Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer

Abstract

Mesenchymal stem cells (MSCs), as an undifferentiated group of adult multipotent cells, have remarkable antitumor features that bring them up as a novel choice to treat cancers. MSCs are capable of altering the behavior of cells in the tumor microenvironment, inducing an anti-inflammatory effect in tumor cells, inhibiting tumor angiogenesis, and preventing metastasis. Besides, MSCs can induce apoptosis and inhibit the proliferation of tumor cells. The ability of MSCs to be loaded with chemotherapeutic drugs and release them in the site of primary and metastatic neoplasms makes them a preferable choice as targeted drug delivery procedure. Targeted drug delivery minimizes unexpected side effects of chemotherapeutic drugs and improves clinical outcomes. This review focuses on recent advances on innate antineoplastic features of MSCs and the effect of chemotherapeutic drugs on viability, proliferation, and the regenerative capacity of various kinds of MSCs. It also discusses the efficacy and mechanisms of drug loading and releasing procedures along with in vivo and in vitro preclinical outcomes of antineoplastic effects of primed MSCs for clinical prospection.

Keywords: angiogenesis; apoptosis; cancer; chemotherapeutic drugs; mesenchymal stem cell; metastasis; proliferation; targeted therapy.

FIGURE 1

Methods of cell delivery. (1) Intratumoral injection provides higher amounts of MSCs in the tumor microenvironment; however, impressive complications including infection, pain, and accessibility to deep tumors reduce the efficacy. (2) Intravenous and intra-arterial injection: (a) injection of MSCs to internal carotid artery results in accumulation of MSCs in brain tumors such as glioblastoma; (b) injection of MSCs in common carotid artery reduces the efficacy of cell delivery to glioma in comparison to internal carotid artery; (c) MSCs injected through the femoral vein enter cardiopulmonary circulation that reduces the efficacy of cell administration. Intravenous and intra-arterial injected MSCs cross the BBB to reach brain malignancies. (3) Intrathecal administration enables MSCs to access cerebrospinal fluid (CSF) and reach meningeal tumors. (4) Intranasal administration of MSCs as a novel method reduces complications of injection and provides MSCs in brain tumors. (5) Intraperitoneal injection of MSCs causes distribution in peritoneal cavity and can be used in ovarian malignancies. (6) Application of catheter-based cell delivery provides a safe pathway to deliver MSCs to deep organs and reduce the complication of direct injection.

FIGURE 2

Mesenchymal stem cell characteristics and activities in tumor suppression. (1) Mesenchymal stem cells express several surface molecules that have a pivotal role in their homing to tumor sites. These surface molecules are important during MSC adhesion to different cell types; for example, MSCs express connexin 43 on their membrane, which plays an important role in MSC adhesion to endothelial cells. (2) Tumor cells are able to produce several growth factors, for example, vascular endothelial growth factor, which stimulates new vessel formation and angiogenesis. Mesenchymal stem cells inhibit tumor angiogenesis by reducing the secretion of these growth factors and inducing apoptosis and/or cell cycle arrest in endothelial cells. (3) During and after tumor formation, tumor cells undergo uncontrolled proliferation. Mesenchymal stem cells inhibit tumor cell proliferation by decreasing the expression of positive regulators of cell cycle and/or regulating cell cycle inhibitory genes. (4) Mesenchymal stem cells can increase tumor cell apoptosis either by up-regulating death receptors expression (extrinsic pathway of apoptosis) or stimulating intrinsic pathway of apoptosis. (5) Mesenchymal stem cells inhibit tumor metastasis by decreasing tumor cell motility in the primary site of a tumor. (6) Decreasing permeability of lymphatic or blood vessels for circulating tumor cells. (7) Early after carcinogen exposure, the initial inflammatory response is started, which recruits other innate immune cells from nearby capillaries. Mesenchymal stem cells affect different types of immune cells in the site of inflammation and modulate the immune response, which results in tumor inhibition. Mesenchymal stem cells decrease the amount of M2 phenotype macrophages (which promote tumor tolerance and angiogenesis through secretion of VEGF, TGF-β, and other soluble factors) and induce more regulatory T cells (which are produced during the active phase of immune response and limit the strong immune response by CD4⁺ and CD8⁺ cells and as a result prevent damage to the host tissue) to enter the inflammatory site.

FIGURE 3

Drugs in MSCs. (1) Drugs enter MSCs through a variety of pathways: (a) drug transporters such as hCNT1 and hENT1, (b) endocytosis, (c) simple diffusion based on the chemical nature of chemotherapeutic drugs. (2) Some types of drugs such as paclitaxel metabolized in mitochondria, but there is no evidence of impressive inactivation. (3) Based on the antineoplastic mechanism of drugs, they are distributed among their place of action such as microtubule networks and centrioles. (4) Chemotherapeutic drugs may interfere with the normal gene expression pattern of MSCs, which mainly influence differentiation capacity. (5) Mesenchymal stem cells produce vesicles that contain drugs close to the cellular membrane. Drugs can be found in Golgi apparatus and Golgi-derived vesicles. (6) Existence of vesicles between MSCs and cancer cells suggests that drugs can be delivered to cancer cells in a vesicular system.