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In participation with Blog Action Day, an event where bloggers from around the world unite to put a single important issue on everyone’s mind - the environment - today’s article discusses recent advances in the use of biodegradable materials for drug and gene delivery.

Drug delivery

Last month, we discussed how green chemistry was recently used by two research groups to mimic the cellular process of drug synthesis, imitating complex biosynthetic processes outside the cell to create antibiotics. Green chemistry attempts to reduce or eliminate the generation and use of hazardous substances in the design and development of chemical products and processes, minimizing its impact on patients and the environment.

Now chemists at the University of Nottingham are using green chemistry to develop new methods for coating drugs in plastics [1]. While conventional methods use high temperatures and volitile solvents such as benzene and chloroform, green chemistry techniques allow for the coating of drugs without damaging or degrading the active ingredients. This means the drugs are free of toxic chemical residues and are more effective.

The Clean Technology Group at Nottingham is exploiting the use of supercritical carbon dioxide, which under high pressure at room temperature is a solvent that can use biodegradable plastics to make polymer drug coatings [2]. The polymer (meaning a material composed of molecules with repeating structural units that form a long chain) is used to encapsulate a drug prior to injection in the body and is based on lactic acid, a compound normally produced in the body, and is thus able to be excreted naturally. The coating is designed for controlled release over a period of time, reducing the number of injections required and maximizing the therapeutic benefit.

Professor Steve Howdle, whose research is focused on exploiting the unique properties of supercritical carbon dioxide, said [1]:

Biodegradable polymers are particularly attractive for use in drug delivery, as once introduced into the body they require no retrieval or further manipulation and are degraded into soluble, non-toxic by-products. Different polymers degrade at different rates within the body and therefore polymer selection can be tailored to achieve desired release rates.

Gene delivery

Another interesting recent development is a report by MIT researchers that they have found a way to create gene carriers from biodegradable polymers instead of viral materials [3].

Gene therapy is the introduction of a gene or genes into the cells of a tissue to treat disease. Although 1,180 gene therapy clinical trials have been conducted since 1989 [4], there are no FDA-approved gene therapies, in part because viruses are used as gene carriers. Viruses present a number of potential problems, including toxicity, immune response and targeting issues.

The MIT study focused on three poly(beta-amino-esters) chains of alternating amine and diacrylate groups that spontaneously assemble with DNA to form nanoparticles when mixed together. The polymer-DNA nanoparticle can act like an artificial virus and deliver DNA when injected into tissue. Researchers chemically modified the ends of the polymer chains using a library of small molecules to attenuate and optimize nanoparticle formation and DNA delivery.

According to Daniel Anderson, the study leader and research associate in MIT’s Center for Cancer Research [5]:

Just by changing a couple of atoms at the end of a long polymer, one can dramatically change its performance. These minor alterations in polymer composition significantly increase the polymers’ ability to deliver DNA, and these new materials are now the best non-viral DNA delivery systems we’ve tested.

Degradable polymers are used in dissolvable stitches and have been utilized in the pharmaceutical industry in various forms for decades. Using the technologies described above, not only are we able to produce purer products that offer therapeutic benefits, but both the processes and products are cleaner and safer for the environment.

References

1. Using green chemistry to deliver cutting-edge drugs. The University of Nottingham. 2007 Sep 13.
2. Tai et al. Putting the fizz into chemistry: applications of supercritical carbon dioxide in tissue engineering, drug delivery and synthesis of novel block copolymers. Biochem Soc Trans. 2007 Jun;35(Pt 3):516-21.
   View abstract
3. Green et al. Combinatorial Modification of Degradable Polymers Enables Transfection of Human Cells Comparable to Adenovirus. Advanced Materials. 2007 Oct;19(19):2836-42.
4. Gene Therapy Clinical Trials Worldwide. Provided by the Journal of Gene Medicine. Updated 2007 July.
5. MIT works toward safer gene therapy. MIT News. 2007 Sep 7.

Two studies were published in the September 2007 issue of Nature Chemical Biology demonstrating for the first time that it’s possible to take a complex chain of enzymatic reactions and reconstruct them in vitro (meaning in a test tube) to synthesize a natural product that has therapeutic potential.

Many natural products have prospective use as drugs. However, the chemistry required to create the molecules is complex. Penicillin was one of the earliest discovered antibiotic compounds produced and isolated from a living organism. In 1928, Sir Alexander Fleming observed that the mold Penicillium notatum could kill colonies of the bacteria Staphylococcus aureus [1]. Over a decade later, Howard Florey and Ernst Chain isolated the active ingredient and successfully treated mice that had been given lethal doses of bacteria [2]. The combined efforts of these three men and others literally changed the practice of medicine by the mid-1940s.

With advances in organic chemistry, many antibiotics today are created by chemical synthesis. However, mimicking nature by identifying, producing and characterizing the appropriate enzymes, not to mention ensuring each enzyme enters the reaction at the proper time in the biosynthetic pathway, is exceedingly complicated. Two U.S. research groups have demonstrated the ability to do just this, thus imitating a biosynthetic process outside the cell.

The first study, carried out at the University of California, demonstrated the multienzyme biosynthesis of the Streptomyces maritimus bacteriostatic agents (meaning an antibiotic that inhibits the growth and reproduction of bacteria without killing them) enterocin and wailupemycin [3]. The production of enterocin from benzoic acid required 12 enzymes. Both antibiotics are naturally created by a Hawaiian sea sediment bacterium.

The second study done at Harvard Medical School in Boston, Massachusetts, demonstrated the biosynthesis of the antitumor fungal metabolite terrequinone A [4]. The researchers first identified the biosynthetic pathway in the fungi Aspergillus nidulans and then reconstituted it in a test tube. The reaction required 5 enzymes and the study constitutes the first identification of a biosynthetic pathway for that class of fungal toxins.

Until now, only the complex biosynthetic pathways inside a cell could manipulate the chemical structure of a substance and produce a natural molecule. One of the lead authors of the University of California study said [5] that it:

… may signal the start of a new era in how drugs are synthesized. Assembling all the enzymes together in a single reaction vessel is a different way to make a complex molecule.

More work is required to scale up the process for mass production. However, the studies prove that biosynthesis of natural products is possible without the use of man-made chemicals - a concept known as green chemistry - and can be done relatively cheaply.

Green chemistry attempts to reduce or eliminate the generation and use of hazardous substances in the design and development of chemical products and processes. Green chemistry began in the United States following the passage of the Pollution Prevention Act of 1990, which established a national policy to prevent or reduce pollution at its source whenever feasible. Following the act’s passage, the EPA Office of Pollution Prevention and Toxics (OPPT) launched a program that included grant support of research to prevent pollution in the synthesis of chemicals. Today, the mission of the EPA Green Chemistry Program is to promote innovative chemical technologies that reduce or eliminate the use or generation of hazardous substances in the design, manufacture, and use of chemical products.

References

1. The Most Important People of the Century - Scientists & Thinkers - Alexander Fleming. The Time 100. 2003.
2. Chain et al. Penicillin as a Chemotherapeutic Agent. Lancet, vol. 2. 1940, pp. 226-228.
3. Cheng et al. Enzymatic total synthesis of enterocin polyketides. Nat Chem Biol. 2007 Sep;3(9):557-8. Epub 2007 Aug 12.
   View abstract
4. Balibar et al. Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation. Nat Chem Biol. 2007 Sep;3(9):584-92. Epub 2007 Aug 12.
   View abstract
5. Simple Method To Create Natural Drug Products Developed. ScienceDaily. 2007 Sept. 5.