Intratumoral therapy of glioblastoma multiforme using genetically engineered transferrin for drug delivery.
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with median survival of only 12 to 15 months under the current standard of care. To both increase tumor specificity and decrease nonspecific side effects, recent experimental strategies in the treatment of GBM have focused on targeting cell surface receptors, including the transferrin (Tf) receptor, that are overexpressed in many cancers. A major limitation of Tf-based therapeutics is the short association of Tf within the cell to deliver its payload. We previously developed two mutant Tf molecules, K206E/R632A Tf and K206E/K534A Tf, in which iron is locked into each of the two homologous lobes. Relative to wild-type Tf, we showed enhanced delivery of diphtheria toxin (DT) from these mutants to a monolayer culture of HeLa cells. Here, we extend the application of our Tf mutants to the treatment of GBM. In vitro treatment of Tf mutants to a monolayer culture of glioma cells showed enhanced cellular association as well as enhanced delivery of conjugated DT. Treatment of GBM xenografts with mutant Tf-conjugated DT resulted in pronounced regression in vivo, indicating their potential use as drug carriers.
Yoon
Dennis J
DJ
Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.
Kwan
Byron H
BH
Chao
Felix C
FC
Nicolaides
Theodore P
TP
Phillips
Joanna J
JJ
Lam
Gretchen Y
GY
Mason
Anne B
AB
Weiss
William A
WA
Kamei
Daniel T
DT
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D004167:Diphtheria Toxin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D014168:Transferrin / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D004167:Diphtheria Toxin; D000922:Immunotoxins; D011994:Recombinant Proteins; D014168:Transferrin
J Neurooncol. 2003 Oct;65(1):3-13
14649881
J Biol Chem. 1988 Jan 25;263(3):1295-300
3257214
Semin Immunol. 2008 Oct;20(5):267-75
18539480
Neurosurg Focus. 2006 Apr 15;20(4):E5
16709036
Protein Expr Purif. 2001 Oct;23(1):142-50
11570856
J Clin Neurosci. 2004 Nov;11(8):807-18
15519855
Cancer Res. 1994 Dec 15;54(24):6387-94
7987833
Biochemistry. 1998 Jun 2;37(22):7919-28
9609685
J Control Release. 2009 Feb 10;133(3):178-84
18992290
Biochemistry. 1999 Jul 27;38(30):9704-11
10423249
Nature. 1984 Nov 8-14;312(5990):162-3
6095085
Biochemistry. 1993 Sep 14;32(36):9398-406
8369310
J Biol Inorg Chem. 2009 Jun;14(5):771-81
19290554
Curr Treat Options Neurol. 2009 Jul;11(4):297-305
19523355
J Clin Pathol. 1983 May;36(5):539-45
6302135
Biochemistry. 2002 Jul 30;41(30):9448-54
12135367
J Clin Oncol. 2002 Mar 1;20(5):1389-97
11870184
Oncogene. 2005 Jan 27;24(5):829-37
15580296
Nat Med. 1997 Dec;3(12):1362-8
9396606
Agressologie. 1980;21(1):27-30
6263123
Pharmacol Rev. 2002 Dec;54(4):561-87
12429868
J Biol Chem. 1983 Apr 25;258(8):4715-24
6300098
Blood. 1990 May 15;75(10):1903-19
2186818
Neurotherapeutics. 2009 Jul;6(3):539-46
19560743
Int J Biochem Cell Biol. 1999 Oct;31(10):1111-37
10582342
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2076-80
8134351
J Neurosurg. 1994 Mar;80(3):520-6
8113865
N Engl J Med. 2008 Jul 31;359(5):492-507
18669428
Eur J Clin Invest. 2002 Mar;32 Suppl 1:61-9
11886434
J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
2359136
Tohoku J Exp Med. 1987 Nov;153(3):239-43
3433281
Biochemistry. 2003 Apr 8;42(13):3701-7
12667060
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009
J Control Release. 2007 Feb 26;117(3):403-12
17239470