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A non invasive method for obtaining rna from buccal mucosa epithelial cells for gene expression profiling

Novel method for increasing the selective localization of Photodynamic Therapy (PDT)
dyes using the nuclear estrogen receptor (ER) as a target

Photodynamic therapy (PDT) is an established method for the treatment of cancer. However,
developing an effective method for selective targeting of PDT-dyes has proved difficult. The invention
describes a novel method for significantly increasing selective localization of PDT dyes, and identifies specific
compounds to be used.
Introduction: Estrogen Receptor (ER) provides a viable target for the selective breast tumor delivery of
drugs/toxins, because breast tumor cells express ER in higher levels than other tissues, particularly in the earlier
stages of malignancy and under post-operative hormone-treatment. Therefore, conjugates of estrogen/anti-
estrogen and toxins are viable candidates for selective tumor-delivery. However, such conjugates migrate into
any cell that expresses ER (although to a higher extent to tumor cells due to the presence of significantly more
copies of ER than normal cells expressing ER). Therefore, some selectivity is achieved, but not to the extent
that is required for selective tumor cell-killing. The inventors hypothesized that (1) a synthetic conjugate of
estradiol and a porphyrin might combine the high-affinity binding of estrogen for endogenous ER, and natural
tumor localization property of porphyrin to localize the conjugate into tumor with much higher degree of
selectivity than what is achievable with estrogen-mimics and porphyrins individually, and (2) such a process
could effectively lower the concentration of porphyrin required for desired cell-killing. Therefore, there would
be significantly less systemic photo-toxicity.
Stage of Development:
Proof of Principle Experiments strongly supported the hypotheses that ER containing breast tumor cells would
selectively take up the estradiol-porphyrin conjugate, and such a process might lower the amount of porphyrin
(in the form of conjugate) required for a selective cell killing. Specifically, experiments included:
• Coupled chlorin e6, a known photo-toxin, to a derivative of C17-α-alkynylestradiol to make an estrogen-
porphyrin conjugate which bounds to ER in a specific and dose-dependent manner. Furthermore, this conjugate was taken up by ER-positive MCF-7 cells in a dose-dependent manner, but not the parent porphyrin i.e. chlorin e6-dimethyl ester, while there was low and dose-independent uptake of estrogen-chlorin e6 conjugate or chlorin e6-dimethyl ester by ER-negative MDA-MD-231 cells. • In addition, exposure of ER containing MCF-7 cells, incubated with the conjugate, induced strong cell killing. In contrast, cells (MCF-7 and MDA-MB-231) that were kept in the dark, or cells that did not contain ER (MDA-MB 231) showed very little cell death.
The invention is not limited to the estrogen receptor interaction system. This method of selective delivery
might be adopted to target other nuclear receptors by coupling an appropriate ligand to a drug or toxin e.g.
androgen and porphyrin for hormone-sensitive prostate cancer.
Intellectual Property: US patent application under prosecution (US20030220313). No foreign rights
Publications: James, DA et al. Synthesis and Estrogen Receptor Binding Affinity of A Porphyrin-Estradiol
Conjugate for Targeted Photodynamic Therapy of Cancer. Bioorg. Med. Chem. Lett 9 (1999)2379-2384
Inventors: Rahul Ray, Scott Mohr and Narasimha Swamy
OTT Contact: Catherine Ives Tel: (617) 358-4550 Fax: (617) 358-5001 em



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