ORLANDO, FL—Japanese investigators are testing a novel drug delivery system that uses a stent graft to release drugs directly into the wall of the aorta, a strategy that could discourage aneurysm progression. Early encouraging studies in mice were reported on Tuesday, November 15, 2011, at the American Heart Association Scientific Sessions.

Researchers led by Koichi Yoshimura, MD, PhD, of Yamaguchi University School of Medicine (Ube, Japan), are evaluating the device as a method for adjuvant drug delivery to counteract aneurysm exclusion failures after endovascular repair. Dr. Yoshimura has previously demonstrated that abdominal aortic aneurysms (AAA) can be successfully treated in mice by pharmacologically inhibiting c-Jun N-terminal kinase (JNK) and that statins exert beneficial effects on AAAs by inhibiting the secretion of MMP-9, a marker of wall degeneration. He noted that other investigators have shown that statins may be able to attenuate the growth of AAAs in humans.

DES, Systemic Delivery Not the Answer

A JNK inhibitor or statin could be delivered systemically to prevent expansion and rupture of an aneurysm after EVAR. However, systemic administration of potential therapeutic agents has been associated with adverse systemic effects. Drug-eluting stents also could be a means of delivering drugs to aortic aneurysms. However, control of drug elution is often poor, Dr.  Yoshimura said.

Dr. Yoshimura and colleagues are developing a novel alternative to systemic drug therapy or DES: a hybrid drug delivery system that incorporates chemical compounds or drugs in a target-recognizing nanocarrier. The nanocarrier encloses the desired drug within a drug-release shell. The nanocarrier transports the drug through the bloodstream until a target-recognition molecule on its surface can find and attach itself to a corresponding target molecule on the surface of a vascular stent graft. Once it is stimulated, or charged, the nanocarrier releases the drug through the stent graft and into the wall of the aorta.

Development of a Hybrid Drug-Delivery Device

A bio-nanocapsule consisting of a biotinylated hepatitis B virus surface antigen plus a lipid bilayer has been constructed. Liposomes have been loaded with drugs such as a JNK inhibitor and statins for treating aneurysms. The bio-nanocapsule has been conjugated with the drug-containing liposomes to create a bio-nanocapsule-liposome complex.

A target-recognizing nanocarrier capable of transporting the bio-nanocapsule-liposome complex and attaching it to a stent graft also has been created. Biotin on the surface of the nanocarrier has been linked with biotin on the surface of a prosthetic vascular graft and visualized by means of a fluorescent-labeled conjugate, NeutriAvidin.

Preclinical Work 

In in vitro studies the targeted nanocarrier-liposome complex successfully linked with a biotinylated targeted graft but not an untreated graft. A sham nanocarrier-liposome construct did not connect to an untreated graft or a biotinylated targeted graft.

In murine studies, NeutriAvidin was able to bind to a biotinylated stent graft. Fifteen minutes after injection, NeutriAvidin was detected at the site of the biotinylated graft in the inferior vena cava.

The drug delivery system was charged and recharged in vivo. The target-recognizing bio-nanocapsule-liposome complex accumulated at the site of the targeted graft after intravenous injection in the initial charge. The complex accumulated again at the targeted graft after a second charge 24 hours later.

The researchers examined the local drug delivery from the graft to the aortic wall in mice. For this experiment, the graft bound to statin-containing nanocarriers was placed close to the mouse abdominal aorta. When high expression of MMP-9 was induced in the aortic tissue, the statin-containing graft significantly reduced MMP-9 expression, indicating successful local drug delivery from the graft to the aortic wall in vivo.

Future Prospects

“The development of a rechargeable drug delivery system could be a major step forward for endovascular aneurysm repair,” Dr. Yoshimura said. “The system could be used to release drugs to aneurysms when needed and perhaps produce better long-term outcomes.”

 

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Source:
Yoshimura K. Development of a novel hybrid device with rechargeable drug-eluting capability for minimally invasive treatment of aortic aneurysms. Presented at: American Heart Association Scientific Sessions 2011; November 15, 2011; Orlando, FL.