Camptothecine encapsulated composite drug delivery system for colorectal peritoneal carcinomatosis therapy: Biodegradable microsphere in thermosensitive hydrogel

Abstract

In this work, we developed a biodegradable and injectable composite drug delivery system (DDS), camptothecine (CPT) loaded polymeric microsphere in thermosensitive hydrogel, for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ɛ-caprolactone)–poly(ethylene glycol)–poly(ɛ-caprolactone) (PCL–PEG–PCL, PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administrated to form microsphere or thermosensitive hydrogel, respectively. Therefore, the composite DDS was composed of CPT loaded microsphere (CPT-MS) and thermosensitive hydrogel. CPT-MS was prepared by CPT and PCEC copolymer (Mn=31,600) using an oil-in-water emulsion solvent evaporation method. Besides, biodegradable and injectable thermosensitive PCEC hydrogel (Mn=3150) with lower sol–gel transition temperature at around body temperature was also prepared. The CPT-MS in thermosensitive hydrogel (CPT-MS/hydrogel) composite is a free-flowing sol at ambient temperature and instantly converts into a non-flowing gel at body temperature. Furthermore, cytotoxicity assay indicated that both microsphere and hydrogel were biocompatible with very low cytotoxicity. In vitro release profile demonstrated a significant difference between rapid release of free CPT and much slower and sustained release of CPT-MS/hydrogel. In addition, intraperitoneal administration of CPT-MS/hydrogel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Compared with CPT-MS or free CPT, CPT-MS/hydrogel induced a stronger anti-tumor effect by increasing apoptosis of tumor cells and inhibiting microvessel density of tumor tissue. Besides, side effects of CPT were also alleviated in CPT-MS/hydrogel-treated mice. Thus, our results suggested that CPT-MS/hydrogel may have great potential applications in clinic.