Aminopeptidase P Mediated Targeting for Breast Tissue Specific Conjugate Delivery

Abstract

Cytotoxic chemotherapies are used to treat breast cancer, but are limited by systemic toxicity. The key to addressing this important issue is the development of a nontoxic, tissue selective, and molecular specific delivery system. In order to potentially increase the therapeutic index of clinical reagents, we designed an Aminopeptidase P (APaseP) targeting tissue-specific construct conjugated to a homing peptide for selective binding to human breast-derived cancer cells. Homing peptides are short amino acid sequences derived from phage display libraries that have the unique property of localizing to specific organs. Our molecular construct allows for tissue-specific drug delivery, by binding to APaseP in the vascular endothelium. The breast homing peptide evaluated in our studies is a cyclic nine-amino-acid peptide with the sequence CPGPEGAGC, referred to as PEGA. We show by confocal microscopy that the PEGA peptide and similar peptide conjugates distribute to human breast tissue xenograft specifically and evaluate the interaction with the membrane-bound proline-specific APaseP (KD = 723 ± 3 nM) by binding studies. To achieve intracellular breast cancer cell delivery, the incorporation of the Tat sequence, a cell-penetrating motif derived from HIV, was conjugated with the fluorescently labeled PEGA peptide sequence. Ultimately, tissue specific peptides and their conjugates can enhance drug delivery and treatment by their ability to discriminate between tissue types. Tissue specific conjugates as we have designed may be valuable tools for drug delivery and visualization, including the potential to treat breast cancer, while simultaneously minimizing systemic toxicity.

Serum Levels of Alanine Aminopeptidase and Aggrecan in Women with Breast Cancer: A Comparative Study

“…(21) In the present study it was found that there were an increase in the weight of women with breast cancer more than that of the control group. The mean of BMI in breast cancer women that show in table (3), this finding was consistence with Platet N. et al (22) and Rebbeck R. et al (23) who reported a high prevalence of overweight and obesity in women with breast cancer. Epidemiological studies have shown that postmenopausal obesity causes an increase in the risk of breast cancer, (24) since the obesity has a close relationship with increased levels of insulin and insulin like growth factors.…”

“…(11) Alanine aminopeptidase spreads in various regions of mammalian body, because it is responsible for many physiological functions inside the human body, like kidney, pancreas, liver, (12) and intestine specially in duodenum. (13) Aggrecan (ACAN) is a proteoglycan that present in all cellular and tissue compartments. It is one of the major structural component of cartilage therefore it is known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1 (may have >100 chondroitin sulphate chain) which are key to its function in the maintenance of a hydrated, compression-resisting matrix.…”