Elsevier

Journal of Controlled Release

Volume 147, Issue 2, 15 October 2010, Pages 154-162
Journal of Controlled Release

Review
Mesenchymal stem cells: A promising targeted-delivery vehicle in cancer gene therapy

https://doi.org/10.1016/j.jconrel.2010.05.015Get rights and content

Abstract

The targeting drug delivery systems (TDDS) have attracted extensive attention of researchers in recent years. More and more drug/gene targeted delivery carriers, such as liposome, magnetic nanoparticles, ligand-conjugated nanoparticles, microbubbles, etc., have been developed and under investigation for their application. However, the currently investigated drug/gene carriers have several disadvantages, which limit their future use in clinical practice. Therefore, design and development of novel drug/gene delivery vehicles has been a hot area of research. Recent studies have shown the ability of mesenchymal stem cells (MSCs) to migrate towards and engraft into the tumor sites, which make them a great hope for efficient targeted-delivery vehicles in cancer gene therapy. In this review article, we examine the promising of using mesenchymal stem cells as a targeted-delivery vehicle for cancer gene therapy, and summarize various challenges and concerns regarding these therapies.

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.

  1. Download : Download full-size image

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.

References (111)

  • K. Lee et al.

    Human mesenchymal stem cells maintain transgene expression during expansion and differentiation

    Mol. Ther.

    (2001)
  • C.W. Cho et al.

    Improvement of gene transfer to cervical cancer cell lines using non-viral agents

    Cancer Lett.

    (2001)
  • C.R. Dass et al.

    Selective gene delivery for cancer therapy using cationic liposomes: in vivo proof of applicability

    J. Control. Release

    (2006)
  • C.X. He et al.

    Non-viral gene delivery carrier and its three-dimensional transfection system

    Int. J. Pharm.

    (2010)
  • J. Jo et al.

    Non-viral gene transfection technologies for genetic engineering of stem cells

    Eur. J. Pharm. Biopharm.

    (2008)
  • H. Hosseinkhani et al.

    Combination of 3D tissue engineered scaffold and non-viral gene carrier enhance in vitro DNA expression of mesenchymal stem cells

    Biomaterials

    (2006)
  • T.C. Mackenzie et al.

    Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep

    Blood Cells Mol. Dis.

    (2001)
  • T. Saito et al.

    Xenotransplant cardiac chimera: immune tolerance of adult stem cells

    Ann. Thorac. Surg.

    (2002)
  • S. Yip et al.

    Neural stem cells as novel cancer therapeutic vehicles

    Eur. J. Cancer

    (2006)
  • D. Hanahan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • I. Sekiya et al.

    BMP-6 enhances chondrogenesis in a subpopulation of human marrow stromal cells

    Biochem. Biophys. Res. Commun.

    (2001)
  • Y. Chen et al.

    Mesenchymal stem cells: a promising candidate in regenerative medicine

    Int. J. Biochem. Cell Biol.

    (2008)
  • J. Xiang et al.

    Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma

    Cytotherapy

    (2009)
  • X. Chen et al.

    A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs

    Mol. Ther.

    (2008)
  • S. Einhorn et al.

    Why do so many cancer patients fail to respond to interferon therapy?

    J. Interferon Cytokine Res.

    (1996)
  • H. Okada et al.

    Cytokine gene therapy for malignant glioma

    Expert Opin. Biol. Ther.

    (2004)
  • S. Moritake et al.

    Functionalized nano-magnetic particles for an in vivo delivery system

    J. Nanosci. Nanotechnol.

    (2007)
  • D. Peer et al.

    Nanocarriers as an emerging platform for cancer therapy

    Nat. Nanotechnol.

    (2007)
  • K. Yachi et al.

    Pharmaceutical and biological properties of doxorubicin encapsulated in liposomes (L-ADM): the effect of repeated administration on the systemic phagocytic activity and pharmacokinetics

    Biopharm. Drug Dispos.

    (1995)
  • A. Samad et al.

    Liposomal drug delivery systems: an update review

    Curr. Drug Deliv.

    (2007)
  • O.P. Medina et al.

    Targeted liposomal drug delivery in cancer

    Curr. Pharm. Des.

    (2004)
  • J.K. Vasir et al.

    Targeted drug delivery in cancer therapy

    Technol. Cancer Res. Treat.

    (2005)
  • Y. Liu et al.

    Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles

    Int. J. Cancer

    (2007)
  • J.M. Tsutsui et al.

    The use of microbubbles to target drug delivery

    Cardiovasc. Ultrasound

    (2004)
  • A.C. Lo Prete et al.

    Evaluation in melanoma-bearing mice of an etoposide derivative associated to a cholesterol-rich nano-emulsion

    J. Pharm. Pharmacol.

    (2006)
  • G. Han et al.

    Functionalized gold nanoparticles for drug delivery

    Nanomedicine (Lond.)

    (2007)
  • L.G. Remsen et al.

    Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model

    Neurosurgery

    (2000)
  • V. Guillemard et al.

    Taxane-antibody conjugates afford potent cytotoxicity, enhanced solubility, and tumor target selectivity

    Cancer Res.

    (2001)
  • A. Muvaffak et al.

    Preparation and characterization of a biodegradable drug targeting system for anticancer drug delivery: microsphere-antibody conjugate

    J. Drug Target

    (2005)
  • R. Suzuki et al.

    Development of effective antigen delivery carrier to dendritic cells via Fc receptor in cancer immunotherapy

    Yakugaku Zasshi

    (2007)
  • S. Ni et al.

    Folate receptor targeted delivery of liposomal daunorubicin into tumor cells

    Anticancer Res.

    (2002)
  • X.Q. Pan et al.

    In vivo antitumor activity of folate receptor-targeted liposomal daunorubicin in a murine leukemia model

    Anticancer Res.

    (2005)
  • X.Q. Pan et al.

    Antitumor activity of folate receptor-targeted liposomal doxorubicin in a KB oral carcinoma murine xenograft model

    Pharm. Res.

    (2003)
  • C. Alexiou et al.

    Medical applications of magnetic nanoparticles

    J. Nanosci. Nanotechnol.

    (2006)
  • C. Alexiou et al.

    Targeting cancer cells: magnetic nanoparticles as drug carriers

    Eur. Biophys. J.

    (2006)
  • S.C. Goodwin et al.

    Single-dose toxicity study of hepatic intra-arterial infusion of doxorubicin coupled to a novel magnetically targeted drug carrier

    Toxicol. Sci.

    (2001)
  • M. Babincova et al.

    Magnetic drug delivery and targeting: principles and applications

    Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub.

    (2009)
  • S.C. McBain et al.

    Magnetic nanoparticles for gene and drug delivery

    Int. J. Nanomedicine

    (2008)
  • K. Harrington et al.

    Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery?

    Hum. Gene Ther.

    (2002)
  • S.H. Thorne et al.

    Combining immune cell and viral therapy for the treatment of cancer

    Cell. Mol. Life Sci.

    (2007)
  • Cited by (0)

    View full text