Engineered Mesenchymal Stem Cells for Targeting Solid Tumors: Therapeutic Potential beyond Regenerative Therapy

Abstract

Mesenchymal stem cells (MSCs) have previously demonstrated considerable promise in regenerative medicine based on their ability to proliferate and differentiate into cells of different lineages. More recently, there has been a significant interest in using MSCs as cellular vehicles for targeted cancer therapy by exploiting their tumor homing properties. Initial studies focused on using genetically modified MSCs for targeted delivery of various proapoptotic, antiangiogenic, and therapeutic proteins to a wide variety of tumors. However, their use as drug delivery vehicles has been limited by poor drug load capacity. This review discusses various strategies for the nongenetic modification of MSCs that allows their use in tumor-targeted delivery of small molecule chemotherapeutic agents. SIGNIFICANCE STATEMENT There has been considerable interest in exploiting the tumor homing potential of MSCs to develop them as a vehicle for the targeted delivery of cytotoxic agents to tumor tissue. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. While significant progress has been made in the area of the genetic modification of MSCs, studies focused on identification of molecular mechanisms that contribute to the tumor tropism along with optimization of the engineering conditions can further improve their effectiveness as drug delivery vehicles.

Stem cell homing: From physiology to therapeutics

“…Genetic modifications have used permanent overexpression of homing factors via viral transduction such as overexpression of CXCR4 134 . Overexpression of VLA‐4 has also been attempted in rat models 135 .…”

Engineering Targeting Materials for Therapeutic Cancer Vaccines

“…Mammalian cells are living materials also delimited by a lipid bilayer, with a typical size of 10-50 µm of various shapes, that can be used as carriers to deliver drugs or as therapeutic agents per se when administered into patients (Cheng et al, 2019;Gong et al, 2019). To prevent cell rejection upon delivery, cells for clinical use are often derived from autologous sources, processed ex vivo and re-administered into the patient.…”

“…Tumor inflammation induces the secretion of chemokines, such as CXCL12, which are able to recruit specific cell types. Based on this mechanism, active tumor targeting can be achieved by the delivery of cells capable of sensing these chemokine gradients and actively migrating into tumor-inflamed regions (Cheng et al, 2019), such as myeloid cells, T cells, neural stem cells and mesenchymal stem cells (MSCs) for example (Leibacher and Henschler, 2016;Combes et al, 2018). Furthermore, these cells can be engineered to deliver anti-cancer drugs; for example, MSCs have been genetically modified to overexpress IFNβ or to carry paclitaxel into tumors (Ling et al, 2010;Sadhukha et al, 2014).…”

Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells

“…Since their discovery by A.J. Friedenstein in early 1970s [ 1 ], mesenchymal stem cells (MSCs) have been widely used in various therapeutic areas [ 2 ], especially in regenerative medicine [ 3 , 4 ]. Based on unique characteristics such as high growth and differentiation potential [ 5 , 6 , 7 ] and low immunogenicity [ 8 , 9 ], MSCs have been investigated in over 700 clinical trials worldwide for various clinical applications ( ) [ 10 ].…”