title: Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites.
abstract: In this work, we aim to develop a dual drug delivery system (DDDS) of self-assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (M(n) = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (M(n) = 3000) with a lower sol-gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles-Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles-Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles-Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX-micelles-Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol® plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles-Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol® plus Fu group. Thus, the results suggested the micelles-hydrogel DDDS may have great potential clinical applications.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Changyang
authors.initials: C
authors.lastname: Gong
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Yujun
authors.initials: Y
authors.lastname: Wang
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Wu
authors.forename: Doudou
authors.initials: D
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Luo
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D011817:Rabbits; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C492324:poly(epsilon-caprolactone)-poly(oxyethylene)-poly(epsilon-caprolactone); D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D017239:Paclitaxel; D005472:Fluorouracil