CAMBRDIGE, Mass.—The success of chemotherapy is always tempered by its side effects, and unfortunately, hair and weight loss, nausea and increased susceptibility to certain infections are common with many chemotherapeutic drugs. But recently, researchers at the Massachusetts Institute of Technology (MIT) and Brigham and Women's Hospital have published a study detailing how combining chemotherapeutic drugs with nanotechnology can make smaller doses of the drugs just as effective, with lessened side effects.
The study, published the week of Jan. 10 in Proceedings of the National Academy of Sciences, details how researchers were able to shrink prostate tumors in mice while using a third of the standard dose of cisplatin, by encasing the platinum-based drug within a nanoparticle.
In the experiment, the researchers modified cisplatin with two hexanoic acid units to render it hydrophobic, a modification which results in a prodrug that is inactive until it enters a target cell. By encasing that prodrug within a nanoparticle and coating the nanoparticle with molecules that naturally bind to PSMA (prostate specific membrane antigen), a protein found in most prostate cancer cells, the cisplatin can be delivered directly to the tumor. The prodrug, with and without the aptamer targeting, was tested on prostate tumors in mice and rats, as was cisplatin in regular dosages.
"In order to encapsulate cisplatin within the polymer, we had to modify it," says Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry and a senior author of the paper. The result, Lippard explains, is "a dihexanoate of platinum (IV), an oxidized form of cisplatin," or a prodrug. Once the nanoparticle has entered the cell, it releases the prodrug and reverts to cisplatin by releasing the hexanoates, units that made it hydrophobic. The targeting agent within the nanoparticles ensures that what Lippard terms "the platinum payload" is delivered directly to the prostate cancer cells.
"The results were, I think, remarkable," says Omid Farokhzad, associate professor at Harvard Medical School, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital, and another senior author of the paper. "The nanoparticles target the cell in the cancer, and the payload becomes active in the cell. It was equally effective cancer therapy with only about 30 percent of the drug. We're also not seeing the same toxicity, the kidney and liver damage."
Cisplatin's shortcomings include kidney and nerve damage, and short circulation time in the bloodstream; generally, only one percent of the drug ever reaches the cancer cells. However, when delivered via nanoparticles, and in prodrug form, many of cisplatin's limitations were overcome. The study notes that even high doses of "the prodrug-loaded NPs" resulted in less renal toxicity compared with cisplatin in "its conventional dosage form." Additionally, an hour after administration, the amount of platinum still in circulation was at 77 percent for the nanoparticles, while the study establishes "the literature value" for cisplatin as being 1.5 percent. In terms of in-vivo testing, after 12 days, the average tumor volume for the cisplatin group was almost twice as large as that of the targeted prodrug nanoparticles group. After two weeks, the targeted prodrug nanoparticles were more effective at 0.3 mg/kg than regular cisplatin was at 1 mg/kg.
Despite the animal testing being "very promising," Farokhzad says that testing the cisplatin nanoparticle in human clinical trials is "at least two years away." In terms of when this platform might go into production, Farokhzad says it will probably be seven to eight years before it becomes marketable. The next step for this platform will be to move on to further animal studies.
Lippard lists shorter treatment, fewer side effects and "a more broad spectrum of response of different types of cancers" as the outcomes they hope for with animal studies. There are no disadvantages apparent in the treatment so far, but "the cell is not the rodent, and the rodent is not the primate, and the primate is not the human, so at each stage the level of complexity increases," Lippard says. Still, Lippard says that preliminary testing has them "encouraged to move forward."
There are other drugs that could also be combined with the nanoparticles, according to Lippard, and he says that he looks forward to further collaboration with Farokhzad. He declines to comment as to whether they have any commercial partners in mind, but says that they are in "continual discussions about them."
The co-lead authors for the study, "Targeted delivery of cisplatin prodrug for safer and more effective prostate cancer therapy in vivo," are Shanta Dhar, a postdoctoral associate in Lippard's lab, and Nagesh Kolishetti, a postdoctoral associate in Farokhzad's lab. Funding for the study was provided by the National Cancer Institute, the National Institute of Biomedical Imaging and Bioengineering, the Koch-Prostate Cancer Foundation Award in Nanotherapeutics and the Koch Institute for Integrative Cancer Research.
The study, published the week of Jan. 10 in Proceedings of the National Academy of Sciences, details how researchers were able to shrink prostate tumors in mice while using a third of the standard dose of cisplatin, by encasing the platinum-based drug within a nanoparticle.
In the experiment, the researchers modified cisplatin with two hexanoic acid units to render it hydrophobic, a modification which results in a prodrug that is inactive until it enters a target cell. By encasing that prodrug within a nanoparticle and coating the nanoparticle with molecules that naturally bind to PSMA (prostate specific membrane antigen), a protein found in most prostate cancer cells, the cisplatin can be delivered directly to the tumor. The prodrug, with and without the aptamer targeting, was tested on prostate tumors in mice and rats, as was cisplatin in regular dosages.
"In order to encapsulate cisplatin within the polymer, we had to modify it," says Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry and a senior author of the paper. The result, Lippard explains, is "a dihexanoate of platinum (IV), an oxidized form of cisplatin," or a prodrug. Once the nanoparticle has entered the cell, it releases the prodrug and reverts to cisplatin by releasing the hexanoates, units that made it hydrophobic. The targeting agent within the nanoparticles ensures that what Lippard terms "the platinum payload" is delivered directly to the prostate cancer cells.
"The results were, I think, remarkable," says Omid Farokhzad, associate professor at Harvard Medical School, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital, and another senior author of the paper. "The nanoparticles target the cell in the cancer, and the payload becomes active in the cell. It was equally effective cancer therapy with only about 30 percent of the drug. We're also not seeing the same toxicity, the kidney and liver damage."
Cisplatin's shortcomings include kidney and nerve damage, and short circulation time in the bloodstream; generally, only one percent of the drug ever reaches the cancer cells. However, when delivered via nanoparticles, and in prodrug form, many of cisplatin's limitations were overcome. The study notes that even high doses of "the prodrug-loaded NPs" resulted in less renal toxicity compared with cisplatin in "its conventional dosage form." Additionally, an hour after administration, the amount of platinum still in circulation was at 77 percent for the nanoparticles, while the study establishes "the literature value" for cisplatin as being 1.5 percent. In terms of in-vivo testing, after 12 days, the average tumor volume for the cisplatin group was almost twice as large as that of the targeted prodrug nanoparticles group. After two weeks, the targeted prodrug nanoparticles were more effective at 0.3 mg/kg than regular cisplatin was at 1 mg/kg.
Despite the animal testing being "very promising," Farokhzad says that testing the cisplatin nanoparticle in human clinical trials is "at least two years away." In terms of when this platform might go into production, Farokhzad says it will probably be seven to eight years before it becomes marketable. The next step for this platform will be to move on to further animal studies.
Lippard lists shorter treatment, fewer side effects and "a more broad spectrum of response of different types of cancers" as the outcomes they hope for with animal studies. There are no disadvantages apparent in the treatment so far, but "the cell is not the rodent, and the rodent is not the primate, and the primate is not the human, so at each stage the level of complexity increases," Lippard says. Still, Lippard says that preliminary testing has them "encouraged to move forward."
There are other drugs that could also be combined with the nanoparticles, according to Lippard, and he says that he looks forward to further collaboration with Farokhzad. He declines to comment as to whether they have any commercial partners in mind, but says that they are in "continual discussions about them."
The co-lead authors for the study, "Targeted delivery of cisplatin prodrug for safer and more effective prostate cancer therapy in vivo," are Shanta Dhar, a postdoctoral associate in Lippard's lab, and Nagesh Kolishetti, a postdoctoral associate in Farokhzad's lab. Funding for the study was provided by the National Cancer Institute, the National Institute of Biomedical Imaging and Bioengineering, the Koch-Prostate Cancer Foundation Award in Nanotherapeutics and the Koch Institute for Integrative Cancer Research.
