No one really knows what effect, including potential toxicities, the long-term harboring of these nanoparticles in the body may have. Speakers agreed that the process of FDA approval for nanotechnology products in oncology may be more challenging and may require some rethinking in terms of a regulatory framework. For example, the FDA may need to regulate a new nanotechnology product as a combination product (which the agency has the power to do) since the product may span the boundaries between pharmaceuticals, medical devices, and biologicals.
Also, said Dr. Benz, institutional review boards may need to gear up for challenging scientific reviews of proposed nanotechnology clinical trials in oncology, especially at centers where nanotechnology expertise is limited. The National Cancer Policy Forum plans to release a workshop summary from this meeting and then a formal report, he noted.
NCI's Alliance for Nanotechnology in Cancer
The National Cancer Institute is actively supporting and funding nanotechnology research, and has established the Alliance for Nanotechnology in Cancer. Currently, more than 200 nanomaterials have been characterized by more than 65 collaborators, with three nanomaterials now in clinical trials, said Scott E. McNeil, PhD, Director of NCI's Nanotechnology Characterization Laboratory, noting that more than 90% of these investigators are extramural—i.e., not NCI staff.
Major Issues for Clinical Researchers
Oncology clinical trials represent a new frontier for nanotechnology, said Steven K. Libutti, MD, Director of the Montefiore-Einstein Center for Cancer Care, Associate Director of the Albert Einstein Cancer Center, and Professor and Vice-Chairman of Surgery and Professor of Genetics at Montefiore Medical Center and Albert Einstein College of Medicine. He said the major issues for clinical researchers are:
- What tests nanomaterials must undergo.
- What the potential and known risks are with the use of nanotechnology and how the unknowns are being addressed.
- Whether there are any real advantages to nanotechnology in terms of diagnosis and treatment.
Noting that colloidal gold as nanomedicine has been used safely for 70 years, and can be tumor targeted, has improved biodelivery, and has increased efficacy with lower toxicities, Dr. Libutti described what is one of the first nanomedicine clinical trials, his Phase I trial of CYT-6091. This investigational drug consists of recombinant human tumor necrosis factor alpha (TNF-α), bound to the surface of pegylated colloidal gold nanoparticles. Up until now, use of TNF-α as anti-cancer therapy has been limited by its side effects, and it cannot be administered systemically.
In this trial, which included 30 patients with various cancers and documented progressive disease, the drug was well tolerated, said Dr. Libutti, and one patient with Stage IV ocular melanoma had a partial response for seven months.
“CYT-6091 can be administered safely with doses up to 600 micrograms per meter squared by systemic injection,” Dr. Libutti said. “The particles appeared to traffic to tumors selectively as determined by electron microscopy.”
Now planned, he said, are Phase II trials of CYT-6091 combined with chemotherapy.
Asked whether he thinks new nanodrugs will initially be used in oncology in combination with traditional therapies, Dr. Libutti said yes—”Combination therapies, I think, are going to rule the day.”
Asked how, if a nanodrug is used in combination, it will be possible to measure its efficacy compared with that of an approved chemotherapeutic agent, he said, “I think you have to study this in staged studies, so that you have a good understanding of each individual therapy.”
Asked in an interview if he had difficulty with FDA approval for the Phase I trial, he said, “The FDA was pretty good,” and the agency used the “appropriate balance of caution.” The main hurdle, he said, was getting approval for the minimally invasive biopsies of study subjects called for in the Phase I study design.
“The promise of nanomedicine for in vivo diagnosis and therapy is control,” said King C. Li, MD, MBA, Professor of Radiology at Weill Cornell Medical College and holder of the M.D. Anderson Foundation Distinguished Chair in the Department of Radiology at the Methodist Hospital in Houston. “What doctors really want is to have precision.”
Dr. Li said the ideal tumor-targeted nanomedicine should increase drug localization in the tumor; decrease drug localization in sensitive, non-target tissues; ensure minimal drug leakage during transit to target; protect the drug from degradation and premature clearance; retain the drug at the target site for the desired period of time; facilitate cellular uptake and intracellular trafficking; and be biocompatible and biodegradable.
What concerns physicians, said Dr. Li, is the unknowns related to new nanodrugs. But these concerns should be at least partly blunted by the fact that nanomedicine is already in oncology practice, he noted, citing liposomes (“nanovectors”) as an example of clinically used, cancer-targeted nanomedicine—for example, liposomal doxorubicin and liposomal cisplatin. He also cited albumin-paclitaxel as an example of a commonly used nanodrug in oncology.
Adverse Event Issues in Nanomedicine
Among the types/classes of nanostructures are liposomes, metal nanoparticles, nanoshells, polymer nanoparticles, and fullerenes. Dr. King Li listed the following as potential considerations in using nanomedicine clinically in oncology, giving credit to a paper in Current Opinion in Biotechnology by HC Fischer and WC Chan of the University of Toronto titled “Nanotoxicity: The Growing Need for In Vivo Study” (2007; 18:565-571):
© 2010 Lippincott Williams & Wilkins, Inc.
- In vivo biodistribution cannot be predicted based on nanostructure physical and chemical properties.
- Because nanostructures can travel to various organs whether intact, modified, or metabolized, they are difficult to track.
- Nanostructures can enter the cells of various organs and reside there for an unknown amount of time before moving to other organs or being excreted, with unknown effects.
- Unique routes of exposure will dictate the specific fate of the nanostructures (for example, inhalation, dermal administration).
- Binding kinetics between nanostructures and protein(s) is not well known.
- It is not fully known how different components of nanostructures are metabolically processed and excreted.
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