Omid Farokhzad, MD

Research Round-up

Nanoparticles Rule Antibiotic and Chemotherapy Delivery

In a prominent study, Omid Farokhzad, MD, director of the BWH Laboratory of Nanomedicine and Biomaterials, Robert Langer, ScD of MIT and colleagues from Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), BIND Biosciences, Translational Genomics Research Institute (TGen), Wayne State University Karmanos Cancer Institute, and Weill Cornell Medical College have found promising effects of a first-in-class targeted cancer drug called BIND-014 in treating solid tumors.

It is the first targeted and programmed nanomedicine to enter human clinical studies. The researchers demonstrate the encapsulated nanoparticle’s ability to effectively target a receptor expressed in tumors to achieve high tumor drug concentrations.

The researchers produced data that include pharmacokinetic characteristics consistent with prolonged circulation and controlled drug release with plasma concentrations remaining up to at least 100-fold higher than conventional docetaxel for over 24 hours, as well as up to a 10-fold increase in intratumoral drug concentrations with prolonged and enhanced tumor growth suppression in multiple tumor models compared with conventional docetaxel (Taxotere).

Moreover, initial clinical data in a heavily pretreated patient population with 17 patients with advanced or metastatic solid tumor cancers indicated that BIND-014 displays pharmacological characteristics consistent with preclinical findings of differentiated pharmacokinetics and accumulation at tumor sites with clinical effects seen at doses as low as 20 percent of the normally prescribed docetaxel dose and in cancers in which docetaxel has minimal activity.

The study was published in the April 4, 2012 online issue of Science Translational Medicine.

Farokhzad and colleagues at MIT have also developed a nanoparticle designed to evade the immune system and home in on infection sites, then unleash a focused antibiotic attack. The approach would mitigate the side effects of some antibiotics and protect the beneficial bacteria that normally live inside our bodies.

Farokhzad, Langer and team created the new nanoparticles from a polymer capped with polyethylene glycol (PEG). They then induced the particles to specifically target bacteria. The antibiotic-carrying nanoparticles can switch their charge depending on their environment. While they circulate in the bloodstream, the particles have a slight negative charge. However, when they encounter an infection site, the particles gain a positive charge, allowing them to tightly bind to bacteria and release their drug payload.

The researchers designed the particles to deliver vancomycin, used to treat drug-resistant infections, but the particles could be modified to deliver other antibiotics or combinations of drugs. The researchers found that antibiotics carried by nanoparticles retained their potency better than traditional antibiotics in an acidic environment.

The study was published in the April 3, 2012 online issue of ACS Nano.

Communicating Immune Response

Samia Khoury, MD

Interleukin-9, a protein involved in cell-to-cell communication, is responsible for regulating autoimmune response. In a study led by Wassim Elyaman, PhD, instructor of neurology in the laboratory of Samia Khoury, MD, Center for Neurologic Diseases, researchers analyzed the co-stimulatory requirements of Th9 cells, the white blood cells responsible for making interleukin-9. The researchers demonstrated that two types of cell-signaling pathways, known as Notch and TGF-beta/Smad3, worked together to induce interleukin-9 production.

Moreover, using an animal model of encephalomyelitis, the researchers showed how these proteins regulated immune response. They demonstrated that a Notch pathway protein called Jagged2, expanded regulatory T cells (a type of immune cell) and suppressed encephalomyelitis when given before antigen immunization. However, encephalomyelitis worsened when Jagged2 was given alongside immunization.

“Although interleukin-9 was discovered over two decades ago, Th9 cells were only recently identified,” said Elyaman. “There is still much unknown about interleukin-9 and the cells that produce it in the context of autoimmunity. But the data collected so far by our group and others underscore the uniqueness of the interleukin-9 system."

The study was published in the April 12, 2012 online issue of Immunity.

Wassim Elyaman, PhD, Elizabeth Bradshaw, PhD, Ribal Bassil, MD, and William Orent

Natural Selection at Work: Genes Encoding Protein Network for AD Susceptibility

A study led by Philip De Jager, MD, PhD, and Towfique Raj, PhD, both from the Department of Neurology, explored large-scale human genome data to better understand the functions and interactions of loci (specific locations of genes on a chromosome) associated with Alzheimer’s disease (AD).

They found significant evidence for signatures of recent natural selection acting on several haplotypes (a collection of DNA gene sequences). The findings suggest that several genes associated with AD risk (specifically at PICALM, BIN1, CD2AP and EPHA1) have evolved together, and that the proteins encoded by these genes physically interact. Therefore, these genes may be components of a shared molecular mechanism that affects AD susceptibility. The researchers speculate that the positive selection of these loci might be due to various reasons, such as pathogen resistance or environmental and dietary changes as humans evolved. The existence of a shared pathway through which multiple genes and their byproducts affect AD risk would be an important focus for future gene discovery and the development of targeted therapies to fight against this disease.

The study was published in the April 5, 2012 issue of The American Journal of Human Genetics.