title: 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(ε-caprolactone)-poly(ethylene glycol)-poly(ε-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.
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors: Lei
authors: L
authors: Liu
authors: Qinjie
authors: Q
authors: Wu
authors: Xuelei
authors: X
authors: Ma
authors: Dake
authors: D
authors: Xiong
authors: Changyang
authors: C
authors: Gong
authors: Zhiyong
authors: Z
authors: Qian
authors: Xia
authors: X
authors: Zhao
authors: Yuquan
authors: Y
authors: Wei
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D002166:Camptothecin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D005260:Female; D020100:Hydrogels; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D008863:Microspheres; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020100:Hydrogels; D002166:Camptothecin