There is no doubt that ongoing research in nanotechnology is finally opening the door to potential new therapeutic applications. Though the next phase in its evolution will see the translation of promising lab discoveries into the clinic, it’s all still in formative stages. But confidence is building that innovative medicines and companion diagnostics based on nanotech will soon expand treatment options for major diseases such as cancer and central nervous system (CNS) disorders. Certainly interest has intensified in recent years among pharma and biotech companies as nanotechnology-related products enter into later-stage clinical trials.

Proponents of the technology believe the promise of nanomedicine has “reached an inflection point,” and its proof of principle is being demonstrated almost daily in labs and by companies globally.

The excitement for this science of the “very small” relates to the technology’s ability to improve the study of biological mechanisms.

For example, scientists have developed a nanoparticle to cage a certain class of toxins, allowing them to present those toxins to the immune system without first modifying them through chemical or heat treatment – a process that makes vaccines less toxic, but also less effective. Mice vaccinated with a nanovaccine against the Staphylococcus aureus toxin hemolysin A were better protected from hemolysin than animals who received heat-treated hemolysin. (See BioWorld Today, Dec 5, 2013.)

Breaking down barriers

One of the problems for nanoparticles is that they are not absorbed by the intestine, making it necessary to deliver them intravenously. Now Brigham and Women’s Hospital (BWH) researchers may have come up with a solution. They report in the Nov. 28, 2013, issue of Science Translational Medicine that they have developed a nanoparticle that can be given orally rather than intravenously, an advance that could significantly broaden the technology’s use.

In their work, the authors developed a nanoparticle that could cross the intestinal epithelium via the neonatal Fc receptor, which, it so happens, is not specific to babies but expressed in adults as well. In their studies, the authors were able to deliver insulin via orally delivered nanoparticles.

“The novelty of actively being able to transport targeted nanoparticles across cell barriers can potentially open up a whole new set of opportunities in nanomedicine,” according to senior study author Omid Farokhzad, director of the BWH Laboratory of Nanomedicine and Biomaterials. “The body has receptors that are involved in shuttling proteins across barriers, as is the case in the placenta between the mother and fetus, or in the intestine, or between the blood and the brain. By hitching a ride from these transporters the nanoparticles can enter various impermeable tissues.”

This emerging and disruptive technology, which offers to impact a variety of industries including healthcare, catalyzed the National Nanotechnology Initiative (NNI), a federal interagency program – created by the 21st Century Nanotechnology Research & Development Act of 2003. The aim of the NNI is to move nanotech discoveries from the lab into new products for commercial and public benefit.

The 2014 Federal Budget provides more than $1.7 billion for the NNI, which supports nanoscale science and engineering R&D at 15 agencies including the FDA and the National Institutes of Health (NIH). Of this budget the NIH has been earmarked for $460 million in 2014 and the FDA almost $17 million. The NNI is currently seeking comments on its draft strategic plan for 2014, which is based on four goals: advancing a world-class nanotechnology R&D program, fostering the transfer of new technologies, supporting the responsible development of nanotechnology, and developing the educational resources, work force, infrastructure and toolset needed to advance nanotechnology.

There is no doubt that the government’s support for the science will help accelerate research.

Investors like ‘nano’

A positive sign that the technology is on the radar screen of investors is their willingness to back companies working in the space. A good example of this is Bind Therapeutics Inc., of Cambridge, Mass., a clinical-stage nanomedicine platform company developing targeted and programmable therapeutics called Accurins. The company completed its initial public offering (IPO) on Sept. 25 resulting in gross proceeds of approximately $76 million, which included the exercise of the underwriters’ option to purchase additional shares.

In August the company dosed its first patient in a Phase II trial of BIND-014, for metastatic castrate-resistant prostate cancer. The open-label study will enroll 40 patients who are naïve to chemotherapy with the goal of determining progression-free survival. BIND-014 is a nano-engineered drug containing docetaxel targeted at prostate specific membrane antigen.

Bind also has collaborations with Amgen Inc., Pfizer Inc. and Astrazeneca plc, which have provided up-front payments and milestones to advance its internal pipeline of Accurins.

The company said its Accurins are the “next stage in the evolution of targeted therapies and nanomedicine.” The targeting ligands on the surface of the Accurin bind to specific cell-surface markers. A “stealth” layer using polyethylene glycol (PEG) protects the Accurin from the immune system. That layer is necessary because the size threshold for a nanoparticle, about 100 nm, is also the size range of a viral particle, and the immune system is primed to detect and clear particles of that size.

Inside, a controlled-release polymer matrix traps the therapeutic payload and mediates its release at the disease site. The therapeutic payload can be any of a number of types of molecules including small-molecule compounds, peptides, or nucleic acids.

Bind’s Accurin platform is designed to target cytotoxic drugs such as docetaxel at the molecular level to cancer cells, thereby minimizing toxic effects on healthy cells. The approach involves three levels: targeting ligands that recognize disease-associated cell surface proteins or receptors coat the outside of the Accurin particle; a “stealth” layer protects the targeted Accurin particles from detection by the immune system; and a matrix of biocompatible polymers encapsulates the therapeutic payload for release at the site of disease.

Abingdon, UK-based Midatech Ltd. received an injection of £10 million (US$16 million) in its first formal round and is planning to move its gold nanoparticle delivery technology into Phase II trials. The company will conduct two Phase IIa trials for lead product, Midaform, in which insulin linked to gold nanoparticles is delivered via a patch inside the cheek. One trial will assess the patch in Type I diabetes, the second in Type II. (See BioWorld Today, Nov. 6, 2013.)

In the Phase I trial of Midaform, the level of delivery of insulin via the cheek was between 25 percent and 35 percent of that achieved by injection, for the same dose of insulin. Philips said it is not expected to be able to deliver the same amount of insulin dose-for-dose, as by injection. The benefit will be in ease of administration and the ultrafast onset of action, with Midaform closely mimicking the characteristics of monomeric insulin from the pancreas, giving faster delivery than subcutaneous injections.

The new funding also will allow Midatech to advance other projects, using gold nanoparticles to improve the targeting and side effect profile of chemotherapeutics. Work has started testing particles with a tumor-targeting agent and a chemotherapeutic linked to them. The overall effect of linking targeting molecules to the multiple ligands on the particles is to create a “velcro-like structure” that sticks to a tumor.

Nanobiotix SA, of Paris, has reported positive safety data from the first clinical study of NBTXR3, a nanoparticle drug that enhances the effects of radiotherapy on tumor cells without damaging healthy tissue. NBTXR3, a nanoparticle formulation of hafnium oxide, a material that absorbs X-rays, is injected into tumors in advance of conventional radiotherapy treatment. According to preclinical data this increases the radiotherapy dose in tumor cells nine-fold, overcoming the main shortcoming of this form of treatment, which is that although X-rays are very effective in killing cancer cells, the damage caused to healthy tissue limits the dose.

Laurent Levy, CEO, said NBTXR3 represents a new generation of nanomedicine, in which rather than using nanoparticles as the vehicles for intracellular drug delivery, the nanoparticles themselves are the active drug.

Also, in late November, Cambridge, Mass.-based Merrimack Pharmaceuticals Inc. said it entered into a collaboration agreement with Actavis plc. Merrimack will use its nanoliposomal technology platform to develop and manufacture various pharmaceutical products for Actavis to commercialize globally. In return it is eligible to receive up to $15.5 million, including $2 million up front and the remainder in committed near-term funding and development, regulatory and commercial milestone payments related to the first product to come out of the collaboration. In addition, Merrimack will receive a double-digit share of profits on future global sales of any commercialized products derived from the collaboration. Merrimack will be responsible for manufacturing bulk product at its Cambridge-based nanoliposomal manufacturing facility. (See BioWorld Today, Nov. 27, 2013.)

Another recent nano deal saw Beijing start-up Canbridge Life Sciences Ltd. partnered with emerging nanotech specialist Azaya Therapeutics Inc., of San Antonio, to develop non-small-cell lung cancer (NSCLC) treatment ATI-1123 in China and North Asia. (See BioWorld Today, Sept. 25, 2013.)

ATI-1123 is a liposomal formulation of docetaxel that has successfully completed U.S. FDA-approved Phase I trials for multiple solid tumor cancers. Lung cancer is the most prevalent solid tumor cancer in China. Under terms of the agreement, Canbridge will finance the development and commercialization of ATI-1123 for China, South Korea and Taiwan and will make undisclosed royalty and milestone payments. Phase II trials are planned by Azaya in the U.S. for the use of the drug in NSCLC, gastric cancer, pancreatic cancer and soft-tissue sarcoma.