Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites

Nanoscale. 2012 May 21;4(10):3095-104. doi: 10.1039/c2nr30278k. Epub 2012 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / toxicity
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Carriers / chemistry*
  • Drug Carriers / toxicity
  • Erythrocytes / drug effects
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / toxicity
  • Hydrogel, Polyethylene Glycol Dimethacrylate / chemistry*
  • Hydrogel, Polyethylene Glycol Dimethacrylate / toxicity
  • Mice
  • Mice, Inbred BALB C
  • Micelles*
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / toxicity
  • Peritoneal Neoplasms / drug therapy*
  • Peritoneal Neoplasms / pathology
  • Polyesters / chemical synthesis
  • Polyesters / chemistry
  • Polyethylene Glycols / chemical synthesis
  • Polyethylene Glycols / chemistry
  • Rabbits
  • Temperature

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Micelles
  • Polyesters
  • poly(epsilon-caprolactone)-poly(oxyethylene)-poly(epsilon-caprolactone)
  • Hydrogel, Polyethylene Glycol Dimethacrylate
  • Polyethylene Glycols
  • Paclitaxel
  • Fluorouracil