title: CD44-targeting for antitumor drug delivery: a new SN-38-hyaluronan bioconjugate for locoregional treatment of peritoneal carcinomatosis.
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.
authors.affiliation: Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy. annalucia.serafino@ift.cnr.it
authors.forename: Annalucia
authors.initials: A
authors.lastname: Serafino
authors.forename: Manuela
authors.initials: M
authors.lastname: Zonfrillo
authors.forename: Federica
authors.initials: F
authors.lastname: Andreola
authors.forename: Rossana
authors.initials: R
authors.lastname: Psaila
authors.forename: Luana
authors.initials: L
authors.lastname: Mercuri
authors.forename: Noemi
authors.initials: N
authors.lastname: Moroni
authors.forename: Davide
authors.initials: D
authors.lastname: Renier
authors.forename: Monica
authors.initials: M
authors.lastname: Campisi
authors.forename: Cynthia
authors.initials: C
authors.lastname: Secchieri
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pierimarchi
mesh_terms: D034861:Abdominal Wall / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000009:adverse effects / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000009:adverse effects / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D000077146:Irinotecan; D008297:Male; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D018960:Hyaluronan Receptors; C561038:ONCOFID-S; D000077146:Irinotecan; D006820:Hyaluronic Acid; D002166:Camptothecin