We have synthesized a series of novel prodrugs consisting of amphiphilic heparin-paclitaxel conjugates. Each prodrug in the series consists of a succinylated-heparin carrier conjugated to paclitaxel via a single amino acid spacer, either valine, leucine, or phenylalanine (prodrug1, prodrug2, and prodrug3, respectively). Unlike physically encapsulated drugs, these prodrugs can self-assemble to form nanoparticles in aqueous solution while still maintaining structural integrity for loading parent drug due to the dual hydrophilic/hydrophobic nature of the carrier and drug compound. The structure of prodrugs has been characterized by 1H NMR, FT-IR, and GPC. Their morphology has been investigated by SEM. Our results show that these self-assembled nanoparticles have a narrow size distribution (140-180 nm) and form an approximately spherical shape composed of a paclitaxel core and carrier shell. The anticoagulant activity of all the prodrugs is sharply decreased compared to that of heparin, as measured by activated partial thromboplastin time (aPTT), thereby reducing the risk of severe hemorrhagic complication during systemic administration. Furthermore, the prodrugs exhibit better in vitro cell inhibition for MCF-7 cells than free paclitaxel. Flow cytometric analyses (FCM) have shown that MCF-7 cells treated with prodrugs are arrested in the G(2)/M phase of the cell cycle. Meanwhile, these three prodrugs each exhibit unique hydrolysis properties under various physiological or plasma conditions. In particular, prodrug2 with leucine spacer may result in favorable hydrolysis of the ester bond between the amino acid and paclitaxel under physiological conditions. In mice, prodrug2 shows a similar ovarian tumor growth inhibition as paclitaxel and induces no obvious body weight loss. Hence, the prepared nanoscale prodrugs are expected not only to render structural integrity to the parent drug, but also enhance targeting capacity to solid tumors.

Prodrugs synthesized as HA-amino acid-paclitaxel conjugates exhibited enhanced cytotoxicity in breast cancer cell lines and hence may have potential application as tumor-specific nanoparticulate therapeutic agents.

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Amino acids as linkers between paclitaxel and carrier are appropriate to facilitate the release of paclitaxel from carrier. Mixed anhydrides mediate the synthesis of prodrugs and HD2 conjugates are expected to further investigate in vivo experiment.

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