Folate receptor-mediated targeted polymeric gadolinium complexes for magnetic resonance imaging in pulmonary tumor xenografts

Yuan,Zheng; Li,Wen-Tao; Ye,Xiao-Dan; Liu,Shi-Yuan; Xiao,Xiang-Sheng

doi:10.3892/etm.2012.504

Folate receptor-mediated targeted polymeric gadolinium complexes for magnetic resonance imaging in pulmonary tumor xenografts

Authors:
- Zheng Yuan
- Wen-Tao Li
- Xiao-Dan Ye
- Shi-Yuan Liu
- Xiang-Sheng Xiao
View Affiliations

Affiliations: Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Radiology, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200030, P.R. China, Department of Radiology, Affiliated Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
Published online on: March 5, 2012 https://doi.org/10.3892/etm.2012.504
Pages: 903-907

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Targeted delivery is a highly desirable strategy for diagnostic imaging due to enhanced efficacy and reduced dosage/toxicity. The need to develop target-specific magnetic resonance imaging (MRI) contrast agents to aid in disease characterization is highly essential. In this study, a specific contrast agent, Gd-DTPA-poly-L-lysine (PL-Gd-DTPA)-folate, was synthesized and evaluated for its efficacy as a targeted agent for the imaging of tumors that overexpress the folate receptor. Folic acid was conjugated to PL-Gd-DTPA via the ε-amino groups. The receptor binding properties of folate-PL-Gd-DTPA were studied in cultured tumor cells that overexpressed the folate receptor. The tumor-selecting properties of folate-PL-Gd-DTPA were then evaluated in BALB/c mice bearing subcutaneously implanted folate receptor-positive tumors. Tissue MR signal intensities were measured at six different time-points. In the in vitro study, the folate-PL-Gd-DTPA was able to bind to these cells, which overexpressed the folate receptor, as with free folic acid. Excellent tumor selectivity was also shown in the animal model; after the success of injection of folate-PL-Gd-DTPA, a maximum intensity increase of 125.4% was observed from pre-injection compared to post‑injection images of the tumor at the 48 h time-point. The liver enhancement was non-specific and the muscle signal intensity at any time-point after injection showed no statistical difference with that observed before injection. Folate-PL-Gd‑DTPA is a promising, novel receptor-specific MRI contrast agent with potential applications in the imaging of human folate receptor-positive tumors.

View Figures

View References

1.	Moghimi SM and Rajabi-Siahboomi AR: Recent advances in cellular, subcellular and molecular targeting. Adv Drug Deliv Rev. 41:129–133. 2000. View Article : Google Scholar : PubMed/NCBI
2.	Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R and Cheresh DA: Tumor regression by targeted gene delivery to the neovasculature. Science. 296:2404–2407. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D and Conley PB: Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 409:202–207. 2001. View Article : Google Scholar : PubMed/NCBI
4.	Low RN, Saleh F, Song SYT, Shiftan TA, Barone RM, Lacey CG and Goldfarb PM: Treated ovarian cancer: comparison of MR imaging with serum CA-125 level and physical examination – a longitudinal study. Radiology. 211:519–528. 1999.PubMed/NCBI
5.	Ke CY, Mathias CJ and Green MA: The folate receptor as a molecular target for tumor-selective radionuclide delivery. Nucl Med Biol. 30:811–817. 2003. View Article : Google Scholar : PubMed/NCBI
6.	Brasch RC: Rationale and applications for macromolecular Gd-based contrast agents. Magn Reson Med. 22:282–287. 1994. View Article : Google Scholar : PubMed/NCBI
7.	Unger EC, Totty WG, Neufeld DM, Otsuka FL, Murphy WA, Welch MS, Connett JM and Philpott GW: Magnetic resonance imaging using gadolinium labeled monoclonal antibody. Invest Radiol. 20:693–700. 1985. View Article : Google Scholar : PubMed/NCBI
8.	Gohr-Rosenthal S, Schmit-Willich H, Ebert W and Conrad J: The demonstration of human tumors on nude mice using gadolinium-labeled monoclonal antibodies for magnetic resonance imaging. Invest Radiol. 28:789–795. 1993. View Article : Google Scholar : PubMed/NCBI
9.	Zuckier LS, Rodriguez LB and Scharff MD: Immunologic and pharmacologic concepts of monoclonal antibodies. Semin Nucl Med. 28:166–186. 1989. View Article : Google Scholar : PubMed/NCBI
10.	Leamon CP and Low PS: Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. Proc Natl Acad Sci USA. 88:5572–5576. 1991. View Article : Google Scholar : PubMed/NCBI
11.	Leamon CP and Low PS: Cytotoxicity of mormordin-folate conjugates in cultured human cells. J Biol Chem. 267:24966–24971. 1992.PubMed/NCBI
12.	Leamon CP, Pastan I and Low PS: Cytotoxicity of folate-pseudo-monas exotoxin conjugates toward tumor cells. Contribution of translocation domain. J Biol Chem. 268:24847–24854. 1993.PubMed/NCBI
13.	Antony AC: Folate receptors. Annu Rev Nutr. 16:501–521. 1996. View Article : Google Scholar
14.	Garin-Chesa P, Campbell I, Saigo PE, Lewis JL Jr, Old LJ and Rettig WJ: Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. Am J Pathol. 142:557–567. 1993.PubMed/NCBI
15.	Ross JF, Chaudhuri PK and Ratnam M: Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications Cancer. 73:2432–2443. 1994.PubMed/NCBI
16.	Lu Y and Low PS: Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev. 54:675–693. 2002. View Article : Google Scholar : PubMed/NCBI
17.	Sudimack J and Lee RJ: Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev. 41:147–162. 2000. View Article : Google Scholar : PubMed/NCBI
18.	Xu L, Pirollo KF and Chang EH: Tumor-targeted p53-gene therapy enhances the efficacy of conventional chemo/radiotherapy. J Control Release. 74:115–128. 2001. View Article : Google Scholar : PubMed/NCBI
19.	Maziarz KM, Monaco HL, Shen F and Ratnam M: Complete mapping of divergent amino acids responsible for differential ligand binding of folate receptors alpha and beta. J Biol Chem. 274:11086–11091. 1999. View Article : Google Scholar : PubMed/NCBI
20.	Shen F, Ross JF, Wang X and Ratnam M: Identification of a novel folate receptor, a truncated receptor, and receptor type in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochem. 33:1209–1215. 1994. View Article : Google Scholar : PubMed/NCBI
21.	Yuan Z, Liu SY, Xiao XS, Zhong GR and Jiang QJ: Folate-poly-L-lysine-Gd-DTPA as MR contrast agent for tumor imaging via folate receptor-targeted delivery. Zhonghua Yi Xue Za Zhi. 87:673–678. 2007.(In Chinese).
22.	Brasch RC: Rationale and applications for macromolecular Gd-based contrast agents. Magn Reson Med. 22:282–287. 1991. View Article : Google Scholar : PubMed/NCBI
23.	Jain RK: Transport of molecules in the tumor interstitium: a review. Cancer Res. 47:3039–3051. 1987.PubMed/NCBI
24.	Rijnboutt S, Jansen G, Posthuma G, Hynes JB, Schornagel JH and Strous GJ: Endocytosis of GPI-linked membrane folate-receptor-[alpha]. J Cell Biol. 132:35–47. 1996.
25.	Luhrs CA and Slomiany BL: A human membrane-associated folate binding protein is anchored by a glycosyl-phospatidylinositol tail. J Biol Chem. 264:21446–21449. 1989.PubMed/NCBI
26.	Kane MA, Elwood PC, Portilla RM, Antony AC and Kolhouse JF: The interrelationship of the soluble and membrane-associated folate-binding proteins in human KB cells. J Biol Chem. 261:15625–15631. 1986.PubMed/NCBI
27.	Antony AC: The biological chemistry of folate receptors. Blood. 79:2807–2820. 1992.PubMed/NCBI
28.	Wiener EC, Konda S, Shadron A, Brechbiel M and Gansow O: Targeting dendrimer-chelates to tumors and tumor cells expressing the high-affinity folate receptor. Invest Radiol. 32:748–754. 1997. View Article : Google Scholar : PubMed/NCBI