**4. Concluding remarks**

Ligand‐toxin molecular conjugates for cancer have been studied for several years. Though these conjugates have demonstrated some success, not many have obtained FDA approval for the treatment of cancer. The general lack of FDA‐approved ligand‐toxin conjugates may be attributed to the physiological behavior of the targeting ligand. Although ligands can effec‐ tively target cancer cells via their cell‐surface receptors, they will follow the ligand's physio‐ logical pathway once bound to receptors. For instance, the rapid recycling rate of Tf which aids in iron delivery can restrict the ability to deliver a conjugated toxin [8]. Through quanti‐

tative experiments and modeling, a more thorough understanding of the intracellular traf‐ ficking properties of various ligands can be achieved. The Kamei laboratory has used this approach to find an innovative approach to manipulating the Tf trafficking pathway for the advancement of Tf‐based cancer therapeutics [8, 9]. This example demonstrates that a systems analysis of intracellular trafficking properties can result in the engineering of effective targeting agents to cancers.

[9] Yoon D. J, Chu D. S, Ng C. W, Pham E. A, Mason A. B, Hudson D. M, Smith V. C, MacGillivray R. T, Kamei D. T. Genetically engineering transferrin to improve its in vitro ability to deliver cytotoxins. Journal of Controlled Release 2009;133 78‐184.

Transferrin-Toxin Conjugates for Cancer 319

[10] Yoon D. J, Kwan B. H, Chao F. C, Nicolaides T. P, Phillips J. J, Lam G.Y, Mason A. B, Weiss W. A, Kamei D. T. Intratumoral therapy of glioblastoma multiforme using ge‐ netically engineered transferrin for drug delivery. Cancer research 2010;70 4520‐4527.

[11] Lu Y, Low P. S. Folate targeting of haptens to cancer cell surfaces mediates immuno‐ therapy of syngeneic murine tumors. Cancer Immunol Immunother 2002;51 153‐162.

[12] Lu Y, Sega E, Low P. S. Folate receptor‐targeted immunotherapy: induction of hu‐ moral and cellular immunity against hapten‐decorated cancer cells. International

[13] Shmeeda H, Mak L, Tzemach D, Astrahan P, Tarshish M, Gabizon A. Intracellular uptake and intracavitary targeting of folate‐conjugated liposomes in a mouse lym‐ phoma model with up‐regulated folate receptors. Molecular cancer therapeutics

[14] Davis M. E, Zuckerman J. E, Choi C. H, Seligson D, Tolcher A, Alabi C. A, Yen Y, Heidel J. D, Ribas A. Evidence of RNAi in humans from systemically administered

[15] Aisen P, Leibman A, Zweier J. Stoichiometric and site characteristics of the binding of iron to human transferrin. The Journal of biological chemistry 1978;253 1930‐1937.

[16] Baker E. N, Baker H. M, Kidd R. D. Lactoferrin and transferrin: functional variations on a common structural framework. Biochemistry and cell biology = Biochimie et bi‐

[17] Cazzola M, Bergamaschi G, Dezza L, Arosio P. Manipulations of cellular iron metab‐ olism for modulating normal and malignant cell proliferation: achievements and

[18] Li H, Sun H, Qian Z. M. The role of the transferrin‐transferrin‐receptor system in drug delivery and targeting. Trends in pharmacological sciences 2002;23 206‐209.

[19] Li H, Qian Z. M. Transferrin/transferrin receptor‐mediated drug delivery. Medicinal

[20] Ponka P, Lok C. N. The transferrin receptor: role in health and disease. The interna‐

[21] Ciechanover A, Schwartz A. L, Dautry‐Varsat A, Lodish H. F. Kinetics of internaliza‐ tion and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. The Journal of biological chemistry 1983;

tional journal of biochemistry & cell biology 1999;31 1111‐1137.

siRNA via targeted nanoparticles. Nature 2010;464 1067‐1070.

journal of cancer 2005;116 710‐719.

ologie cellulaire 2002;80 27‐34.

prospects. Blood 1990;75 1903‐1919.

research reviews 2002;22 225‐250.

258 9681‐9689.

2006;5 818‐824.
