October 1, 2008

Researchers use nanoparticles to deliver treatment for brain, spinal cord injuries

WEST LAFAYETTE, Ind. - Purdue University researchers have developed a method of using nanoparticles to deliver treatments to injured brain and spinal cord cells.

A team led by Richard Borgens of the School of Veterinary Medicine's Center for Paralysis Research and Welden School of Biomedical Engineering coated silica nanoparticles with a polymer to target and repair injured guinea pig spinal cords. That research is being published in the October edition of the journal Small.

The team then used the coated nanoparticles to deliver both the polymer and hydralazine to cells with secondary damage from a naturally produced toxin. That research was published in August by the journal Nanomedicine.

Borgens' group had previously shown benefits of the polymer polyethylene glycol, or PEG, to treat rats with brain injuries and dogs with spinal cord injuries. PEG specifically targets damaged cells and seals the injured area, reducing further damage. It also helps restore cell function, Borgens said.

In previous studies, PEG was mixed with saline and injected.

"Composition and concentration limited how much PEG we could get to the injury," he said.

"If you change the composition to make the PEG more potent, it produces ethylene glycol, the poison in antifreeze. If you change the concentration of PEG in another way, the solution becomes syrupy and difficult to inject."

So the team - which includes Youngnam Cho of the Center for Paralysis Research, Riyi Shi of the center and Weldon School, and Albena Ivanisevic of Weldon School and the Department of Chemistry - turned to silica nanoparticles.

"These particles are so tiny they can't be seen with a regular microscope. They are about the size of a large virus. So you can inject as many as you need. And they are safe inside bodies," Borgens said.

In the first study, the researchers coated the nanoparticles with PEG to treat guinea pig spinal cord injuries. The treated spinal cord cells showed improved physiological functioning.

In the second study, the researchers added both PEG and hydralazine, an antihypertension drug, to mesoporous silica nanoparticles. These nanoparticles have pores that can hold the drug, which is later delivered to the damaged cells. The hydralazine was added to fight off secondary damage to cells that occurs after the initial injury.

"When cells are injured, they produce natural toxins," Borgens said. "Acrolein is the most poisonous of these toxins. It's an industrial hazard for which hydralazine is an antidote."

Borgens and his team introduced acrolein into cells and then treated the cells with different combinations of hydralazine and/or PEG delivered by the mesoporous silica nanoparticles.

They found that the treatment restored disrupted cell function caused by acrolein.

The team concluded that the use of nanoparticles to deliver both PEG and hydralazine increased the effectiveness of earlier PEG-only treatment by controlling and concentrating release of the drug and the polymer, producing a dual treatment and prolonging the treatment's duration.

The goal of Borgens' research is to improve the quality of life of those who have suffered head or spinal cord injuries.

"All ambulances should have PEG on board," he said. "It can probably save thousands of people from more severe head and spinal damage."

Financial support for the studies came from the state of Indiana and an endowment from Mari Hulman George.

The researchers now are testing the PEG/hydralazine treatment on rats with brain injuries. By the end of the year, they hope to test the treatment on naturally injured paraplegic dogs.

Writer: Judith Barra Austin, (765) 494-2432, jbaustin@purdue.edu

Source: Richard Borgens, (765) 494-7600, cpr@purdue.edu

Purdue News Service: (765) 494-2096; purduenews@purdue.edu


Repairing the Damaged Spinal Cord and Brain
with Nanomedicine 

Youngnam Cho, Riyi Shi, Richard B. Borgens,
 Albena Ivanisevic, Purdue University

Nanoparticle bioengineering techniques were used to produce injectable non-toxic polymer surfaced, silica based colloids (PSC). PSCs were found to preferentially target the damaged tissues of adult guinea pig spinal cord; to immediately restore the conduction of nerve impulses through the length of crushed guinea pig spinal cords both in an isolation chamber and in vivo following subcutaneous injection; to seal/restore the integrity of nerve fiber membranes proven by intracellular dye exclusion probes; and to reduce to baseline the efflux of a large intracellular enzyme (Lactic Dehyrogenase) - another indicative probe for membrane compromise. We discuss the medical significance of these findings, and the status of ongoing experiments in spinal cord and head injury animal models.


  Functionalized Mesoporous Silica Nanoparticle-based Drug Delivery System to Rescue
 Acrolein-mediated Cell Death 

Youngnam Cho, Riyi Shi, Richard B. Borgens,
Albena Ivanisevic, Purdue University

Aims: Mesoporous silica nanoparticles (MSNs) were prepared and characterized to develop a drug delivery system by loading them with hydralazine and functionalizing them with polyethylene glycol. These agents restore damaged cell membranes and ameliorate abnormal mitochondria behavior induced by the endogenous toxin acrolein. Such a formulation shows potential as a novel therapeutic agent. Results and discussion: MSNs with encapsulated hydralazine and covalently linked with PEG were synthesized and characterized subsequently by transmission-electron microscopy, N2 adsorption/desorption, x-ray diffraction and UV-vis spectroscopy. MSNs exhibited large surface area, pore volume and tunable pore size. The mean particle size was 100 nm and hydralazine encapsulation efficiency was almost 25%.  These were tested using PC12 in culture to restore their disrupted cell membrane and to improve mitochondria function associated with oxidative stress after exposure to acrolein. LDH, MTT, ATP and glutathione assays were used to examine the physiological functioning of the samples and the loss of LDH from the cytoplasm assayed the integrity of the membranes. These evaluations are sufficient to initially demonstrate drug delivery (concentrated hydralazine) into the compromised cells cytoplasm using the MSNs as a vehicle. Conclusion: MSNs modified with drug/polymer constructs provide significant neuroprotection to cells damaged by a usually lethal exposure to acrolein.

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