A novel monomethoxy polyethylene glycol-polylactic acid polymeric micelles with higher loading capacity for docetaxel and well-reconstitution characteristics and its anti-metastasis study

Chem Pharm Bull (Tokyo). 2012;60(9):1146-54. doi: 10.1248/cpb.c12-00323.

Abstract

Docetaxel (DTX) is hydrophobic, and its available formulations (Taxotere(®) & Duopafei(®)) require Tween80 and ethanol vehicle to allow parental administration. DTX-loaded poly(D,L-lactide)-b-polyethylene glycol-methoxy (mPEG-b-PDLLA) polymeric micelle (PM) is a Tween80-free formulation of DTX, which has been extensively studied but rarely involved with industrialization issues. In this work, novel DTX-PM with improved loading capacity and well-reconsitution ability was developed. The freeze-dried DTX-PM was analyzed by HPLC, transmission electron microscopy (TEM) and dynamic light scattering (DLS) to determine the DTX loading, micelle morphology and size respectively. The in vitro cytotoxic activity of DTX-PM in 4T1 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the corresponding in vivo study was assessed in BALB/c mice bearing 4T1 tumor through intravenous administration. The DTX-loading and efficiency into the micelles were 20.74±1.23% and 93.7±1.03% respectively, which was much higher than ever reported PM. The DTX-PM was spherical with a mean particle size of 16.62±0.31 nm, which suggested that they were able to selectively accumulate in solid tumors by enhanced permeability and retention (EPR) effect. Another important characteristic of DTX-PM is the long term storage and reuses as aqueous injection solution. Many kinds of lyoprotectants were also investigated and dextrose was found to an excellent one. Compared with Duopafei(®), DTX-PM showed better cytotoxicity and anti-metastasis ability against 4T1 cells in vitro and in vivo. In conclusion, DTX-PM significantly enhanced drug-loading capacity of DTX and had well-reconsitution ability, which could be a promising drug delivery system for clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Docetaxel
  • Drug Carriers / chemistry*
  • Guinea Pigs
  • Hemolysis / drug effects
  • Lactic Acid / chemistry
  • Mammary Neoplasms, Animal / drug therapy
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / prevention & control*
  • Polyesters
  • Polyethylene Glycols / chemistry
  • Polymers / chemistry
  • Rats
  • Taxoids / administration & dosage*
  • Taxoids / pharmacology
  • Taxoids / therapeutic use*

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Micelles
  • Polyesters
  • Polymers
  • Taxoids
  • Docetaxel
  • Lactic Acid
  • Polyethylene Glycols
  • poly(lactide)