Nanoparticles Take On Tumors

The drugs cancer patients take to destroy their tumors also cause debilitating side effects such as nausea, weight loss, and even heart problems. But now researchers report that they can curb the spread of cancer cells in mice with drug concentrations far lower than the standard dose. The key is using a microscopic particle that zeroes in on blood vessels around the tumor to deliver low doses of the drug in a more concentrated way.

Metastasis--the ability to spread that makes cancer so pernicious--requires that the primary tumor is well-fed by an ever-expanding network of blood vessels. Without a constant supply of nutrients and oxygen, the tumor stays put. This blood-vessel expansion, called angiogenesis, takes place in certain healthy tissues as well. One thing that distinguishes tumor angiogenesis is a cell receptor called avß3, which is found on the inner wall of the blood vessels that feed the tumor.

A team led by University of California, San Diego, pathologist David Cheresh decided to target this receptor with a tiny particle, or nanoparticle, made up of fat-related compounds. To test the strategy, the researchers added very low doses of an anticancer drug called doxorubicin (Dox) to the particles and injected them into mice implanted with human pancreatic tumor cells. Dox disrupts DNA replication, and the scientists hoped to limit the drug's impact to the tumor vessels. After 11 days, mice that received the targeted nanoparticle infused with Dox showed about 82% less metastasis to a nearby lymph node than did mice that received Dox-carrying nanoparticles that didn't attach to the avß3 receptors. The primary tumor also shrank slightly in the mice that received the avß3-targeted Dox nanoparticles.

In traditional chemotherapy regimens, Dox is simply injected into a patient's bloodstream. Cheresh and his team found that this method had no impact on metastasis in the mice. To achieve the desired effect without nanoparticles, the researchers had to increase the concentration of Dox by 15-fold--a level that caused the mice to lose about 18% of their body weight. Mice injected with the lower dose on targeted nanoparticles lost only about 0.8% of body weight, the team reports online this week in the Proceedings of the National Academy of Sciences.

Cheresh says the study adds further weight to the idea that nanoparticles can enable scientists to achieve the same antitumor effects with a lower drug dosage. "It would be a very dramatic improvement in the way drugs are given," he says.

Gregory Lanza, a nanomedicine specialist at Washington University in St. Louis, Missouri, was pleased though not surprised by the results, calling them "another brick on the pile" of evidence supporting targeted therapies. Lanza, who was not affiliated with the study but has conducted similar work, says scientists will need a better understanding of tumor angiogenesis to know where in the system or at what point in the tumor's development they should administer the therapy to get the best results.

The Kanzius treatment used nano metal particles injected into the tumors and then hit with microwaves. The metal heated from the inside out and cooked the tumor.

Anyway you look at it though, nano something will be big business in the future. See if you can find the articles on super batteries that use nano hairs grown on metal plates. They are 10 times better than what we have now. The cars of the future will be as good as gas engines and go hundreds of miles without a charge.

I had heard of bucky balls filled with chemo 10 years ago injected into the blood of cancer patients. The tumors had larger blood vessel area than the surrounding tissue. The balls would release the poison and kill the tumor with little effect on the less blood vessel dense tissue around it. They were able to concentrate the chemical poison in the tumor but have almost no side effects. I believe it was in Japan. It was on a show called Beyond 2000.

How do we not know that sodium bicarbonate may not be just as, or even more effective with no side effects?

If it sounds too good to be true, it probably isn't true. "Cancer" is about over 200 diseases.

The role of intracellular pH in cell growth arrest induced by ATP

Furthermore, pHi decrease was capable of reducing cell growth.

Influence of CO2 pneumoperitoneum on intracellular pH and signal transduction in cancer cells*

Conclusion: CO2 pneumoperitoneum could promote acidosis in cancer cells, inducing the activation of protein kinase C and deactivation of protein phosphatase 2a, but it could not accelerate the mitosis rate of the cancer cells.

I looked for examples in support of bicarb/pH hypothesis, but only found examples that didn't support it. Save the baking soda for baking and indigestion.

I am not a doctor, so I am having trouble understanding how they were able to make the nano particles go after the avb3 cell receptors.

They knew what binds to it. Go follow the link to the abstract. At the abstract, click on the link for "Supporting Information." You have to open this pdf:

http://www.pnas.org/content/suppl/2008/07/07/0803728105.DCSupplemental/0803728105SI.pdf

On page 3 you find:

Fig. S3. Integrin v3-targeted RGD-Dox-NPs suppress metastasis to the hepatic hilar lymph node. After surgical implantation of the cells, mice were treated on days 7, 8, and 9 with RGD-Dox-NP or RAD-Dox-NP (each with 1 mg/kg total Dox per dose). On day 11, the primary tumor and the hepatic hilar lymph node were resected and weighed. The higher-frequency dosing schedule continued to inhibit metastasis and had a greater effect on the primary tumor growth than dosing on days 5, 7, and 9.

Greek alpha and beta was translated as ''

In Vitro and in Vivo Evaluation of Doxorubicin Conjugates with the Divalent Peptide E-[c(RGDfK)2] that Targets Integrin alphavbeta3.

Integrins, especially integrin alpha vbeta 3, are attractive receptors for vascular targeting strategies. Recently, a divalent RGD peptidomimetic, E-[c(RGDfK) 2], has been described that demonstrates increased uptake in human ovarian carcinoma OVCAR-3 xenograft tumors. Inspired by these results, we set out to develop doxorubicin conjugates with E-[c(RGDfK) 2] by binding two different maleimide derivatives of doxorubicin to E-[c(RGDfK) 2] that was thiolated with iminothiolane. In this way, two water-soluble derivatives were obtained, E-[c(RGDfK) 2]-DOXO-1 and E-[c(RGDfK) 2]-DOXO-2. In E-[c(RGDfK) 2]-DOXO-1, doxorubicin was bound to the peptide through a stable amide bond, and in E-[c(RGDfK) 2]-DOXO-2, a MMP-2/MMP-9 cleavable octapeptide was introduced between doxorubicin and the peptide. The rationale for a MMP-2/MMP-9-cleavable linker was that MMP-2 and MMP-9 bind to integrin alpha vbeta 3 and both are overexpressed in tumor vasculature. In addition, analogous control doxorubicin-containing peptides bearing c(RADfK) that does not bind to integrin alpha vbeta 3 were synthesized, i.e., c(RADfK)-DOXO-1 and c(RADfK)-DOXO-2. Whereas E-[c(RGDfK) 2]-DOXO-2 was cleaved effectively by MMP-2 and in OVCAR-3 tumor homogenates releasing a doxorubicin-tetrapeptide or doxorubicin as the final cleavage product, no release of doxorubicin was observed for E-[c(RGDfK) 2]-DOXO-1. Proliferation of HUVEC in the presence of MMP-2-cleavable doxorubicin-containing peptides exhibited 6- to 10-fold increased inhibition compared to the amide-linked doxorubicin-containing peptides. In addition, inhibition of HUVEC sprouting during a 24 h exposure was approximately 3-fold stronger for E-[c(RGDfK) 2]-DOXO-2 and 20-fold stronger for the reference peptide conjugate c(RADfK)-DOXO-2 than for doxorubicin alone. In vivo studies in an OVCAR-3 xenograft model demonstrated no or only moderate antitumor efficacy for either E-[c(RGDfK) 2], E-[c(RGDfK) 2]-DOXO-1, E-[c(RGDfK) 2]-DOXO-2, or c(RADfK)-DOXO-2, even at doses of 3 x 24 mg/kg doxorubicin equivalents, compared to an improved antitumor effect for doxorubicin at 2 x 8 mg/kg.

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