Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting

Abstract

Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano–engineered MSCs resulted in greater than 9–fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano–engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti–cancer efficacy of conventional chemotherapeutic drugs.

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

“…[52] PTX has also been shown to inhibit tumor angiogenesis when administered at low doses over a prolonged duration. [21] As discussed previously, transport resistance within the tumor microenvironment limits the effective distribution of nanoparticles, resulting in reduced therapeutic efficacy observed with PTX nanoparticles. However, there was a significantly greater induction of tumor cell apoptosis in the case of nanoengineered MSCs, which could have resulted from sustained delivery of the drug in close proximity to tumor cells.…”

“…Poor diffusive and convective transport within solid tumors prevents their efficient distribution into under-perfused regions. [21,33,34] However, small molecules cannot be loaded in MSCs efficiently owing to their diffusional clearance as well as transporter-mediated efflux from the cells. [32] MSCs have been investigated for tumor-targeted delivery of various therapeutic agents because of their unique tumor homing capabilities.…”

“…[21,33,34] However, small molecules cannot be loaded in MSCs efficiently owing to their diffusional clearance as well as transporter-mediated efflux from the cells. [21] Some solid tumors like ovarian tumors are less likely to benefit from the EPR effect because of the existence of under-perfused and hypoxic regions. [36] Our previous IHC studies evaluating the distribution of nanoengineered MSCs in lung tumors showed that MSCs penetrated the tumor tissue, were present amid the tumor cells, were viable (neither necrotic nor apoptotic), and not trapped in blood vessels.…”

“…[21] To reduce the possibility of toxicity associated with injecting large numbers of MSCs and to increase the payload capacity of nanoengineered MSCs, we investigated surface conjugation of drug-encapsulated nanoparticles in the present study. In those studies, we relied on nonspecific endocytosis to load nanoparticle-encapsulated drug in MSCs.…”

“…[16,17] However, the difficulty in immobilizing small molecules within cells for prolonged periods of time has been a critical barrier to the use of MSCs in drug delivery. [21] Yet, the use of nonspecific endocytosis to incorporate nanoparticles in MSCs results in limited intracellular drug retention due to the relatively rapid exocytosis of a large fraction of the internalized nanoparticles. [18][19][20][21] "Nanoengineered" MSCs can actively traffic to tumors within a few minutes of dosing, [13] enabling targeted drug delivery and enhanced tumor growth inhibition.…”