Mesenchymal stem cells (MSCs) can be used for tumor-specific delivery of small molecular weight anticancer drugs by using nanoparticle-encapsulated forms of the drugs. Current approaches to incorporate nanoparticles in MSCs rely on nonspecific endocytosis of nanoparticles or their conjugation to the cell surface via endogenous amines and thiols. These methods result in sub-optimal drug loading, which hinders the widespread application of MSCs as drug carriers. An advanced nanoengineering strategy is reported here that involves generation of MSCs expressing azide functional groups on their surface and conjugation of dibenzyl cyclooctyne-functionalized nanoparticles to the azide groups using copper-free click chemistry. This novel strategy significantly improves the payload capacity of MSCs (≈48 pg of paclitaxel (PTX) per cell) relative to that reported previously (<1–20 pg per cell), without affecting their native phenotype. In vivo, the nanoengineered MSCs significantly inhibit tumor growth (p < 0.05) and improve survival (p < 0.0001) compared to free or nanoparticle encapsulated PTX and Abraxane in an orthotopic ovarian tumor model. In summary, the nanoengineering strategy reported here allows for improved delivery and anticancer efficacy of conventional chemotherapeutic agents using MSCs as drug carriers.
Bibliographical noteFunding Information:
This work was supported by the Minnesota Ovarian Cancer Alliance Research Grant and National Institute of Health (EB022558 to S.P. and EB019893 to J.P.). The authors acknowledge support provided by Dr. Tanmoy Sadhukha for preliminary studies and Paula Overn (Comparative Pathology Shared Resource) for immunohistological staining of tumor tissues. The authors sincerely thank the University Imaging Centers (UIC) at the University of Minnesota for assistance with live animal imaging.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
- cancer therapy
- mesenchymal stem cells
- nanoengineered mesenchymal stem cells
- targeted drug delivery