Peritoneal carcinomatosis still lacks reliable therapeutic options. We aimed at testing a
drug delivery strategy allowing a controlled release of cytotoxic molecules and selective targeting of
tumor cells. We comparatively assessed the efficacy of a loco-regional intraperitoneal treatment in immunocompromised mice with bioconjugates formed by chemical linking of
paclitaxel or
SN-38 to
hyaluronan, against three models of
peritoneal carcinomatosis derived from human colorectal, gastric and esophageal
tumor cell xenografts. In vitro, bioconjugates were selectively internalized through mechanisms largely dependent on interaction with the CD44 receptor and
caveolin-mediated endocytosis, which led to accumulation of compounds into lysosomes of
tumor cells. Moreover, they inhibited
tumor growth comparably to free drugs. In vivo, efficacy of bioconjugates or free drugs against
luciferase-transduced
tumor cells was assessed by bioluminescence optical imaging, and by recording mice survival. The intraperitoneal administration of bioconjugates in
tumor-bearing mice exerted overlapping or improved therapeutic efficacy compared with unconjugated drugs. Overall,
drug conjugation to
hyaluronan significantly improved the profiles of in vivo tolerability and widened the field of application of existing drugs, over their formal approval or current use. Therefore, this approach can be envisaged as a promising therapeutic strategy for loco-regional treatment of
peritoneal carcinomatosis.