Tiny particles called nanodiamonds (NDs) are very promising candidates in nanomedicine. Researchers have demonstrating that nanodiamonds offer a significant potential as gene/drug delivery platforms in the treatment of cancer. While the potential of nanodiamond in drug delivery has been demonstrated, fundamental mechanisms, thermodynamics, and kinetics of drug adsorption on nanodiamond are still poorly understood.

In a study, supported by a National Science Foundation CAREER Award, the Center for Scalable and Integrated NanoManufacturing and published in the advance online issue of the peer-reviewed journalNanomedicine: Nanotechnology, Biology and Medicine, researchers at UCLA’s Jonsson Comprehensive Cancer Center explain how they have developed an innovative drug-delivery system in which nanodiamonds are used to carry chemotherapy drugs directly into brain tumors, including glioblastoma.[1]The scientists found that this new method resulted in greater cancer-killing efficiency and fewer harmful side effects than existing treatments.

Convection-enhanced delivery of ND?DOX offer a powerful treatment delivery system against very difficult and deadly brain tumors.

The research was a collaboration between Dean Ho of the UCLA School of Dentistry and colleagues from the Lurie Children’s Hospital of Chicago and Northwestern University’s Feinberg School of Medicine. Ho co-directs UCLA Dentistry’s Weintraub Center for Reconstructive Biotechnology and is a professor in the division of oral biology and medicine, the division of advanced prosthodontics, and the department of bioengineering.

Glioblastoma is the most common and lethal type of brain tumor. Based on estimates from the U.S. National Cancer Institute (NCI) there will be 23,130 new cases and 14,080 deaths from brain and other nervous system cancers in the United States in 2013.

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Despite treatment with surgery, radiation and chemotherapy, the median survival time for glioblastoma patients is less than one-and-a-half years. The tumors are notoriously difficult to treat, in part because chemotherapy drugs injected alone often are unable to penetrate the system of protective blood vessels that surround the brain, known as the blood?brain barrier. And those drugs that do cross the barrier do not stay concentrated in the tumor tissue long enough to be effective.

Doxorubicin (Adriamycin PFS, Adriamycin RDF, or Rubex), a common chemotherapy agent belonging to a group of medicines known as antineoplastics, has shown promise in a broad range of cancers. the drug, which is often used in combination with other cancer medicines, has served as model drug for the treatment brain tumors when injected directly into the tumor. Ho’s team originally developed a strategy for strongly attaching doxorubicin molecules to nanodiamond surfaces, creating a combined substance called ND?DOX.

Myelogenous Leukemia
In an unrelated study, scientists synthesized nanodiamond vectors capable of chemotherapeutic loading and delivery for the treatment of patients with chemoresistant human myelogenous leukemia. They prepared a nanodiamond-daunorubicin (ND-DNR) conjugate – a novel therapeutic payload for ND – to overcome multidrug resistance conferred by incremental daunorubicin exposure, to demonstrate the efficacy enhancement resulting from ND-based delivery. The results of this study showed that nano diamonds were able to improve daunorubicin delivery into resistant leukemia cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains.[2]

What are nanodiamonds
Nanodiamonds are carbon-based particles roughly ~4 to 5 nanometers (nm) in diamter that can carry a broad range of drug compounds. They are nontoxic, and they do not activate the body’s immune system does not recognize them.And because they are tiny nanodiamonds the kidneys are able to clear them from the body before they block up blood vessels – one of the long-standing problems in nanoparticle therapy.

However, to fully exploit the potential of nanodiamond in anti-cancer drug delivery, researchers need to focus purity, surface chemistry, dispersion quality, as well as to temperature, ionic composition, and other parameters of the environment that may influence drug adsorption and desorption on nanodiamond.

Nanodiamonds can bind tightly to a variety of molecules and deliver them right into a tumor. And while tumor-cell proteins are able to eject most anticancer drugs that are injected into the cell before those drugs have time to work, they can’t get rid of the nanodiamonds. Thus, drug?nanodiamond combinations remain in the cells much longer without affecting the tissue surrounding the tumor.

Ho and his colleagues hypothesized that glioblastoma might be efficiently treated with a nanodiamond-modified drug by using a direct-injection technique known as convection-enhanced delivery, or CED. They used this method to inject ND?DOX directly into brain tumors in rodent models.

The researchers found that ND?DOX levels in the tumors were retained for a duration far beyond that of doxorubicin alone, showing that doxorubicin was taken into the tumor and remained their longer when attached to nanodiamonds. In addition, ND?DOX was also found to increase apoptosis or programmed (cancer) cell death, and decrease cell viability in glioma (brain cancer) cell lines.

The results also demonstrated for the first time that the ND?DOX delivery limited the amount of doxorubicin that was distributed outside the tumor. This reduced toxic side effects and kept more of the drug in the tumor for longer, increasing the drug’s tumor-killing efficiency without affecting the surrounding tissue. Survival time increased significantly in the rats treated with ND?DOX, compared with those given only unmodified doxorubicin.

Nanodiamonds have many facets, almost like the surface of a soccer ball, and can bind to doxorubicin very strongly and quickly, Ho noted. Further research will expand the list of brain-cancer chemotherapy drugs that can be attached to the nanodiamond surfaces to improve treatment and reduce side effects.

Promising vehicles
For a nanoparticle to have translational significance, it has to have as many benefits engineered into one system as simply as possible. “Nanomaterials are promising vehicles for treating different types of cancer,” Ho said. “We’re looking for the drugs and situations where nanotechnology actually helps chemotherapy function better, making it easier on the patient and harder on the cancer.”

“This study showed that convection-enhanced delivery of ND?DOX offers a powerful treatment delivery system against these very difficult and deadly brain tumors,” Ho explained. He noted that “…this large-scale project has been successful thanks to the multidisciplinary and proactive interactions between his team of bioengineers and their outstanding clinical collaborators from Northwestern University and Lurie Children’s Hospital.”

For more information:
[1] Xi G, Robinson E, Mania-Farnell B, Vanin EF, Shim KW, Takao T, Allender EV, Mayanil CS, Soares MB, Ho D, Tomita T.Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment.Nanomedicine. 2013 Aug 3. pii: S1549-9634(13)00354-7. doi: 10.1016/j.nano.2013.07.013. [Epub ahead of print][Article][PubMed]
[2] Man HB, Kim H, Kim HJ, Robinson E, Liu WK, Chow EK, Ho D. Synthesis of nanodiamond-daunorubicin conjugates to overcome multidrug chemoresistance in leukemia.Nanomedicine. 2013 Aug 3. pii: S1549-9634(13)00355-9. doi: 10.1016/j.nano.2013.07.014. [Epub ahead of print][Article][PubMed]

Photo: The retention of doxorubicin and ND-DOX in brain tissue, with light microscopic images (upper rows) and fluorescence images detecting fluorescence generated from doxorubicin (lower rows). The images show the distribution of unmodified doxorubicin and ND-DOX after convection-enhanced delivery (CED) at 6, 16, 24 and 72 hours. Courtesy:UCLA’s Jonsson Comprehensive Cancer Center.

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