Oncology: High hopes for tiny particles
A group of researchers from Massachusetts, led by Professor Tayaba Hasan, have developed and tested two types of nanocapsules combining phototherapy with active molecules that inhibit the growth of cancer cells and blood vessels inside tumors. Such nanoparticles, which exhibit several therapeutic effects, are able to significantly reduce the tumor of the pancreas, and also prevent the spread of metastases.
So far, nanocapsules have only been tested on mice, but the medical community is already excited about their appearance. Pancreatic cancer remains one of the deadliest and most difficult to treat diseases, and mortality rates from this disease have not changed much over the past 30 years. Patients with such a diagnosis, as a rule, live no more than 6 months, and only 5% of them survive for five years, and modern medicine has practically no means to save them.
The first type of nanocapsules, proposed by Hassan and colleagues, is designed to deprive a cancerous tumor of nutrition, disrupting its blood supply. Inside the nanocapsules of a solid polymer, the photosensitive drug verteporfin is enclosed, which releases toxic oxygen radicals under the action of light of a certain wavelength, and the capsules themselves are covered with a lipid layer containing bevacizumab antibodies, specifically suppressing the growth of new blood vessels by blocking the expression of the VEGF protein (vessels endothelial growth factor, vascular epithelial growth factor). Bevacizumab is approved for the treatment of late-stage rectal, lung, breast and kidney cancers and is produced under the commercial name Avastin, and verteporfin is used to eliminate abnormal blood vessels in the "wet form" of retinal degeneration and is known under the trade name Visudin.
In one clinical study, verteporfin increased the average survival rate of pancreatic cancer patients from six to nine months. Avastin did not show a similar effect; this is probably due to the fact that the drug destroys blood vessels, making it difficult to deliver a photosensitive drug to a cancerous tumor.
Unlike traditional chemotherapy, nanocapsules with intravenous infusion deliver both drugs directly into cancer cells. Blood vessels of healthy tissues are impervious to nanoparticles, and large pores in the walls of tumor vessels allow particles to freely penetrate inside. Due to this, nanocapsules accumulate inside the cancer tumor and deliver more "payload" to it than to healthy cells, providing a higher effective dose of the drug inside the tumor while reducing side effects.
Scientists implanted human pancreatic cancer cells into laboratory mice and waited for a tumor to form. Then the animals were injected with a dose of nanocapsules and the tumor was irradiated with long-wavelength light. Mice treated with this treatment showed a significant reduction in tumor size, unlike animals subjected to chemotherapy with a single drug. In addition, mice treated with nanocapsules had twice as many metastases in the lungs, liver and lymph nodes. As a result, the researchers concluded that the combined complex use of these drugs is more effective than separately. The authors of the study, led by Professor Hassan, explain this by the fact that nanocapsules actually merge with tumor cells and deliver Avastin directly into the cells, and not just to the tumor. Although no toxicity studies have been conducted, scientists express the hope that the preferred accumulation of nanocapsules inside tumors will lead to a reduction in the side effects of the drug, which in itself is quite harmful. Almost 30% of patients receiving Avastin have side effects from the cardiovascular system, including high blood pressure, stroke and heart failure.
The idea of targeted drug delivery using nanoparticles has not been new for a long time and serves as a platform for the development of other nanopharmacology technologies. One of its inconvenient aspects is the need to individually optimize carrier particles for each new combination of drugs.
Professor Hassan's laboratory has developed another type of nanocapsules – this time they prevent the development of resistance to chemotherapy, which is a fairly common problem. Previously, scientists identified two proteins – EGFR (receptor for epithelial growth factor) and MET (a membrane receptor involved, among other things, in triggering a cascade of processes that stimulate cell proliferation). Both of these proteins play an important role in the development and growth of pancreatic tumors. In laboratory experiments with cell lines, blocking EGFR increases the production of MET protein by cells, and vice versa. Hoping to achieve a more effective effect on tumors, the scientists set a goal to simultaneously affect EGFR and MET, simultaneously irradiating the tumor to increase the effectiveness of treatment.
The structure of nanocapsules of the second type turned out to be more complex. They are based on a small molecule called PHA-66572, which inhibits the MET protein – it is enclosed in polymer nanoparticles of the same grade as in the first case. This is followed by a layer of cetuximab molecules, a monoclonal antibody that blocks EGFR. And finally, both layers are enclosed in lipid beads containing Visudine.
The experiment showed that after one injection of nanocapsules and phototherapy, tumors in mice significantly decrease in size. Now scientists continue to assess the spread of metastases, but since MET remains active in most metastatic cells, researchers do not lose hope that nanocapsules with growth factor will certainly lead to a significant reduction in the number and size of tumor foci.
According to the researchers, the results obtained are encouraging, since the decrease in the toxicity of drugs is obvious. The drug PHA-66572 was specifically designed to block MET in cancer cells, but turned out to be so toxic that pharmaceutical companies abandoned its production. But in experiments with nanocapsules, the animals maintained normal activity and did not lose weight.
Professor Hassan hopes that in the next few years both types of nanocapsules will be tested on patients with pancreatic cancer. Since Avastin and Visudin are approved for use in the USA, most likely, nanocapsules of the second type will be tested first. Toxicological studies of Avastin-Visudin nanocapsules are currently being conducted, and, according to the author of the development, they will soon get to the clinic. It is also important to choose a more advanced MET factor inhibitor, and some researchers are already testing potential molecules.
Ruslan Kushnir
Eternal Youth Portal www.vechnayamolodost.ru based on Technology Review: Big Hope for Tiny Particles14.12.2009