June 02, 2010

Various Insulin Pills in Clinical Trials and Targeted Nanosponge Drug Delivery is Three to Five times more Effective against Cancer Tumors

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1. There are various clinical trials for insulin pills. Being able to deliver proteins in time released pill form could provide many benefits for insulin and other conditions.

The human body is designed to digest proteins. Acids and enzymes in the gastrointestinal tract will chew up a valuable therapeutic protein as easily as they’ll tear into a bite of steak. To avoid this fate and reach the intended target, most protein pharmaceuticals are formulated for injection or intravenous infusion. As a result, large amounts of drug tend to be administered less often.

The global diabetes market exceeds $30 billion annually, with insulin sales accounting for about half of that, according to the market research firm IMS Health. If new solid doses can perform at least as well as, if not better than, existing products, they might promise new sales, lower costs of delivery, and extended patent life. Fortunately for drug developers, recombinant production can make enough insulin inexpensively for the larger doses required in oral forms.

Put in a tablet, IN-105 retains similar activity to insulin alone, withstands degradation, and is consistently absorbed, according to Biocon. Results from a Phase III clinical trial in India are expected in September. In late 2009, Biocon applied to the U.S. Food & Drug Administration to allow it to start clinical trials.

Solid oral forms could have efficacy and safety advantages, too. Insulin delivered this way, unlike injected forms that circulate systemically, is believed to behave more like the body’s own. Natural insulin is secreted by the pancreas and taken up by the liver, which stores and metes it out when needed. Engineered for release in parts of the small intestine just past the stomach, solid oral insulin can be taken up from there by the portal vein and delivered to the liver.

2. When loaded with an anticancer drug, a delivery system based on a novel material called nanosponge is three to five times more effective at reducing tumor growth than direct injection.

That is the conclusion of a paper published in the June 1 issue of the journal Cancer Research.

To visualize Harth’s delivery system, imagine making tiny sponges that are about the size of a virus, filling them with a drug and attaching special chemical “linkers” that bond preferentially to a feature found only on the surface of tumor cells and then injecting them into the body. The tiny sponges circulate around the body until they encounter the surface of a tumor cell where they stick on the surface (or are sucked into the cell) and begin releasing their potent cargo in a controllable and predictable fashion.

“Effective targeted drug delivery systems have been a dream for a long time now but it has been largely frustrated by the complex chemistry that is involved,” says Eva Harth, assistant professor of chemistry at Vanderbilt, who developed the nanosponge delivery system. “We have taken a significant step toward overcoming these obstacles.”

Targeted delivery systems of this type have several basic advantages: Because the drug is released at the tumor instead of circulating widely through the body, it should be more effective for a given dosage. It should also have fewer harmful side effects because smaller amounts of the drug come into contact with healthy tissue.

“We call the material nanosponge, but it is really more like a three-dimensional network or scaffold,” says Harth. The backbone is a long length of polyester. It is mixed in solution with small molecules called cross-linkers that act like tiny grappling hooks to fasten different parts of the polymer together. The net effect is to form spherically shaped particles filled with cavities where drug molecules can be stored. The polyester is biodegradable, so it breaks down gradually in the body. As it does, it releases the drug it is carrying in a predictable fashion.

“Predictable release is one of the major advantages of this system compared to other nanoparticle delivery systems under development,” says Harth. When they reach their target, many other systems unload most of their drug in a rapid and uncontrollable fashion. This is called the burst effect and makes it difficult to determine effective dosage levels.

Another major advantage is that the nanosponge particles are soluble in water. Encapsulating the anti-cancer drug in the nanosponge allows the use of hydrophobic drugs that do not dissolve readily in water. Currently, these drugs must be mixed with another chemical, called an adjuvant reagent, that reduces the efficacy of the drug and can have adverse side-effects.

It is also possible to control the size of nanosponge particles. By varying the proportion of cross-linker to polymer, the nanosponge particles can be made larger or smaller. This is important because research has shown that drug delivery systems work best when they are smaller than 100 nanometers, about the depth of the pits on the surface of a compact disc. The nanosponge particles used in the current study were 50 nanometers in size. “The relationship between particle size and the effectiveness of these drug delivery systems is the subject of active investigation,” says Harth.

The other major advantage of Harth’s system is the simple chemistry required. The researchers have developed simple, high-yield “click chemistry” methods for making the nanosponge particles and for attaching the linkers, which are made from peptides, relatively small biological molecules built by linking amino acids. “Many other drug delivery systems require complicated chemistry that will be difficult to scale up for commercial production, but we have continually kept this in mind,” Harth says.

The targeting peptide used in the animal studies was developed by the Hallahan laboratory, which also tested the system’s effectiveness in tumor-bearing mice. The peptide used in the study is one that selectively binds to tumors that have been treated with radiation.

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