Scientists at Nanyang Technological University (NTU Singapore) have invented a new way to deliver cancer drugs deep into tumor cells.

They created micro-sized gas bubbles coated with anticancer drug particles embedded in iron oxide nanoparticles and used MRI or other magnetic sources to direct these microbubbles to gather around a specific tumor. Then they used ultrasound to vibrate the microbubbles, providing the energy to direct the drug particles into a targeted kill zone in the tumor. The magnetic nanoparticles also allow for imaging in an MRI machine.

The microbubbles were successfully tested in mice and the study has been published by the Nature Publishing Group in Asia Materials.

Overcoming limitations of chemotherapy

This innovative technique was developed by a multidisciplinary team of scientists led by Asst Prof C. J. Xu from the School of Chemical and Biomedical Engineering and Assoc. Prof Claus-Dieter Ohl from the School of Physical and Mathematical Sciences.

Xu, who is also a researcher at the NTU-Northwestern Institute for Nanomedicine, said their new method may solve some of the most pressing problems faced in chemotherapy used to treat cancer.

The main problem is that current chemotherapy drugs cannot be easily targeted. The drug particles flow in the bloodstream, damaging both healthy and cancerous cells. Typically, these drugs are flushed away quickly in organs such as the lungs and liver, limiting their effectiveness.

The remaining drugs are also unable to penetrate deep into the core of the tumor, leaving some cancer cells alive, which could lead to a resurgence in tumor growth.

Delivering anticancer drugs deep into tumors

The microbubbles are magnetic, so after injecting them into the bloodstream, they can be clustered around the tumor using magnets to ensure that they don’t kill the healthy cells, explains Xu, who has been working on cancer diagnosis and drug delivery systems since 2004.

“More importantly, our invention is the first of its kind that allows drug particles to be directed deep into a tumor in a few milliseconds. They can penetrate a depth of 50 cell layers or more (about 200 micrometers) — twice the width of a human hair. This helps to ensure that the drugs can reach the cancer cells on the surface and also inside the core of the tumor.”

According to Clinical Associate Professor Chia Sing Joo, a Senior Consultant at the Tan Tock Seng Hospital’s Endoscopy Centre and the Urology & Continence Clinic, “For anticancer drugs to achieve their best effectiveness, they need to penetrate into the tumor efficiently in order to reach the cytoplasm of all the cancer cells that are being targeted without affecting the normal cells.

“Currently, this can [only] be achieved by means of a direct injection into the tumor or by administering a large dosage of anticancer drugs, which can be painful, expensive, impractical and might have various side effects. If successful, I envisage [the new drug-delivery system] can be a good alternative treatment in the future, one which is low cost and yet effective for the treatment of cancers involving solid tumors, as it might minimize the side effects of drugs.” Joo is a surgeon experienced in the treatment of prostate, bladder and kidney cancer and a consultant for this study.

According to Ohl, an expert in biophysics who has published previous studies involving drug delivery systems and bubble dynamics, “most prototype drug delivery systems on the market face three main challenges before they can be commercially successful: they have to be non-invasive, patient-friendly, and yet cost-effective. We were able to come up with our solution that addresses these three challenges.”

The 12-person study team included scientists from City University of Hong Kong and Technion – Israel Institute of Technology (Technion). The team plans to use this new drug delivery system in studies on lung and liver cancer using animal models, and eventually clinical studies.

They estimate that it will take another eight to ten years before it reaches human clinical trials.

Abstract of Controlled nanoparticle release from stable magnetic microbubble oscillations

Magnetic microbubbles (MMBs) are microbubbles (MBs) coated with magnetic nanoparticles (NPs). MMBs not only maintain the acoustic properties of MBs, but also serve as an important contrast agent for magnetic resonance imaging. Such dual-modality functionality makes MMBs particularly useful for a wide range of biomedical applications, such as localized drug/gene delivery. This article reports the ability of MMBs to release their particle cargo on demand under stable oscillation. When stimulated by ultrasound at resonant frequencies, MMBs of 450 nm to 200 μm oscillate in volume and surface modes. Above an oscillation threshold, NPs are released from the MMB shell and can travel hundreds of micrometers from the surface of the bubble. The migration of NPs from MMBs can be described with a force balance model. With this technology, we deliver doxorubicin-containing poly(lactic-co-glycolic acid) particles across a physiological barrier bothin vitro and in vivo, with a 18-fold and 5-fold increase in NP delivery to the heart tissue of zebrafish and tumor tissue of mouse, respectively. The penetration of released NPs in tissues is also improved. The ability to remotely control the release of NPs from MMBs suggests opportunities for targeted drug delivery through/into tissues that are not easily diffused through or penetrated.