Abstract
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.
Highlights
Colorectal (CRC) and gastric cancers are the second and third most common causes of cancer-related death worldwide, respectively [1,2]. Both tumor histotypes frequently spread in the peritoneal cavity, causing peritoneal carcinomatosis (PC) even in the early phase of the disease [3,4,5]
HA receptor expression on target cancer cell lines CD44 and CD168 are regarded as important receptors for hyaluronan binding
Analysis of interaction of bioconjugates with target cancer cell lines To assess the direct interaction of ONCOFID-P and ONCOFID-S with CD44 expressing target cells, bioconjugates were labeled with the BODIPY fluorophore, incubated with tumor lines and analyzed cytofluorimetrically at different time points
Summary
Colorectal (CRC) and gastric cancers are the second and third most common causes of cancer-related death worldwide, respectively [1,2]. Both tumor histotypes frequently spread in the peritoneal cavity, causing peritoneal carcinomatosis (PC) even in the early phase of the disease [3,4,5]. The last years have witnessed new therapeutic treatments based on cytoreductive surgery combined with intraperitoneal chemotherapy under hyperthermic condition, to produce a loco-regional control of peritoneal metastasis and to improve long-term survival of patients [9,10]
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