The use of amino acid linkers in the conjugation of paclitaxel with hyaluronic acid as drug delivery system: synthesis, self-assembled property, drug release, and in vitro efficiency.

PURPOSE: A cell-targeted prodrug with good self-assembly properties in aqueous solution was prepared for the anti-cancer drug paclitaxel, offering great potential for further investigation.
METHODS: We synthesized hyaluronic acid (HA) with a specific targeting property as a carrier to conjugate with paclitaxel by inserting different amino acids as spacers, including valine, leucine, and phenylalanine, respectively. The structure of HA-amino acid-paclitaxel conjugates was characterized by (1)H NMR and GPC. The loading weight and hydrolysis rate were detected by UV and HPLC, respectively. Their morphology and mean diameter were investigated by SEM and DLS, respectively. The biological activity of HA-amino acid-paclitaxel conjugates was measured by MTT assay and flow cytometry using MCF-7 cells.
RESULTS: The use of amino acids as spacers between drug and carrier facilitated paclitaxel release from the conjugates. Their morphology demonstrated that the prepared prodrugs could self-assemble to form nanoparticles with a narrow size distribution and spherical shape. Furthermore, the prodrugs exhibited increased cytotoxicity as compared to free drug. Flow cytometry analysis showed that MCF-7 cells treated with conjugates were arrested in the G(2)/M phase of the cell cycle.
CONCLUSIONS: 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.