Cancers can become resistant to standard chemotherapeutic drug. Nanodiamonds have been used deliver the chemotherapeutic drug doxorubicin to cancer cells, a route that bypasses the pumps and inhibits the growth of chemoresistant tumors. [CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE]
Northwestern University – Chemotherapy drug resistance contributes to treatment failure in more than 90 percent of metastatic cancers. Overcoming this hurdle would significantly improve cancer survival rates.
In studies of liver and breast cancer models in vivo, Ho and a multidisciplinary team of scientists, engineers and clinicians found that a normally lethal amount of a chemotherapy drug when bound to nanodiamonds significantly reduced the size of tumors in mice. Survival rates also increased and no toxic effects on tissues and organs were observed.
Enhancing chemotherapeutic efficiency through improved drug delivery would facilitate treatment of chemoresistant cancers, such as recurrent mammary tumors and liver cancer. One way to improve drug delivery is through the use of nanodiamond (ND) therapies, which are both scalable and biocompatible. Here, we examined the efficacy of an ND-conjugated chemotherapeutic in mouse models of liver and mammary cancer. A complex (NDX) of ND and doxorubicin (Dox) overcame drug efflux and significantly increased apoptosis and tumor growth inhibition beyond conventional Dox treatment in both murine liver tumor and mammary carcinoma models. Unmodified Dox treatment represents the clinical standard for most cancer treatment regimens, and NDX had significantly decreased toxicity in vivo compared to standard Dox treatment. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for overcoming chemoresistance and enhancing chemotherapy efficacy and safety.
Nanodiamonds are carbon-based materials approximately 2 to 8 nanometers in diameter. Each nanodiamond’s surface possesses functional groups that allow a wide spectrum of compounds to be attached to it, including chemotherapy agents.
The researchers took these nanodiamonds and reversibly bound the common chemotherapy drug doxorubicin to them using a scalable synthesis process, which enhances sustained drug release.
Ho and his colleagues studied mouse models with liver and breast cancers. In these resistant cancers, drugs are able to get inside the tumors but are kicked right back out because of an innate response in the liver and breast to expel these drugs.
They treated one group of animals with the doxorubicin-nanodiamond complexes and another group with the drug alone. In those treated with the nanodiamond complexes, the chemotherapeutic remained in circulation longer — up to 10 times longer — than those treated with the drug alone. In addition, the drug itself was retained within both types of tumors for a significantly longer period of time. Such a high retention rate means a smaller amount of the very toxic drug would need to be administered, thus reducing side effects.
The researchers also found that the drug-nanodiamond complexes had no negative effect on the white blood cell count. This is especially important for cancer treatment: if the white blood cell count drops below a certain level, treatment is stopped due to the risk of major complications.
“Nanodiamonds have excellent biocompatibility, and the process of formulating nanodiamond-drug complexes is very inexpensive,” said Edward K. Chow, a postdoctoral fellow with the G.W. Hooper Foundation and the University of California, San Francisco, and first author of the paper. “Nanodiamonds possess numerous hallmarks of an ideal drug delivery system and are promising platforms for advancing cancer therapy.”
Materials and Methods
* Fig. S1. 100× H&E histopathological analysis.
* Fig. S2. NDX adsorption spectrophotometry analysis.
* Fig. S3. NDX adsorption comparison.
* Fig. S4. Dox loading analysis.
* Fig. S5. Cancer cell line Dox resistance.
* Fig. S6. Dox efflux analysis in human tumor cells.
* Fig. S7. Dox desorption from ND agglomerates.
* Fig. S8. Dox release spectrophotometry analysis.
* Fig. S9. NDX and Dox tissue retention.
* Table S1. Size and ζ potential of functionalized NDs.
* Table S2. Dox loading efficiency.