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January 21, 2014

Nanotechnology: Is the Magic Bullet Becoming Reality?

Researchers at a recent New York conference discuss what the future of nanomedicine may hold.

Nanotechnology: Is the Magic Bullet Becoming Reality?

Nanotech seems promising, but regulatory and patent issues remain. [© Anterovium - Fotolia.com]

  • Slightly over a century ago, Paul Ehrlich coined the term “magic bullet” to refer to therapeutic compounds designed to selectively target a pathogen without affecting the host. Subsequently, this idea flourished not only for infectious diseases but also for other fields, such as cancer therapy. At the recent “Nanomedicines: Addressing the Scientific and Regulatory Gap” conference held at the New York Academy of Sciences in late November, investigators discussed key concepts shaping a vibrant field that promises to bring this concept closer to the clinic.

  • Liposomes

    “When we entered this field, from the few systems that existed, we chose to work on liposomes,” said Yechezkel Barenholz, Ph.D., professor of biochemistry at the Hebrew University – Hadassah Medical School in Jerusalem. Liposomes presented the advantage that relatively more knowledge existed about their pharmacokinetic properties. The compound that Dr. Barenholz and colleagues started to work on, doxorubicin, is one of the most effective first-line anticancer therapeutics ever developed, but one of its disadvantages is that adverse effects occur in many organs upon systemic administration. Work by Dr. Barenholz and colleagues on a liposome-based doxorubicin formulation culminated with the development of Doxil (doxorubicin), the first nanodrug approved by the FDA in 1995.

    “In a way, the success of this project started from a failure,” Dr. Barenholz said. Investigators in his lab initially developed a liposome-based doxorubicin formulation to reach the liver and treat hepatocellular carcinoma, and even though this worked well in an animal model, the pharmacokinetics was not favorable in humans. “As a result we became more determined, and in a new approach, we decided to first determine what kind of performance we need from liposomes, and then we used a materials science approach,” he added.

    A key concept in developing the doxorubicin-loaded liposomes was the enhanced permeability and retention effect. This phenomenon, which results from differences in vasculature between normal and inflamed tissue, refers to the ability of the poorly aligned, fenestrated endothelial cells from the malignant tumor neovasculature to allow 10–300 nm diameter nanoparticles to cross and become selectively enriched in the tumor.

    “This is not the case in normal tissues, and it represents the Achilles’ heel of the tumor,” said Dr. Barenholz. The defective lymphatic drainage of malignant tissues further facilitates the accumulation of nanoparticles.

    To load the liposomes with doxorubicin, Dr. Barenholz and colleagues relied on a transmembrane ammonium sulfate gradient that acted as the driving force for the loading process. As a result, doxorubicin reached 100-fold higher concentrations in the intraliposomal aqueous phase as compared to the loading medium. The circulation time of liposomes was extended by stabilizing them with a formulation composed of phospholipids with high melting temperature, cholesterol, and a pegylated lipopolymer. Clinical studies in humans revealed that the nanoparticles accumulated in tumors, and doxorubicin reached higher concentrations in the tumor than what could what could be achieved with systemic administration.

    “This formulation improves patient compliance and the quality of life,” Dr. Barenholz said.

  • TNF

    “We wanted to use nanotechnology in cancer therapy and change the way we treat this disease,” said Lawrence Tamarkin, Ph.D., president and CEO of CytImmune. The approach that Dr. Tamarkin and colleagues developed relies on 27 nm gold nanoparticles that have been used since the 1930s to treat psoriatic arthritis and present an established history of safety.

    The surface of the colloidal gold nanoparticles was simultaneously bound to covalently linked thiolyated PEG, to avoid immune detection, and recombinant human tumor necrosis factor (TNF). Clinically, TNF has been successfully used in Europe to treat tumors of the extremities, in a procedure known as isolated limb perfusion. Infusing high-dose TNF prior to chemotherapy can achieve 15–25-fold higher concentrations as compared to systemic administration, without the same risks of adverse effects. With this strategy, several studies found up to 95% response rates after one treatment in patients with melanoma and sarcoma. “We wanted to mimic this clinical experience systemically,” said Dr. Tamarkin.

    The 27 nm-diameter gold nanoparticles are small enough to travel through the blood vessels, and the 2–4 nm gaps between endothelial cells in healthy blood vessels are too small to allow them to cross into tissues, due to the presence of the tight junctions. “But at the site of the tumor, where the neovasculature fenestrations are 200–400 nm, the blood pressure forces them into the tumor bed, where TNF molecules bind to TNF receptors on the endothelial cells and start causing vascular disruption,” he added.

    In a Phase I clinical trial, CYT-6091, the nanotherapeutic that Dr. Tamarkin and colleagues developed, delivered up to 1.2 mg TNF, as compared to 0.4 mg, which is the maximum tolerated human dose, without any signs of dose-limiting toxicity. “The promise of nanotechnology is that we can reduce or eliminate toxicity and improve the therapeutic index,” he said. Moreover, the drug accumulated at tumor sites, and very few gold nanoparticles were seen in healthy tissues.

    “We intended not simply to reformulate an already approved drug, but to create a safe and effective therapeutic by using nanotechnology,” he said. Two patients, one with inoperable breast cancer and another one with pancreatic cancer, neither of them having previously undergone surgical treatment, showed the most nanoparticles accumulating in the tumor, as compared to the adjacent healthy tissue. “This indicated that perhaps treating patients surgically so quickly might not be a good idea, because it tears up the roadway that nanoparticles use to reach their targets,” he commented.

    Gold nanoparticles accumulated in malignant tissues even at the lowest doses, but accumulation was not increasing in a dose-dependent manner. Reducing the tumor burden in situ offers the possibility to reduce the need for sophisticated surgery and the hospitalization time.

    “We have the promise to dramatically improve healthcare because of decreased treatment costs,” he concluded.

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