Chemo Side Effects Could Be Lessened By Nanoprobe-Targeting Of Tumors

Main Category: Breast Cancer
Also Included In: Biology / Biochemistry;  Cancer / Oncology
Article Date: 15 Dec 2009 - 4:00 PDT

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Tiny nanoprobes have shown to be effective in delivering cancer drugs more directly to tumor cells - mitigating the damage to nearby healthy cells - and Purdue University research has shown that the nanoprobes are getting the drugs to right cellular compartments.

Professor Joseph Irudayaraj and graduate student Jiji Chen, both in the Department of Agricultural and Biological Engineering, have found that the nanoprobes, or nanorods, when coated with the breast cancer drug Herceptin, are reaching the endosomes of cells, mimicking the delivery of the drug on its own. Endosomes perform a sorting function to deliver drugs and other substances to the appropriate locations.

"We have demonstrated the ability to track these nanoparticles in different cellular compartments of live cells and show where they collect quantitatively," said Irudayaraj, whose results were published early online in the journal ACS Nano. "Our methods will allow us to calculate the quantities of a drug needed to treat a cancer cell because now we know how these nanoparticles are being distributed to different parts of the cell."

The nanoprobes, which are about 1,000 times smaller than the diameter of a human hair, are made from gold and magnetic particles. An MRI machine can track the magnetic portions of the nanoprobes while a more sensitive microscopy process can detect the gold.

The nanoprobes were inserted into live human tumor cells during laboratory testing. Using fluorescent markers to differentiate organelles, or sub-units of cells, Irudayaraj's group was able to determine the number of nanoprobes accumulating in the endosomes, lysosomes and membranes of those cells.

Cancer treatments often use high drug concentrations that damage healthy cells near a tumor. While Herceptin is attracted to and attaches to the proteins on the surface of breast cancer cells, healthy surrounding cells absorb some of the chemotherapy drugs through normal fluidic intake.

Irudayaraj said targeting only tumor cells with nanoprobes would require less drugs and mitigate the side effects of cancer chemotherapy drugs.

"Each nanoparticle acts like a deliverer of a mail package, or dose, of the drug directly to the appropriate location," Irudayaraj said.

In Irudayaraj's laboratory tests, endosomes received a major portion of the nanorods containing Herceptin. Lysosomes, which act like garbage collection units in cells and hinder a drug's effectiveness, received a lower concentration of nanorods.

Irudayaraj said those percentages are similar to how cells distribute drugs through traditional treatments.

Irudayaraj will next try to attach multiple drugs to a nanoparticle and track their distribution within cells. He also wants to determine the timing of a drug's release from the nanoprobes after attaching to the tumor cells.

The research was funded through a Trask Grant and the Purdue Research Foundation.

Writer: Brian Wallheimer

ABSTRACT

Quantitative Investigation of Compartmentalized Dynamics of ErbB2 Targeting Gold Nanorods in Live Cells by Single Molecule Spectroscopy

Jiji Chen and Joseph Irudayaraj

Understanding the diffusion dynamics and receptor uptake mechanism of nanoparticles in cancer cells is crucial to the rational design of multifunctional nanoprobes for targeting and delivery. In this report, for the first time, we quantify the localization and evaluate the diffusion times of Herceptin-conjugated gold nanorods (H-GNRs) in different cell organelles by fluorescence correlation spectroscopy (FCS) and examine the endocytic diffusion of H-GNRs in live ErbB2 overexpressing SK-BR-3 cells. First, by colocalizing H-GNRs in different cellular organelles depicted by the respective markers, we demonstrate that H-GNRs colocalize with the endosome and lysosome but not with the Golgi apparatus. Our study shows that Herceptin-conjugated GNRs have similar intracellular localization characteristics as Herceptin-ErbB2 complex, with a higher concentration found in the endosome (72 ± 20.6 nM) than lysosome (9.4 ± 4.2 nM) after internalization. The demonstrated approach and findings not only lay the foundations for a quantitative understanding of the fate of nanoparticle-based targeting but also provide new insights into the rational design of nanoparticle delivery systems for effective treatment.

Source: Brian Wallheimer
Purdue University

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