Tuesday, December 13, 2011

FORMULATION - Nanoparticles | Strides for Small Cancer Fighters

James Netterwald, PhD

Nanoparticles used to formulate and deliver drugs to cells and tumors show increasing promise

Nanometer-sized particles, typically made of iron oxide, are beginning to transform the world of medicine. In particular, nanomedicine’s impact has been defined by the potential use of nanoparticles in the formulation and delivery of cancer drugs.
When a nanoparticle-based drug is developed, some thought must be put into how biodistribution, targeting, and post-delivery mechanism of action will be incorporated into its design.
“The research we are doing is really based on the premise that altering the temperature of the tumor can dramatically change its response to things like radiation therapy or chemotherapy,” said Theodore DeWeese, MD, professor and chairman of radiation oncology and molecular radiation sciences at The Johns Hopkins University in Baltimore, Md. Doing that in a reproducible way has been a challenge.
That was until about four to five years ago when cancer biologists decided to employ nanoparticles to do the heating “using so-called iron oxide particles, which, in the right configuration and when placed in an alternating magnetic field, will actually heat to a very high temperature and lead to the sensitization of cancer cells to chemotherapy and radiation therapy,” said Dr. DeWeese. Just heating the tumor by three degrees nearly doubles its sensitivity to therapy.
 One of the major challenges in the path to building a nanoparticle delivery system for cancer therapy has been targeting, the process by which the nanoparticles are coated with either antibodies, RNA molecules, or small proteins so that they are targeted to a certain cancer cell type. Dr. DeWeese and his colleagues coat their particles with dextran as well as polyethylene glycol, which aid in biodistribution of the drug when it is administered either intratumorally or intravenously.
However, these iron particles, which range from 80 to 100 nanometers in diameter, do not specifically carry a drug. In fact, the iron itself is what is delivered to the tumor cell. “When the iron reaches the cell and when that cell is placed in an alternating magnetic field, substantial heating of the targeted cell results,” said Dr. DeWeese. “Even in the untargeted state, these particles are taken up by pinocytosis. Cancer cells like to take up these particles, but non-cancer cells take up the particles as well. So, nonspecific targeting is also possible.”

Targeting a Challenge 

Howard Soule, PhD
Howard Soule, PhD
Although heating the nanoparticle to destroy a target cancer cell is one possible mechanism of action, it is somewhat nonspecific.
“The holy grail is to take a highly toxic substance and target it within a nanoparticle to a specific tissue—and in the case of prostate cancer, that would be the metastatic tumor,” said Howard Soule, PhD, executive vice president and chief science officer of the Prostate Cancer Foundation in Santa Monica, Calif.
The toxic substance referred to is a chemotherapeutic agent for cancer. Just as they are being developed for solid tumors, nanoparticles are also being crafted to target prostate cancer cells. The targeting is made possible by labeling the particles with ligands that selectively bind to prostate-specific membrane antigen (PSMA), a clinical biomarker that is highly expressed on the surface of metastatic prostate cancer cells and many solid-tumor blood vessels.
“So you have a particle filled with the chemotherapy medication decorated with a targeting entity on the outside of the nanoparticles,” said Dr. Soule. “When you introduce these things systemically to the patient, the theory is that these particles will go into circulation and, based on their specificity, they will find the tumor.” He explained that the tumor would take up the particle, degrade it, and then release the drug inside the tumor cell, thereby sparing bystander (normal) cells.
“Targeting is really a complex issue,” he explained. “These are virus-sized particles that distribute in ways that chemicals don’t. However, there are still questions and challenges about the potential of nanotherapies for cancer.” For instance, how specific will a given particle be for a tumor, and how much of the tumor-targeting specificity is due to the vascular leakiness of the tumor, which is a property of meta-static malignancies?
“We just don’t know the answers to these questions yet,” he said.

Nanoparticles to Nanomedicine

Omid Farokhzad, MD, an associate professor at Harvard Medical School and director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital in Boston, Mass., has made some seminal discoveries in the world of nano-medicine. His academic pursuits have led to the development of a platform that enables one to target nanoparticles for a number of therapeutic applications.
That success ended the academic challenges and opened a new set of issues: commercial scale-up and development. The solution was start a company to license the technology from the university so that it could be further developed and eventually marketed. The company, BIND Biosciences, was co-founded in 2007 by Dr. Farokhzad and Robert Langer, ScD, David H. Koch Institute Professor at the Massachusetts Institute of Technology (MIT).
“The company eventually made a modification to the formulation to make the particles much more stable and much more appropriate from a drug development standpoint … BIND started human trials of BIND-014, a targeted nanoparticle therapeutic for treatment of solid tumors, in January 2011,” explained Dr. Farokhzad. “The technology is composed of very long circulating, controlled release, polymeric nanoparticles that are targeted to specific receptors on the surface of disease cells for targeted and controlled release of drugs.”
BIND’s platform enables the company to engineer nanoparticles with the appropriate sizes and surface properties, targeting the ligand density, circulation times, and drug release profiles that would be required for optimizing a drug’s performance for various therapies.
“Based on the research of MIT nano-particle guru Dr. Robert Langer, BIND’s nanoparticles provide the unique opportunity to control the drug load and release profile while actively targeting diseased cells with ligand-directed receptor-mediated binding,” said Jeff Hrkach, PhD, senior vice president of pharmaceutical sciences for BIND. The particle’s surface is coated with polyethylene glycol, which enables it to reach its drug target by evading recognition by the immune system. Ligands can also be attached to the surface of the particles, allowing them to bind directly to the desired cells or tissues to be treated. BIND’s nanoparticles were developed in collaboration with Drs. Langer and Farokhzad.
“BIND has spent the last four years translating that academic bench work into more robust processes for development and clinical translation,” said Dr. Hrkach.
BIND’s lead program is a targeted nanoparticle loaded with docetaxel, the active ingredient in Taxotere—a well-known and successful Sanofi-Aventis cancer drug that has recently gone off patent. The product, BIND-014, which is in Phase 1 clinical trials for a number of solid-tumor indications, targets PSMA.
“We are working with partners who have existing approved drugs or candidates in their pipeline and are looking for opportunities to improve them or expand their existing indications,” said Dr. Hrkach. “Some of these products are currently in clinical development and show signs of promise but have limitations related to their therapeutic index. Our technology can increase a drug’s efficacy and reduce its toxicity by keeping the drug sequestered in our long-circulating nanoparticles until they reach and actively bind to their specific target cells for maximal concentration at the site of action and minimal systemic exposure.”
The Prostate Cancer Foundation funds both the work done by Dr. Langer at MIT and that of Dr. Farokhzad at Harvard

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