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HOME > PAST ISSUE > March-April 2014 > Article Detail

FEATURE ARTICLE

Engineered Molecules for Smarter Medicines

Specially designed polymers can dodge the body’s immune defenses to deliver vital medicine where it is needed most.

Darlene K. Taylor, Uddhav Balami

Thermo-Responsive Drug Delivery

With their unprecedented ability to alter their physical properties in response to temperature changes, thermo-responsive polymers make good building blocks for intelligent drug delivery systems, either on their own or in combination with other materials. Medical scientists, biotechnologists, and pharmaceutical researchers have been quick to seize the opportunity. A growing number of polymer-based drug delivery systems are already under development. In some cases, a particular polymer is engineered to serve a specific purpose. ReGel® is a broadly used delivery platform made by Allergan and marketed in two formulations: OncoGel® when coupled with chemotherapeutic agent paclitaxel for esophageal cancer, and Cytoryn™ when coupled with interleukin-2 (IL-2) for cancer immunotherapy. In similar fashion, Timoptic-XE® (Merck & Co.) is used for slow-release delivery of the drug timolol to treat hypertension within the eye.

2014-03TaylorFp112.jpgClick to Enlarge ImageAt North Carolina Central University, our laboratory has pioneered the development of LiquoGel, another synthetic thermo-responsive polymer for targeted drug delivery. (We have filed for a patent on this work, but have not yet begun to commercialize it.) At room temperature, LiquoGel forms an aqueous solution that can be administered by syringe to specific sites in the body. Once in place, the solution warms up to body temperature and assumes the form of a gel. The therapeutic drug suspended in the solution becomes trapped within the gel, to be released gradually at the site of administration as the gel degrades.

The physical changes of LiquoGel on exposure to mild heat make it suitable for a variety of medical applications. In one of its most extensively tested applications so far, collaborators at Duke University have identified targets in the treatment of uterine fibroids, for which LiquoGel can be pivotal in delivering insoluble, highly effective medicines.

Fibroid growths in the uterus, composed of muscle and fibrous tissue, affect 70 to 80 percent of all American women by the age of 50. Although benign, uterine fibroids pose a significant public health problem when they cause pain or excessive menstrual bleeding, or problems in pregnancy. As the leading indication for hysterectomy in the United States today, this condition entails healthcare costs of more than $2 billion each year. Nevertheless, the current treatment options for uterine fibroids are unsatisfactory.

Surgical procedures (myomectomy, uterine artery embolization, and MRI-guided focused ultrasound) can destroy fibroids while preserving the uterus, but they are lengthy and expensive, and the fibroids frequently recur afterward. Medical therapies, too, are often short-lived or accompanied by significant side effects, or their clinical trial results have been disappointing. Effective drug molecules exist—selective progesterone receptor modulators, for example, have demonstrated significant shrinkage of fibroids and symptomatic improvement—but have not yet received FDA approval, owing to concerns over the effect of these agents on the endometrium.

2014-03TaylorFp114top.jpgClick to Enlarge ImageUsing polymers to deliver a therapeutic agent directly into uterine fibroids is a novel approach that has the potential to reduce systemic side effects considerably. As an additional advantage, administering a drug directly to the fibroid can be used to deliver small peptides that would be degraded in the gastrointestinal tract if the drug were taken orally. Treating fibroids by means of a local injection—a procedure that can be accomplished in a doctor’s office—could significantly improve the feasibility of helping women who want to maintain fertility while seeking relief from troubling uterine symptoms. Moreover, by slowing the diffusion of the drug away from the injected fibroid, prolonging the release of the drug and delaying its inactivation, polymer-based treatments should reduce the need for repeated injections.

Other research teams have designed a different kind of thermo-responsive drug delivery system, one that uses a synthetic type of fluid-filled pouch called a liposome, for treating various medical conditions. Although liposomes do not occur in nature, they are derived from biological polymers: Their bilayer, the membrane that encloses them, is made of the same phospholipids found in all living cells.

Clinical trials now under way are testing these thermo-sensitive liposomes (TSLs), as they are known, in several applications. As an example, TSLs designed with a trigger temperature of 40 to 45 degrees C can deliver the antitumor drug doxorubicin (commercially known as ThermoDox®, made by Celsion Corporation) to specific sites. Currently in Phase II clinical trials for the treatment of breast cancer and colorectal liver metastasis, the same drug delivery system has recently entered Phase III trials for the treatment of primary liver cell carcinoma.

Yet another approach was described by the research team of Z. S. Al-Ahmady at the Centre for Drug Discovery, University College London, using a peptide-liposome hybrid with a coil of the amino acid leucine embedded in the lipid bilayer, like a plug in a hole. This system combines the TSL benefit of supramolecular assembly (the lipid bilayer plus the drug inside) with the property of responding to heat by unfolding its protein structure. At cool temperatures, the peptide portion curls up on itself. But above the trigger temperature—typically about 40 to 45 degrees C—the peptide’s primary fold opens like the two halves of a zipper, unsealing the outer membrane of the bilayer and releasing the drug at the desired site. The ability to fine-tune the trigger temperature and the way the configuration of the molecules change in response to heat make leucine peptides attractive for the design of smart drug delivery vesicles.

The liposomes suitable for transporting drugs within the body must all be capable of releasing their contents, but not all liposomes are rendered permeable by the same means. In some instances the lipid bilayer takes on a gel-like state that then degrades in the body, gradually releasing the drug. In others, a peptide embedded in the bilayer breaks apart, leaving a hole.

2014-03TaylorFp115.jpgClick to Enlarge ImagePerhaps the most unexpected mechanism for opening a liposome at the right critical temperature is the use of bubbles. This innovative approach relies on creating permeable defects in the lipid bilayer with carbon dioxide bubbles. The carbon dioxide is generated (along with water and ammonia) as a result of the decomposition of ammonium bicarbonate—more commonly known as baking ammonia—at about 42 degrees C. (This is, in fact, the same principle used to leaven bread and cakes.) In this type of liposome delivery system, the gas bubbles created inside the membrane build up pressure and distort the arrangement of the membrane bilayers. As the carbon dioxide bubbles permeate the lipid bilayer, the compartmentalized drug is quickly released. The bubbles not only create the necessary defects in the lipid bilayer, enabling the drug to escape, they also help yield clearer results in ultrasound-guided tissue imaging.








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