Although doxorubicin (DOX) has been widely used as an effective chemotherapeutic agent in the treatment of metastatic prostate cancer, its short half-life and circulation time as well as serious undesired side effects (e.g., alopecia, hematopoietic depression, gastrointestinal disorders, and cardiotoxicity) have deterred its further application in the clinic.
To improve the therapeutic efficacy and reduce the side effects of DOX, we synthesized a pH-responsive, luteinizing hormone-releasing hormone (LHRH)-conjugated hydroxyethyl starch-doxorubicin (HES-DOX/LHRH) prodrug by conjugating oxidized HES (HES-CHO) with DOX and LHRH analog through an acid-sensitive Schiff base bond. The resulting prodrug spontaneously assembled into nanoscopic micelle with a radius of ~ 55 nm in the aqueous environment. The HES-DOX conjugate significantly improved the in vivo tissue distribution of free DOX. Compared to its non-targeted counterpart, the targeted HES-DOX/LHRH demonstrated greater in vitro anti-proliferative capability toward RM-1 cells. More importantly, the targeted HES-DOX/LHRH exhibited higher levels of anti-tumor and anti-metastasis activities in an RM-1-xenografted mouse model, with lower systemic toxicity compared to the non-targeted HES-DOX and free DOX·HCl.
These results revealed that the LHRH-modified HES-DOX conjugate has great potential for clinical chemotherapeutic treatment of metastatic prostate cancer. Additionally, our design can be extended further by conjugating the aldehyde groups of different polysaccharides with the amino groups of various small-molecule drugs and targeting ligands to treat malignancies that express the corresponding receptors.
To the best of our knowledge, this is the first reported application of LHRH-targeted polymer-drug conjugate to the chemotherapeutic treatment of metastatic prostate cancer. We believe that this article will be of considerable interest to a wide range of researchers involved in biomaterials science, controlled drug delivery, oncology, pharmaceutics, translational medicine, and urology.
Written by: Jianxun Ding
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