ReviewMesenchymal stem cells: A promising targeted-delivery vehicle in cancer gene therapy
Graphical abstract
The review describes the potential of using of mesenchymal stem cells as a targeted-delivery vehicle in cancer gene therapy and they mat serve as an effective platform for delivering biological agents into tumors. Schematic of nanocarrier systems and MSCs for site-targeted drug/gene delivery (modified from [5,92]). Folate receptor; EGFR: Epidermal growth factor receptor.
Introduction
With the development of molecular biology, cancer gene therapy becomes a promising field in the treatment of malignant tumor. Cytokines, such as IL-2, IL-12 and IFN-β et al., can stimulate anti-tumor responses through the activation of T cells, which mediates immune response to eliminate tumors. Nevertheless, the therapeutic application of exogenously administered cytokines is limited by their short half-lives and poor accessibility to tumor sites [1]. These cytokines exhibit rapid blood clearance and poor retention time in the target, which results in the necessity for the frequent administration of such agents. Therefore, therapeutic utility of these cytokines in vivo is limited by its excessive toxicity when administered systemically at high doses and with high frequency [1]. Additionally, previous studies have largely relied on viral vectors to deliver these therapeutic genes, which are associated with safety concerns [2] and limit the clinical application of these cytokines.
Targeted delivery of anticancer agents is one of promising fields in anticancer therapy. A major disadvantage of anticancer agents is their lack of selectivity for tumor tissue, which causes severe side effects and results in low therapeutic efficiency. Therefore, tumor-targeting approaches have been developed for improved efficiency and minimizing systematic toxicity by altering biodistribution profiles of anticancer agents. In recent years, the targeting drug delivery systems (TDDS) attracted extensive attention of researchers. More and more drug/gene targeted delivery carriers, such as stealth liposome [3], magnetic nanoparticles [4], ligand-conjugated nanoparticles [5], and ultrasound microbubbles [6], have been developed and under investigation for their tumor target efficiency and effectiveness for cancer treatment (Table 1) [7]. However, these drug/gene delivery vehicles are limited by their several disadvantages. For example, the magnetic nanoparticles have low drug loading capacities, non-uniform particle size distribution, and are prone to form agglomerates that may lead to an occlusion of capillaries [4]. Also, the rapid recognition and clearance of liposome themselves by the reticuloendothelial system (RES) from blood stream, limited the usefulness of liposomes as drug carriers (Table 1).
Cell-based therapies are emerging as a promising therapeutic option for cancer treatment. However, the clinical application of differentiated cells is hindered by the difficulty in obtaining a large quantity of cell number, their lack of ability to expand in vitro, as well as the poor engraftment efficiency to targeted tumor sites. Mesenchymal stem cells (MSCs) have been attractive cell therapy vehicles for the delivery of agents into tumor cells because of their capability of self-renewal, relative ease of isolation and expansion in vitro, and homing capacity allowing them to migrate toward and engraft into the sites of tumor [36]. Several studies have provided evidences supporting the rationale for genetically modified MSC to deliver therapeutic cytokines directly into the tumor microenvironment to produce high concentrations of anti-tumor proteins at the tumor sites, which have been shown to inhibit tumor growth in experimental animal models. The anti-tumor effects of intravenous injections of gene-modified MSCs have been demonstrated in lung, brain, and subcutaneous tumors [33], [34], [35], [37].
Section snippets
The gene recombination of MSC
To develop MSCs as therapeutic agents, efficient gene transfer to the cells is a prerequisite. The strategies for gene delivery into MSCs include using viral vectors, non-viral vectors and three dimensional/reverse transfection systems.
Rationale for using MSCs as a vehicle for gene delivery
In 1987, Friedenstein et al. [63] found the bone marrow single-cell can differentiate into bone, cartilage-forming, adipocytes cells under certain conditions. These cells retain the ability of forming bone and cartilage after being transplanted in diffusion chambers after 20–30 cell doublings in vitro, and were called as mesenchymal stem cells or bone marrow stromal cells. Mesenchymal stem cells could also be isolated from other tissues, such as adipose tissue [64] and placenta [65]. It was
Future perspectives
Targeted delivery of anticancer drugs/genes to tumor cells/tissues can improve the therapeutic index of drugs by minimizing their toxic effects. Currently, a variety of delivery systems have been employed for developing TDDS for anticancer agents to enhance their therapeutic values [103]. For instance, nanocarrier drug delivery systems were designed to reach target cells and tissues or respond to stimuli in a well-controlled manner to induce desired physiological responses [7]. Also, cell- or
Acknowledgement
This work was financially supported by National Natural Science Foundation of China (30873173, 30973648), Zhejiang Provincial Natural Science Foundation of China (R2090176) and China–Japan Scientific Cooperation Program (81011140077) supported by both NSFC, China and JSPS, Japan. We would like to thank Dr. Guping Tang (Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University) for providing Cyd and TAT-cyd and thank Ms. Cai-Xia He for technical assistance.
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