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.
|Original language||English (US)|
|Number of pages||13|
|State||Published - May 1 2016|
Bibliographical noteFunding Information:
We thank the University Imaging Centers at the University of Minnesota for assistance with in vivo imaging. We thank Dr. S. Ramakrishnan and his lab (Department of Pharmacology, University of Minnesota) for help with MA148 ovarian tumor model. We also thank Brenda Koniar (Research Animal Resources, University of Minnesota) for assistance with animal studies. This work was partially funded by Grant-in-Aid of Research, Artistry and Scholarship (GIA) support from the Office of the Vice President for Research, University of Minnesota, College of Pharmacy/College of Veterinary Medicine (COP/CVM) Research grant 2014-2015, University of Minnesota and Minnesota Ovarian Cancer Alliance Research Grant 2015.
© 2016 Elsevier Ltd.
- Cancer therapy
- Click chemistry
- Two-step targeting
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