Nanoparticles and Mesenchymal Stem Cell (MSC) Therapy for Cancer Treatment: Focus on Nanocarriers and a si-RNA CXCR4 Chemokine Blocker as Strategies for Tumor Eradication In Vitro and In Vivo

Abstract

Mesenchymal stem cells (MSCs) have a high tropism for the hypoxic microenvironment of tumors. The combination of nanoparticles in MSCs decreases tumor growth in vitro as well as in rodent models of cancers in vivo. Covalent conjugation of nanoparticles with the surface of MSCs can significantly increase the drug load delivery in tumor sites. Nanoparticle-based anti-angiogenic systems (gold, silica and silicates, diamond, silver, and copper) prevented tumor growth in vitro. For example, glycolic acid polyconjugates enhance nanoparticle drug delivery and have been reported in human MSCs. Labeling with fluorescent particles (coumarin-6 dye) identified tumor cells using fluorescence emission in tissues; the conjugation of different types of nanoparticles in MSCs ensured success and feasibility by tracking the migration and its intratumor detection using non-invasive imaging techniques. However, the biosafety and efficacy; long-term stability of nanoparticles, and the capacity for drug release must be improved for clinical implementation. In fact, MSCs are vehicles for drug delivery with nanoparticles and also show low toxicity but inefficient accumulation in tumor sites by clearance of reticuloendothelial organs. To solve these problems, the internalization or conjugation of drug-loaded nanoparticles should be improved in MSCs. Finally, CXCR4 may prove to be a promising target for immunotherapy and cancer treatment since the delivery of siRNA to knock down this alpha chemokine receptor or CXCR4 antagonism has been shown to disrupt tumor-stromal interactions.

Keywords: CXCR4; PLAG; chemokine blockers (AMD-3100; exosomes; gene therapy; glycolic acid; homing; mesenchymal stem cells (MSC); nanocarriers; nanoparticles; plerixafor); stem cell therapy: CXCL12 (SDF-1 alpha); tumors.

Figure 1

Homing of mesenchymal stem cells (MSCs) toward the tumor site is regulated by CXCR4/SDF1 alpha levels. Inflammation is a calling signal for CXCR4 receptor-bearing MSCs and enhances the recruitment of MSCs [1].

Figure 2

Immunodulatory effects of mesenchymal SCs (MSCs).

Figure 3

Mobilization of hematopoietic SCs (HSCs) by drugs (plerixaform, AMD-3100, CSF, or even viagre).

Figure 4

Trophic factors released by MSCs contribute to cell adhesion, migration, survival, and senescence. For example, CXCR4 or CXCR5 chemokines increase MSC mobilization, while trophic factors such as HGF VGEF play a role in survival.

Figure 5

Nanoparticle technology and physical methods for the introduction of several carriers in different types of cells (MSC, eritrocytes, etc…). Adapted from [87].

Figure 6

MSCs with antitumor drugs can eradicate a tumor using nanoparticle technology. Circulating MSCs can be targeted to the tumor by gene therapy when they overexpress the CXCR4 receptor by i.v injection in a rodent model of cancer, whereby tumor-reaching cells attempt to eradicate the tumor once released (Adapted from Pereboeva et al. [124]).