BOSTON—If typical cancer treatment with chemotherapy could be compared to a military campaign that "carpet bombs" an enemy location and possibly endangers innocent bystanders as a result, nanoparticles may finally offer something more akin to small guided missiles. At least, that's the theory with the work done by an interdisciplinary team of researchers at Brigham and Women's Hospital (BWH) and the Harvard-MIT Division of Health Sciences and Technology.
What the team has now demonstrated is way to deliver cancer drugs directly to tumors by using specially engineered nanoparticles. More than just hauling chemotherapeutic cargo, though, these nanoparticles can inhibit a signaling pathway and deliver a higher concentration of medication to the specific area. Details of the work appeared on April 21 in an early online edition of the Proceedings of the National Academy of Science, in an article titled "Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy."
The nanoparticles, constructed from a biodegradable, biocompatible polymer already approved by the U.S. Food and Drug Administration, are chemically engineered to deliver a MAPK inhibitor. The researchers chose to inhibit the MAPK pathway because it is involved in most human tumors, and doing so both hinder the multiplication of cancerous cells and predispose those cells to the cytotoxic effects of chemotherapeutic drugs.
More than that, though, the team modified the polymer to increase drug loading by 20 times, because one of the major drawbacks in nanomedicine of late has been low efficiency of drug loading. And more selective targeting and better deliver of chemotherapeutics is necessary to getting away from the "carpet bombing" approach.
"Current chemotherapeutic drugs must be administered in high concentration throughout the body in order to destroy tumor cells, translating to high toxicity and discomfort for the patient, mainly due to the effects on normal cells," says Rania Harfouche, one of the lead authors of the study and a fellow in the Health Sciences and Technology (HST) Division at BWH. By selectively targeting the tumor cells and predisposing them to chemotherapeutic drugs, she notes, "This will allow for lower drug concentration to be used, and provide opportunity for more potent treatments with lesser side effects for the patient."
"The nanoparticles target pathways involved in multiple cancer types and can be applied to a diverse set of cancers, including hard-to-treat cancers, such as breast, pancreatic and liver cancer," notes senior study author Dr. Shiladitya Sengupta, of the Department of Medicine at BWH. "The potential to add homing beacons on the surface of the nanoparticles can increase the efficiency of selectively targeting specific tumors and abolish off-target side effects."
In their research, the team demonstrated that the combination of nanoparticles and the cancer drug cisplatin was successful both in preventing the growth of cancerous skin and lung cells and also inducing cell death.
When researchers gave the same combination of nanoparticles, cisplatin and MAPK inhibitor to mice with melanoma, the entire tumors regressed in 50 percent of mice. On the other hand, tumors regressed in none of the mice that received cisplatin and the inhibitor without the benefit of nanoparticles.
In previous work, the team had shown that a combination of two drugs delivered with a nanoparticle could exert superior anti-cancer effects. However, most cancers converge into a few pathways for survival and uncontrolled division, notes one of the study's other lead authors, Sudipta Basu, a fellow in the HST Division at BWH. "We thought a better strategy might be to target these pathways using nanoparticles, almost like shutting the escape route before exposing the cancer to the drugs."
The team also included BWH research fellows Dr. Shivani Soni, Dr. Geetanjali Chimote, and Dr. Raghunath Anant Mashelkar, a polymer chemist and visiting professor at HST from the National Chemical Laboratory in India. This research was funded by grants from the Coulter Foundation, the Mary Kay Ash Charitable Foundation and the Department of Defense Breast Cancer Research Program.
Nanoparticles are a clear area of interest for the National Cancer Institute, with the NCI noting on its Web site not only the potential for such particles to enhance molecular imaging of tumors but also to allow for "effective and targeted drug delivery by overcoming the many biological, biophysical and biomedical barriers that the body stages against a standard intervention such as the administration of drugs or contrast agents."
In mid-April, researchers at the University of Washington noted that nanoparticles could more than double the effectiveness of chlorotoxin in treating brain tumors, adding that one of the benefits of nanoparticles in improving cancer therapy may be in their potential to increase the length of time a therapeutic agent can last in the body. Also, the University of Washington researchers noted that nanoparticles also can boost effectiveness of anti-cancer compounds because therapeutic molecules tend to "clump" around each nanoparticle.
What the team has now demonstrated is way to deliver cancer drugs directly to tumors by using specially engineered nanoparticles. More than just hauling chemotherapeutic cargo, though, these nanoparticles can inhibit a signaling pathway and deliver a higher concentration of medication to the specific area. Details of the work appeared on April 21 in an early online edition of the Proceedings of the National Academy of Science, in an article titled "Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy."
The nanoparticles, constructed from a biodegradable, biocompatible polymer already approved by the U.S. Food and Drug Administration, are chemically engineered to deliver a MAPK inhibitor. The researchers chose to inhibit the MAPK pathway because it is involved in most human tumors, and doing so both hinder the multiplication of cancerous cells and predispose those cells to the cytotoxic effects of chemotherapeutic drugs.
More than that, though, the team modified the polymer to increase drug loading by 20 times, because one of the major drawbacks in nanomedicine of late has been low efficiency of drug loading. And more selective targeting and better deliver of chemotherapeutics is necessary to getting away from the "carpet bombing" approach.
"Current chemotherapeutic drugs must be administered in high concentration throughout the body in order to destroy tumor cells, translating to high toxicity and discomfort for the patient, mainly due to the effects on normal cells," says Rania Harfouche, one of the lead authors of the study and a fellow in the Health Sciences and Technology (HST) Division at BWH. By selectively targeting the tumor cells and predisposing them to chemotherapeutic drugs, she notes, "This will allow for lower drug concentration to be used, and provide opportunity for more potent treatments with lesser side effects for the patient."
"The nanoparticles target pathways involved in multiple cancer types and can be applied to a diverse set of cancers, including hard-to-treat cancers, such as breast, pancreatic and liver cancer," notes senior study author Dr. Shiladitya Sengupta, of the Department of Medicine at BWH. "The potential to add homing beacons on the surface of the nanoparticles can increase the efficiency of selectively targeting specific tumors and abolish off-target side effects."
In their research, the team demonstrated that the combination of nanoparticles and the cancer drug cisplatin was successful both in preventing the growth of cancerous skin and lung cells and also inducing cell death.
When researchers gave the same combination of nanoparticles, cisplatin and MAPK inhibitor to mice with melanoma, the entire tumors regressed in 50 percent of mice. On the other hand, tumors regressed in none of the mice that received cisplatin and the inhibitor without the benefit of nanoparticles.
In previous work, the team had shown that a combination of two drugs delivered with a nanoparticle could exert superior anti-cancer effects. However, most cancers converge into a few pathways for survival and uncontrolled division, notes one of the study's other lead authors, Sudipta Basu, a fellow in the HST Division at BWH. "We thought a better strategy might be to target these pathways using nanoparticles, almost like shutting the escape route before exposing the cancer to the drugs."
The team also included BWH research fellows Dr. Shivani Soni, Dr. Geetanjali Chimote, and Dr. Raghunath Anant Mashelkar, a polymer chemist and visiting professor at HST from the National Chemical Laboratory in India. This research was funded by grants from the Coulter Foundation, the Mary Kay Ash Charitable Foundation and the Department of Defense Breast Cancer Research Program.
Nanoparticles are a clear area of interest for the National Cancer Institute, with the NCI noting on its Web site not only the potential for such particles to enhance molecular imaging of tumors but also to allow for "effective and targeted drug delivery by overcoming the many biological, biophysical and biomedical barriers that the body stages against a standard intervention such as the administration of drugs or contrast agents."
In mid-April, researchers at the University of Washington noted that nanoparticles could more than double the effectiveness of chlorotoxin in treating brain tumors, adding that one of the benefits of nanoparticles in improving cancer therapy may be in their potential to increase the length of time a therapeutic agent can last in the body. Also, the University of Washington researchers noted that nanoparticles also can boost effectiveness of anti-cancer compounds because therapeutic molecules tend to "clump" around each nanoparticle.
