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PMID: 19774344 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer.

Pharmaceutical research ·Vol. 26 ·No. 11 ·2009-11-00 ·Pages 2486-94

Thomas FC, Taskar K, Rudraraju V, Goda S, Thorsheim HR, Gaasch JA, Mittapalli RK, Palmieri D, Steeg PS, Lockman PR, Smith QR

Abstract

We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. The transfer coefficient (K(in)) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. The BBB K(in) for (125)I-ANG1005 uptake (7.3 +/- 0.2 x 10(-3) mL/s/g) exceeded that for (3)H-paclitaxel (8.5 +/- 0.5 x 10(-5)) by 86-fold. Over 70% of (125)I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain (125)I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of (125)I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of (14)C-paclitaxel by 4-54-fold. The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.

MeSH Terms
Animals Antineoplastic Agents, Phytogenic/pharmacokinetics,pharmacology Blood-Brain Barrier/metabolism Brain Neoplasms/drug therapy Breast Neoplasms/drug therapy Chromatography, High Pressure Liquid Female Mice Mice, Nude Paclitaxel/analogs & derivatives,pharmacokinetics,pharmacology Peptides Rats
Chemicals
Antineoplastic Agents, Phytogenic Peptides paclitaxel-Angiopep-2 conjugate Paclitaxel
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Thomas Fancy C
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Taskar Kunal
Rudraraju Vinay
Goda Satyanarayana
Thorsheim Helen R
Gaasch Julie A
Mittapalli Rajendar K
Palmieri Diane
Steeg Patricia S
Lockman Paul R
Smith Quentin R
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Article Info
Journal
Pharmaceutical research
Abbr.
Pharm Res
ISSN
1573-904X
DOI
10.1007/s11095-009-9964-5
Published
2009-11-00
Epub
2009-00-23
Pages
2486-94
Language
English
Region
United States
NLM ID
8406521
PMCID
PMC2896053
Subset
IM
Grants
NINDS NIH HHS · R01 NS052484 · United States
NINDS NIH HHS · R01 NS052484-04 · United States
External Links
PubMed source DOI: 10.1007/s11095-009-9964-5 PMC Full Text View journal details
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