Formulation Development Forum: Nanosized Dendrimers

Nanosized systems are important in drug delivery. Such nanosized systems include liposomes, nanocrystals, micelles, colloidal particles, quantum dots, and dendrimers. Dendrimers are class of synthetic macromolecules with highly branched, monodispersed, circular, and symmetrical architecture that are used as carrier molecules in drug delivery (1). Researchers at the Mayo Clinic in Rochester, Minnesota, Wayne State University in Detroit, Michigan, and John Hopkins Medicine in Baltimore, Maryland, recently reported on using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices to treat age-related macular degeneration and retinitis pigmentosa (2).

Dry age-related macular degeneration and retinitis pigmentosa are caused by neuroinflammation, which progressively damages the retina and can lead to blindness. The research tested the dendrimer delivery system in rats that develop neuroinflammation. The researchers showed that steroids attached to the dendrimers targeted the damage-causing cells associated with neuroinflammation but left the rest of the eye unaffected and preserved vision, according to a Dec. 13, 2011, Wayne State University press release.

The principal authors of the study, Raymond Iezzi, MD, an ophthalmologist at the Mayo Clinic, and Rangaramanujam Kannan, PhD, a professor of ophthalmology at The Wilmer Eye Institute of Johns Hopkins, developed a clinically relevant, targeted, sustained-release drug delivery system using a simple nanodevice construct (2). The experimental work in rat models showed that one intravitreal administration of the nanodevice in microgram quantities could offer neuroprotection at least for a month, according to the press release.

Because steroids have neuroprotective and anti-inflammatory properties, the researchers tried to deliver them precisely to the right target. The PAMAM dendrimers were used as drug delivery vehicles. “Dendrimers are tree-like, noncytotoxic polymeric drug delivery vehicles (approximately 4 nm),” explained Kannan in the press release. “Surprisingly, the activated microglia in the degenerating retina appeared to eat the dendrimer selectively and retain them for at least a month. The drug is released from the dendrimer in a sustained fashion inside these cells, offering targeted neuroprotection to the retina,” said Kannan.

Upon intravitreal administration, the PAMAM dendrimers selectively localized within the activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This biodistribution covalently conjugated fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. According to the researchers, these studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia and to deliver drugs. Although the steroid offers only temporary protection, the treatment as a whole provided sustained relief from neuroinflammation. The patent-pending technology will be advanced further through a multi-university collaboration among Johns Hopkins, the Mayo Clinic, and Wayne State University, according to the release.

Sources

1. G. T. Tolia and H.H. Choi, Pharm. Technol. 32 (11), 88–98 (2008).

2. R. Iezzi et al., “Dendrimer-Based Targeted Intravitreal Therapy for Sustained Attenuation of Neuroinflammation in Retinal Degeneration,” Biomaterials online, DOI 0.1016/j.biomaterials.2011.10.010, Nov. 1, 2011.