This report describes the synthesis of four novel paclitaxel based prodrugs with glycan conjugation (1-4). Glycans were conjugated using an ester or ether bond as the linker between 2'-paclitaxel and the 2'-glucose or glucuronic acid moiety. These prodrugs showed good water solubility and selective cytotoxicity against cancer cell lines, but showed reduced toxicity toward normal cell lines and cancer cell lines with low expression levels of GLUTs. The ester conjugated prodrug 1 showed the most cytotoxicity among the prodrugs examined and could be transported into cells via GLUTs. Fluorescent and confocal microscopy demonstrated that targeted cells exhibited morphological changes in tubulin and chromosomal alterations that were similar to those observed with paclitaxel treatment. Therefore, these glycan-based prodrugs may be good drug candidates for cancer therapy, and the glycan conjugation approach is an alternative method to enhance the targeted delivery of other drugs to cancer cells that overexpress GLUTs.

Tumor secreted substances (secretome), including extracellular matrix (ECM) components, act as mediators of tumor-host communication in the breast tumor microenvironment. Proteomic analysis has emphasized the value of the secretome as a source of prospective markers and drug targets for the treatment of breast cancers. Utilizing bioinformatics, our recent studies revealed global changes in protein expression after the activation of ECM-mediated signaling in breast cancer cells. A newly designed technique integrating a capillary ultrafiltration (CUF) probe with mass spectrometry was demonstrated to dynamically sample and identify in vivo and pure secretome from the tumor microenvironment. Such in vivo profiling of breast cancer secretomes may facilitate the development of novel drugs specifically targeting secretome.