[Lys(DOTA)(4)]BVD15, a novel and potent neuropeptide Y analog designed for Y-1 receptor-targeted breast tumor imaging
ABSTRACT We substituted a truncated neuropeptide Y (NPY) analog, [Pro(30), Tyr(32), Leu(34)]NPY(28-36)NH(2) also called BVD15, at various positions with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid) and evaluated the effect of the coupling position with the binding affinity for NPY Y(1) receptors (NPY1R). Our data suggest that [Lys(DOTA)(4)]BVD15 (K(i)=63+/-25 nM vs. K(i)=39+/-34 nM for BVD15) is a potent NPY analog suitable for radiolabeling with metallo positron emitters for PET imaging of breast cancer.
SourceAvailable from: Zheyu Shen[Show abstract] [Hide abstract]
ABSTRACT: By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or co-expression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that significantly over-expressed on the surface of the breast cancer cells, and the drug loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is high selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells express Y2 receptors only. It is anticipated that this study may provide a guidance to develop Y1 receptors based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.ACS Applied Materials & Interfaces 02/2015; 7(9):5574–5582. DOI:10.1021/acsami.5b00270 · 5.90 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) Y1 receptors are overexpressed in human breast carcinomas. They also have important functional roles in breast tumour growth and metastasis. This study investigates the synthesis of 15 truncated NPY analogues as models for Y1 receptor specific radiopharmaceuticals, using competition radioreceptor binding assays from brain tissue homogenates from Y2Y4-double knockout mice. These peptides are based on the previously reported BVD15 scaffold. Different measures to improve Y1 affinity and plasma metabolic stability were investigated. Extending from the previously reported [Lys(DOTA)4]BVD15 analogue, it was found that lysine4 is capable of tolerating various modifications, including prosthetic groups and other bifunctional chelators, but also that [Lys4]BVD15 has improved Y1 affinity, relative to BVD15 itself. Substitution of lysine4 for side chain shortened analogues retains Y1 receptor affinity of the analogues. Furthermore, modifications at the N-terminal isoleucine resulted in dramatic reduction of Y1 affinity.International Journal of Peptide Research and Therapeutics 01/2013; 19(1). DOI:10.1007/s10989-012-9330-z · 0.83 Impact Factor
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ABSTRACT: The potent Y1 receptor antagonist, 1229U91 has an unusual cyclic dimer structure that makes syntheses of analogue series quite challenging. We have examined three new routes to the synthesis of such peptides that has given access to novel structural variants including heterodimeric compounds, ring size variants and labelled conjugates. These compounds, including a fluorescently labelled analogue VIII show potent antagonism that can be utilised in studying Y1 receptor pharmacology.Organic & Biomolecular Chemistry 04/2014; DOI:10.1039/c4ob00176a · 3.49 Impact Factor