March 20, 2006
Nanoliposome Delivers Anticancer Drug to Brain Tumors, Avoids Healthy Tissue
One reason why patients with brain cancer face such a poor prognosis is that there are so few anticancer drugs that can actually cross the so-called blood-brain barrier and reach tumors growing in the brain. But using a nanoscale, drug-loaded liposome and a pressure-driven drug administration technique known as convection-enhanced delivery, investigators at the University of California at San Francisco (UCSF) have developed an efficient method of getting anticancer drugs into the brain and keeping them there. This new approach can also reduce the therapy-limiting toxicities that are often associated with the most potent anticancer agents.
Writing in the journal Cancer Research, a research team headed by UCSF colleagues John Park, M.D., and Krystof Bankiewicz, M.D., Ph.D., first described a new type of nanoscale, stabilized liposome they have created and the methods they used to load approximately 10,000 molecules of the anticancer drug CPT-11 per liposomal nanoparticle. The investigators then showed that this formulation, when delivered to the brain using convection-enhanced delivery in tumor-bearing mice, can remain in brain tissue for over 2 weeks – the exact duration of drug exposure depends on the initial dose of liposomes. In one experiment, the effective dose of CPT-11 reaching brain tissue was 1,636 times higher than when free CPT-11 was administered intravenously.
The value of using convection-enhanced delivery for getting the liposomal nanoparticles into the brain was clear from data showing that the researchers were not able to detect any CPT-11 in the bloodstream. In contrast, levels of CPT-11 in glial tumors remained elevated 4-fold longer than in healthy brain tissue. Taken together, these data raise the possibility that CPT-11 delivered in these nanoparticulate liposomes should produce far fewer side effects than does CPT-11 alone. Indeed, when the investigators looked for signs of neural toxicity, a common side effect produced by CPT-11, they found nerve damage only in animals receiving free drug, not in any animals receiving the liposomal nanoparticle loaded with CPT-11, despite the higher doses of active drug delivered to the brain by the nanoparticles.
Most importantly, the drug-loaded liposomes were more effective at killing glial cell tumors in the experimental animals. When given empty liposomes, animals with glial cell tumors survived an average of 22 days following treatment, while those given free CPT-11 survived an average of 28 days. When given CPT-11-loaded liposomal nanoparticles, the majority of the animals survived beyond 100 days, with an average survival time of 83 days.
This work, which was funded in part by the National Cancer Institute’s Specialized Programs of Research Excellence in Brain Tumors, is detailed in a paper titled, “Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy.” Investigators from Hermes Biosciences, Inc., in South San Francisco, CA, also participated in this study. An abstract of this paper is available through PubMed.