Linked Life Data

9548533

Source:http://linkedlifedata.com/resource/pubmed/id/9548533

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1998-5-28
pubmed:abstractText
The uptake of macromolecular agents in tumor cells (LX-1, human small cell lung carcinoma) and in corresponding tumor xenografts was compared in a parallel study utilizing a long-circulating biocompatible graft copolymer, MPEGs-PL-DTPA [Bogdanov, A., Jr., et al. (1995) Adv. Drug Delivery Rev. 16, 335-348; Bogdanov, A., Jr., et al. (1996) Bioconjugate Chem. 7, 144-149] and a tumor-specific chimeric monoclonal antibody, BR96 [Hellstrom, I., et al. (1990) Cancer Res. 50, 2183-2190; Garrigues, J., et al. (1993) Am. J. Pathol. 142, 607-622]. Covalent grafted conjugates of methoxy-(polyethylene glycol)succinate and polylysine and BR96 were modified with DTPA, biotinyl, or rhodamine-X-residues. Using radionuclide and fluorescent labeled derivatives of the copolymer and the antibody, we established that (1) the copolymer does not associate with the plasma membrane in N-ethylmaleimide-treated cells and is slowly internalized by live cells at 37 degrees C; (2) the antibody binds rapidly to the surface of LX-1 cells and shows active internalization in vesicles with a subsequent slow decrease in the cell-associated antibody concentration; (3) LX-1 cells bear more than 1 million BR96 binding sites/cell (with an apparent Kd of 4.5 x 10[-7] M); and (4) intravesicular fluorescence intensity in LX-1 cells was linearly dependent on copolymer concentration, suggesting fluid phase endocytosis. Tumor localization by nuclear imaging, biodistribution, microdistribution by histology, and determination of tumor cell fraction uptake was performed in LX-1 tumor xenografts. In vivo study showed that MPEGs-PL-DTPA progressively accumulates in the tumor, yielding from 2.8+/-1.5% injected dose per gram of tissue (ID/g) at 24 h to 5.2+/-1.7% ID/g of tissue at 48 h. The antibody accumulation peaked at 24 h (6.0+/-3.2% ID/g) and decreased thereafter. We determined that at 24 h 43.9+/-11.29% of the polymer accumulated in the tumor was associated with tumor cell fraction with the remainder of the accumulated dose localized in the interstitium. Accumulation of the biotinylated graft copolymer and the antibody in LX-1 xenografts and their uptake in cells were confirmed by histology using avidin-peroxidase staining. Our study demonstrates that, although BR96 is highly specific in vitro, tumoral drug delivery in vivo can be equally high with long-circulating graft copolymers because of slow extravasation at the tumor site.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1043-1802
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
184-91
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9548533-Animals, pubmed-meshheading:9548533-Antibodies, Monoclonal, pubmed-meshheading:9548533-Antineoplastic Agents, pubmed-meshheading:9548533-Biotinylation, pubmed-meshheading:9548533-Carcinoma, Small Cell, pubmed-meshheading:9548533-Female, pubmed-meshheading:9548533-Fluorescent Dyes, pubmed-meshheading:9548533-Humans, pubmed-meshheading:9548533-Immunotoxins, pubmed-meshheading:9548533-Indium Radioisotopes, pubmed-meshheading:9548533-Lung Neoplasms, pubmed-meshheading:9548533-Mice, pubmed-meshheading:9548533-Mice, Nude, pubmed-meshheading:9548533-Microscopy, Fluorescence, pubmed-meshheading:9548533-Neoplasm Transplantation, pubmed-meshheading:9548533-Polyethylene Glycols, pubmed-meshheading:9548533-Tissue Distribution, pubmed-meshheading:9548533-Tumor Cells, Cultured
pubmed:articleTitle
Antibody-mediated versus nontargeted delivery in a human small cell lung carcinoma model.
pubmed:affiliation
Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Boston 02129, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't