Tuesday, July 03, 2007

Nanoparticles carry chemotherapy drug deeper into solid tumors

JNCI Journal of the National Cancer InstituteFig. 1 Nanoassembly of doxorubicin and polyethylene glycol–phosphatidylethanolamine (PEG-PE) and characterization of micelle-encapsulated doxorubicin (M-Dox).
A) Schematic illustration of self-assembly of doxorubicin and PEG-PE. Both PEG-PE and doxorubicin are amphiphilic. Upon encapsulation in micelles, the hydrophobic anthracene ring of doxorubicin inserted between the PE phospholipids, with the hydrophilic amino sugar of doxorubicin in the outer shell of the micelle between PEG chains.

B) Transmission electron microscopy (TEM) image of empty PEG-PE micelles stained with 1% uranyl acetate and examined by electron microscopy. C) TEM image of M-Dox. D) TEM image of micelles incorporating doxorubicin after storage for 6 months at 4 °C. Scale bar = 100 nm. E) Time course of doxorubicin release from micelles at 37 °C at pH 5.0 or pH 7.0. Released doxorubicin was separated from M-Dox by dialysis and quantified fluorimetrically using HPLC.

A new drug delivery method using nano-sized molecules to carry the chemotherapy drug doxorubicin to tumors improves the effectiveness of the drug in mice and increases their survival time, according to a study published online June 26 in the Journal of the National Cancer Institute.

In the past, similar drug carriers have improved targeted delivery of the drugs and reduced toxicity, but they sometimes decreased the drugs’ ability to kill the tumor cells. Using a new drug carrier, Ning Tang of the Chinese Academy of Sciences in Beijing and colleagues compared tumor growth and survival in mice that were given doxorubicin in the nanocarriers or on its own.

Doxorubicin delivered by nanocarriers was more effective in preventing tumor growth than free doxorubicin, and the mice receiving this treatment method lived longer and had fewer toxic side effects.

“Encapsulation of doxorubicin…increased its accumulation and penetration in tumors in terms of both the percentage of cells that were reached by the drug and the intracellular levels that were attained,” the authors write.

In an accompanying editorial, Matthew Dreher, Ph.D., of the National Institutes of Health in Bethesda, Md., and Ashutosh Chilkoti, Ph.D., of Duke University in Durham, N.C., discuss the future of drug delivery, which they think should focus on three important research areas—drug combinations, targeting, and integration.

“The study by Tang [and colleagues] is a simple but effective demonstration of the benefits of integration of a drug with an appropriate carrier to yield a striking gain in efficacy,” the authors write. “May the days of pharmacological missiles that miss their target and friendly fire that kills patients soon be over!” ###

Fig. 2 Cellular uptake and cytotoxic effect of free doxorubicin and micelle-encapsulated doxorubicin (M-Dox) in A549 cells.
A) Time course of doxorubicin accumulation in cells exposed to 1 µM free doxorubicin (Free Dox, filled diamonds) or equivalent concentration of drug encapsulated in micelles (filled triangles) as measured by fluorescence. Error bars correspond to 95% confidence intervals from three independent experiments.

B) Internal doxorubicin fluorescence in cells after 6 hours of exposure to 1 µM M-Dox at 4 °C or 37 °C; 95% confidence intervals are shown. C) Killing of A549 cells exposed to free doxorubicin (filled diamonds) or M-Dox (filled triangles) doses ranging from 1 to 10000 nM for 48 hours. The percentage of viable cells was quantified using the methylthiazoletetrazolium method. Mean values and 95% confidence intervals derived from three independent experiments are shown.

Improving Penetration in Tumors With Nanoassemblies of Phospholipids and Doxorubicin Full Text in PDF Format

Contact: Article: Wei Liang, +6810-6488 9861 or + 6813-9117 43032, weixx@sun5.ibp.ac.cn
Editorial: Kendall Morgan, Duke University, (919) 660-8414, kendall.morgan@duke.edu

Contact: Liz Savage jncimedia@oxfordjournals.org 301-841-1287 Journal of the National Cancer Institute

Citations: Article: Tang N, Du G, Wang N, Liu C, Hang H, Liang W. Improving Penetration in Tumors With Nanoassemblies of Phospholipids and Doxorubicin. J Natl Cancer Inst 2007; 99: 1004-1015, Editorial: Dreher MR, Chilkoti A. Toward a Systems Engineering Approach to Cancer Drug Delivery. J Natl Cancer Inst 2007; 99: 983-985

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