Targeting and inhibition of cell growth by an engineered dendritic nanodevice

被引：225

作者：

Thomas, TP ^{[1
]}

Majoros, IJ ^{[1
]}

Kotlyar, A ^{[1
]}

Kukowska-Latallo, JF ^{[1
]}

Bielinska, A ^{[1
]}

Myc, A ^{[1
]}

Baker, JR ^{[1
]}

机构：

[1] Univ Michigan, Sch Med, Ctr Biol Nanotechnol, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 11期

关键词：

D O I：

10.1021/jm040187v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cellular uptake and cytotoxicity of an engineered multifunctional dendritic nanodevice containing folic acid (FA) as the targeting molecule, methotrexate (MTX) as the chemotherapeutic drug, and fluorescein (FI) as the detecting agent were studied in vitro. FI and FA were conjugated to the generation 5 poly(amidoamine) (G5) dendrimer carrier through a thiourea and amide linkage and MTX was conjugated through an ester linkage to the carrier to generate the trifunctional dendritic device, G5-FI-FA-MTX. This trifunctional dendrimer-drug conjugate bound to FA receptor-expressing KB cells in a dose-dependent and saturable manner. Confocal microscopic analysis demonstrated cellular internalization of the conjugate. G5-FI-FA-MTX induced a time- and dose-dependent inhibition of cell growth in KB cells. The targeted dendrimer conjugates G5-FI-FA-MTX and G5-FA-MTX inhibited cell growth in KB cells, whereas the nontargeted G5-MTX failed to induce growth inhibition. These studies show the potential of G5-FI-FA-MTX or G5-FA-MTX for targeting and growth suppression of tumor cells that overexpress FA-receptors.

引用

页码：3729 / 3735

页数：7

共 58 条

[1]

ANTONY AC, 1985, J BIOL CHEM, V260, P4911

[2] Folate receptors [J].

Antony, AC .

ANNUAL REVIEW OF NUTRITION, 1996, 16 :501-521

[3] IDENTIFICATION OF METHOTREXATE TRANSPORT DEFICIENCY IN MAMMALIAN-CELLS USING FLUORESCEINATED METHOTREXATE AND FLOW-CYTOMETRY [J].

ASSARAF, YG ;

SCHIMKE, RT .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (20) :7154-7158

[4] Regulation of in vitro gene expression using antisense oligonucleotides or antisense expression plasmids transfected using starburst PAMAM dendrimers [J].

Bielinska, A ;

KukowskaLatallo, JF ;

Johnson, J ;

Tomalia, DA ;

Baker, JR .

NUCLEIC ACIDS RESEARCH, 1996, 24 (11) :2176-2182

[5] Nanoparticles in cancer therapy and diagnosis [J].

Brigger, I ;

Dubernet, C ;

Couvreur, P .

ADVANCED DRUG DELIVERY REVIEWS, 2002, 54 (05) :631-651

[6] Folate status and the safety profile of antifolates [J].

Calvert, H .

SEMINARS IN ONCOLOGY, 2002, 29 (02) :3-7

[7]

Corona G, 1998, INT J CANCER, V75, P125, DOI 10.1002/(SICI)1097-0215(19980105)75:1<125::AID-IJC19>3.0.CO

[8]

2-F

[9] ROLE OF THE MEMBRANE-ASSOCIATED FOLATE BINDING-PROTEIN (FOLATE RECEPTOR) IN METHOTREXATE TRANSPORT BY HUMAN KB CELLS [J].

DEUTSCH, JC ;

ELWOOD, PC ;

PORTILLO, RM ;

MACEY, MG ;

KOLHOUSE, JF .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1989, 274 (02) :327-337

[10]

ELWOOD PC, 1986, J BIOL CHEM, V261, P5416

← 1 2 3 4 5 6 →