Nanogels used with drugs

Carnegie Mellon researchers have developed non-toxic, biodegradable nanogels that can be used for delivery of carbohydrate-based drugs.

The nanogels were developed using atom transfer radical polymerization (ATRP) in professor Krzysztof Matyjaszewski’s laboratory.

ATRP allows chemists to control the number and length of polymers, or molecular chains, by adjusting the ratio of initiator to monomer.

“Using ATRP, we can make spheres of the same diameter, therefore the nanogels are all uniform in size,” said Daniel Siegwart, a graduate student in the Matyjaszewski lab. “We are creating a more homogenous system.”

The nanogels have even mesh sizes, meaning that the distance of polymer chains between the cross-linking points is equal.

“This is unique because it allows the gels to have improved swelling properties and enhances the release of the drug trapped inside in a uniform, time-controlled manner.”

The nanogels offer many advantages to current drug delivery techniques due to their unique physical characteristics.

“Gels are polyethylene oxide (PEO) based — this can repel proteins and reduce absorption to material, hence enhancing circulation time in the blood.”

The nanogels are also biodegradable, and they are not toxic to cells.

“If a foreign antigen is too big, phagocytes of the immune system will engulf the particles. The size of our nanogels — about 200 nanometers in diameter — is the perfect size because it will not be filtered through the liver or kidneys, nor will it be engulfed. It won’t be easily removed,” Siegwart said.

Brian Belardi, a senior chemistry major conducting research in the lab, stated, “Nanogels are ideal for drug delivery, because they are able to traverse the cellular membrane via endocytosis or, if they are sufficiently small, through pores in the membrane.”

Endocytosis is a method cells use to absorb material from the outside through their cell membrane.

“In addition, because of the nature of ATRP, the various cross-linked polymeric chains are end-functionalized, allowing chemical modification to take place. We are able to modify the nanogels so that any ligand of a cellular receptor can be attached, which targets the nanogels to specific cells and facilitates their endocytosis,” Belardi said.

A ligand is a molecule that can recognize a cellular receptor and attach to it, making the nanogels cell–specific.

The nanogels were developed using inverse miniemulsion ATRP, a process developed by former postdoctoral associate Jung Kwon Oh in the Matyjaszewski lab.

While regular ATRP involves a water-oil emulsion in which the majority phase is water and the minority phase is a hydrophobic substance, inverse miniemulsion is just the opposite. The majority phase is hydrophobic, and the minority phase is water.

The two phases are then mixed using sonification, which creates water droplets dispersed in the oil phase.

The components needed to synthesize polymers — the monomer, initiator and catalyst — are in the water droplets.
The emulsion is stabilized by a soap surfactant that allows the water droplets to remain immersed in the oil.

Siegwart said, “While regular emulsion, in which the majority phase is water and the minority phase is hydrophobic, is cheaper and environmentally friendly, it is not so applicable to biological systems.

“With inverse miniemulsion, a polymer chemist can make water-soluble materials, which are much more applicable to biological applications.”

The ability of the nanogels to enter a cell and allow the release of the encapsulated drug was demonstrated using doxorubicin, an anti-cancer drug. According to a Carnegie Mellon press release, researchers encapsulated doxorubicin in the nanogels, and mixed them with HeLa cancer cells.

Before gel degradation, the cancer cells were healthy and proliferating. After release of the cancer drug, however, cancer cell growth became significantly inhibited.

The Matyjaszewski lab hopes to make these nanogels applicable to other materials besides carbohydrates.

“We want to address another difficult problem in medicinal biology, the cellular delivery of antigene agents,” said Belardi. Scientists are working on the delivery of agents that suppress gene expression.

“Specifically, I am looking at the delivery of small interference RNA, siRNA, molecules which suppress the expression of a target gene in the cell.”

This research was funded by the National Science Foundation and the National Institutes of Health.