumor models. Subsequent systemic administration of dibenzyl cyclooctyne (DBCO)-labeled fluorophores or nanoparticles to MSC pretreated mice resulted in enhanced tumor accumulation of these agents through bio-orthogonal copper-free click chemistry. Further, administration of glycoengineered MSCs along with paclitaxel-loaded DBCO-functionalized nanoparticles resulted in significant (p < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in an orthotopic metastatic ovarian tumor model. These results provide evidence for the potential of MSC-based two-step targeting strategy to improve the tumor specificity of diagnostic agents and drugs, and thus potentially improve the treatment outcomes for patients diagnosed with cancer.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
authors.forename: Buddhadev
authors.initials: B
authors.lastname: Layek
authors.affiliation: Albany Medical Research Inc., 21 Corporate Circle, Albany, NY 12203, USA.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Sadhukha
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA; Center for Translational Drug Delivery, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA. Electronic address: prabh025@umn.edu.
authors.forename: Swayam
authors.initials: S
authors.lastname: Prabha
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D001386:Azides / Q000737:chemistry; D060846:Cell Engineering; D045744:Cell Line, Tumor; D057930:Click Chemistry; D034242:Cyclooctanes / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000737:chemistry / Q000166:cytology*; D016513:Mice, SCID; D061848:Optical Imaging / Q000379:methods; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D010053:Ovary / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use; D000068936:Theranostic Nanomedicine / Q000379:methods
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001386:Azides; D034242:Cyclooctanes; D005456:Fluorescent Dyes; D017239:Paclitaxel
keywords: Cancer therapy; Click chemistry; Glycobiology; Imaging; Nanoparticles; Theranostics; Two-step targeting