Journal of the National Cancer Institute Advance Access published online on June 27, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm027
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ARTICLES |
Improving Penetration in Tumors With Nanoassemblies of Phospholipids and Doxorubicin
Affiliations of authors: Protein & Peptide Pharmaceutical Laboratory, National Laboratory of Biomacromolecules (NT, GD, WL) and Center for Infection and Immunity (CL, HH), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China (NW)
Correspondence to: Wei Liang, PhD, Protein & Peptide Pharmaceutical Laboratory, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China (e-mail: weixx{at}sun5.ibp.ac.cn) or Haiying Hang, PhD, Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China (e-mail: hh91{at}sun5.ibp.ac.cn).
Background: Drug delivery and penetration into neoplastic cells distant from tumor vessels is critical for the effectiveness of solid tumor chemotherapy. We hypothesized that 10- to 20-nm nanoassemblies of phospholipids containing doxorubicin would improve the drug's penetration, accumulation, and antitumor activity.
Methods: Doxorubicin was incorporated into polyethylene glycol–phosphatidylethanolamine (PEG-PE) block copolymer micelles by a self-assembly procedure to form nanoassemblies of doxorubicin and PEG-PE. In vitro cytotoxicity of micelle-encapsulated doxorubicin (M-Dox) against A549 human non–small-cell lung carcinoma cells was examined using the methylthiazoletetrazolium assay, and confocal microscopy, total internal reflection fluorescence microscopy, and flow cytometry were used to examine intracellular distribution and the cellular uptake mechanism. C57Bl/6 mice (n = 10–40 per group) bearing subcutaneous or pulmonary Lewis lung carcinoma (LLC) tumors were treated with M-Dox or free doxorubicin, and tumor growth, doxorubicin pharmacokinetics, and mortality were compared. Toxicity was analyzed in tumor-free mice. All statistical tests were two-sided.
Results: Encapsulation of doxorubicin in PEG-PE micelles increased its internalization by A549 cells into lysosomes and enhanced cytotoxicity. Drug-encapsulated doxorubicin was more effective in inhibiting tumor growth in the subcutaneous LLC tumor model (mean tumor volumes in mice treated with 5 mg/kg M-Dox = 1126 mm3 and in control mice = 3693 mm3, difference = 2567 mm3, 95% confidence interval [CI] = 2190 to 2943 mm3, P<.001) than free doxorubicin (mean tumor volumes in doxorubicin-treated mice = 3021 mm3 and in control mice = 3693 mm3, difference = 672 mm3, 95% CI = 296 to 1049 mm3, P = .0332, Wilcoxon signed rank test). M-Dox treatment prolonged survival in both mouse models and reduced metastases in the pulmonary model; it also reduced toxicity.
Conclusions: We have developed a novel PEG-PE–based nanocarrier of doxorubicin that increased cytotoxicity in vitro and enhanced antitumor activity in vivo with low systemic toxicity. This drug packaging technology may provide a new strategy for design of cancer therapies.
| CONTEXT AND CAVEATS Prior knowledge The inadequate penetration and limited distribution of doxorubicin in tumors reduce its effectiveness as a chemotherapeutic agent. Although various nanocarriers that encapsulate chemotherapeutic agents have shown potential to improve drug delivery to the tumor and reduce systemic toxicity, they also tend to decrease the cytoxicity of the drugs. Study design Properties of a drug-loaded nanocarrier and the free drug were compared using in assays of cellular uptake and cytotoxicity and by studying tumor growth and survival in mouse models. Contribution This work presents a strategy for micelle encapsulization of doxorubicin that enhances its cytoxicity and accumulation in cells and increases its efficacy in inhibiting tumor growth in vivo. Implications Micelle encapsulization of doxorubicin and other drugs may have the potential to improve the effectivness of these agents while reducing side effects. Limitations A comprehensive physical and structural characterization of the drug-loaded nanocarrier is needed for a mechanistic understanding of its action.
|
Manuscript received November 8, 2006; revised May 2, 2007; accepted May 23, 2007.
Editorial about this Article
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 983-985.
J Natl Cancer Inst 2007 99: 981.
J Natl Cancer Inst 2007 99: 981.
This article has been cited by other articles:
|
|
 |
|
  S. Basu, R. Harfouche, S. Soni, G. Chimote, R. A. Mashelkar, and S. Sengupta Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy PNAS, May 12, 2009; 106(19): 7957 - 7961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Dreher and A. Chilkoti Toward a Systems Engineering Approach to Cancer Drug Delivery J Natl Cancer Inst, July 4, 2007; 99(13): 983 - 985. [Full Text] [PDF]
|
|