Nanoengineering of Mesenchymal Stem Cells via Surface Modification for Efficient Cancer Therapy

Abstract

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.

Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer

“…MSCs were found to not be sensitive to paclitaxel induced cytotoxicity [45]. In addition, these studies also demonstrated improved tumor growth inhibition in a platinum-sensitive orthotopic ovarian tumor model [22,44]. Tumor xenografts established from immortalized cell lines are easy to develop, reproducible, easy to measure by incorporating bioluminescence, and relatively inexpensive [46].…”

“…In our previous studies, we optimized the glycoengineering protocol to achieve high azide expression on MSCs without affecting their viability or tumor homing characteristics [22,44]. MSCs were found to not be sensitive to paclitaxel induced cytotoxicity [45].…”

“…Paclitaxel and NIR dye SDB5491 loaded DBCO-functionalized PLGA nanoparticles (DBCO-PTX NIR NP) were prepared by interfacial activity assisted surface functionalization technique [22,44,61]. In brief, PLGA (32 mg), paclitaxel (8 mg), and SDB5491 (0.25 mg) were dissolved in chloroform (1 mL) and added to aqueous PVA solution (7.5 mL, 2.5% w/v).…”

Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications

“…Meanwhile, NPs can be targeted toward tumors by anchoring on stem cells, often via interaction with amine or thiol functional groups of cell surface [77][78][79][80]. Recently, Layek et al reported that the loading efficiency and retention of NPs on cells could be improved by conjugating cyclooctyne-modified NPs with azide-functionalized MSCs to form a stable triazole at ambient conditions [81]. By this method, the content of PTX was~48 pg per cell, much higher than that reported by other techniques (~1-20 pg per cell), while maintaining cell phenotype.…”

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

“…Layek et al (2016) demonstrated that culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media effectively generated azide-bearing sialic acid on the cell surface without affecting their viability, migration, and differentiation potential. Azide groups on the surface have been used to conjugate dibenzyl cyclooctyne (DBCO)-functionalized, paclitaxel-loaded NPs to MSCs, which allowed for significantly increased NP loading in MSCs (Layek et al, 2019). Incorporation of DBCO-functionalized NPs on MSCs did not affect the viability and migration of MSCs.…”