CD44-Targeting for Antitumor Drug Delivery: A New SN-38-Hyaluronan Bioconjugate for Locoregional Treatment of Peritoneal Carcinomatosis

A.      Serafino; M.      Zonfrillo; F.      Andreola; R.      Psaila; L.      Mercuri; N.      Moroni; D.      Renier; M.      Campisi; C.      Secchieri; P.      Pierimarchi

Abstract

An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID™-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID™-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID™-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID™-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient.

Keywords: CD44, colorectal cancer, drug delivery, hyaluronic acid, locoregional treatment, peritoneal carcinomatosis, target therapy, confocal laser scanning microscopy, camptothecin, 7-ethyl-10-hydroxy-camptothecin, 7-ethyl-10-[4-(l-piperidino)-lpiperidino] carbonyloxy-camptothecin or Irinotecan