Theranostics and Image Guided Drug Delivery

Maya Thanou, Maya Thanou

• Publisher: Royal Society of Chemistry
• Year: 2018
• ISBN:
  9781788013932
• Edition: 1
• Topic: Sciences physiques
• Subtopic: Chimie clinique

Molecular imaging of drugs or drug carriers is a valuable tool that can provide important information on spatiotemporal distribution of drugs, allowing improved drug distribution at target sites. Chemically labelled drugs can be used to both diagnose and treat diseases. This book introduces the topic of image guided drug delivery and covers the latest imaging techniques and developments in theranostics, highlighting the interdisciplinary nature of this field as well as its translational ability. These technologies and techniques hold potential for individualised, safer therapies.
The book introduces the chemistry behind labelling drugs or drug carriers for imaging. It then discusses current scientific progress in the discovery and development of theranostic agents as well as the latest advances in triggered drug delivery. Novel imaging techniques that can be combined with therapeutics are presented, as well as results and findings from early clinical trials.
This text will provide postgraduates and researchers in various disciplines associated with drug discovery, including chemistry, device engineering, oncology, neurology, cardiology, imaging, and nanoscience, an overview of this important field where several disciplines have been combined to improve treatments. Readers will be introduced to techniques that can be translated to the clinic and be applied widely.

CHAPTER 1

Image Guided Focused Ultrasound as a New Method of Targeted Drug Delivery

M. WRIGHT^a, M. CENTELLES^a, W. GEDROYC,^b AND M. THANOU*^a

^a Institute of Pharmaceutical Science, King’s College London, London, UK

^b Department of Experimental Medicine, Imperial College London, UK

*E-mail: [email protected]

1.1 Introduction to Image Guided Focused Ultrasound Drug Delivery

Focused Ultrasound (FUS) is promoting the deposition of energy inside the human body in a non-invasive way.¹ (http://www.fusfoundation.org/for-researchers/mechanisms-of-action). Focused ultrasound energy can be deposited in tissues and lesions with a diameter as little as 1 mm providing a substantial advantage for induction of heat.^2,3 This in turn has a lot of advantages for drug targeting due to the locally increased temperature. When ultrasound is applied in biological systems it can induce local tissue heating, cavitation, and radiation force, which can be used to initiate local (focal) drug delivery, increased molecule permeation through membranes and enhanced diffusivity of drugs, only at the site of sonication therefore allowing control of local drug delivery.⁴ Delivery of certain therapeutics largely benefits from local drug delivery. Cytotoxics, immune suppressive drugs and certain biologicals would have an improved therapeutic index when administered locally with limited exposure to the healthy tissues. Smart drug delivery forms that encapsulate the drug can be designed to deliver their cargo in tissues with increased temperature. FUS (or HIFU: high intensity focused ultrasound) induced local hyperthermia can be the trigger of drug release from thermosensitive carriers.⁵

The ability of FUS waves to induce thermal or mechanical effects at a defined location in living tissue was first described in 1942, when Lynn et al. tested FUS in the brain.⁶ In the 1950s the Fry brothers developed a clinical device to treat patients with Parkinson disease. They used an ultrasound system in combination with X-rays (imaging) to determine the target location relative to skull and to focus the ultrasound beam through a craniotomy into the deep brain for functional neurosurgery.⁷ Later on, in the 1980’s the first FDA-approved FUS system, Sonocare CST-100, was developed to treat ocular disorders such as glaucoma and many patients were clinically treated with this system.⁸ More recently technological developments have delivered new FUS equipment coupled most of the time with an imaging device such as diagnostic ultrasound and/or MRI. Current research and development aim to design and develop novel transducer technology and array designs to achieve rapid delivery of focal sonication, to improve transducer accessibility (smaller devices) or devices to conform/fit to certain parts of the body such as a helmet of arrays for brain focal treatment of diseases.^9,10

Several FUS devices are currently in clinical practice either for approved treatments or for research purposes. These devices are combined with either ultrasound (US) imaging or MR imaging for guidance and thermometry.¹¹ Insightec manufactures the ExAblate2000® which uses MRI for extracorporeal treatment of uterine fibroids (FDA approved) with significant success, and extensive current research focuses on investigating its application in other parts of the body.^12,13 Recently the FDA approved the transcranial MR-guided focused ultrasound for the treatment of essential tremor.¹⁴ This is a hemispheric phased-array transducer (ExAblate Neuro; InSightec Ltd, Tirat Carmel, Israel) with each element directed separately, providing individual correction of skull distortion as well as electronic guidance. The Ablatherm HIFU/US consists of a transrectal probe for prostate treatment and has CE mark approval. In this case imaging is performed with ultrasound.¹⁵ The Sonablate 500, an ultrasound guided system, uses a transrectal FUS probe to carry out prostate cancer focal ablation surgery.¹⁶ The Sonalleve HIFU/MR is an MR compatible device developed to examine applications such as fibroids and bone metastases.¹⁷ The device has been used for the treatment of neuropathic pain and essential tremor and there is also promise of possible application for brain tumours.^18–20 Essential tremor non-interventional functional neurosurgery treatment has shown an immense potential of transcranial MRgFUS application to induce lesions focally and treat patients non-surgically.^21,22 MRgFUS devices are constantly developed. Currently there are 32 manufacturers of image guided FUS worldwide that develop equipment for ablative treatments. There is an on-going interest to use these devices in combination with novel formulations for image guided targeted drug delivery.

1.1.1 Fundamentals of Focused Ultrasound Treatment in Living Tissues

Ultrasound propagates as mechanical vibrations that make molecules within their medium oscillate around their positions and in the direction of the waves’ propagation. As a result the molecules form compressions and rarefactions that propagate the wave. The ultrasound energy is attenuated exponentially through the tissue.²³ The rate of energy flow through a unit area, in the direction of the wave propagation, is called acoustic intensity. At 1 MHz the ultrasound wave is attenuated approximately 50% and it propagates through 7 cm of tissue. The attenuated energy is then transformed into temperature elevation; heat in the tissue.^24,25

Ultrasound waves are transmitted from one soft tissue to another adjacent tissue. In soft tissues a small amount of waves are reflected back. However, in the soft tissue–bone interface almost one-third of the incident energy is reflected back. In addition, the amplitude attenuation coefficient of ultrasound waves is 10–20 times higher in bone than in the soft tissues. This causes the transmitted ultrasound beam to be absorbed rapidly within the bone, leading to high temperature increase.²⁶ When the ultrasound beams are focused at one point, a focal diameter of 1 mm can be achieved at 1.5 MHz. The length of the focus is 5–20 times larger than the diameter (cigarette or rice shaped focus point). If the ultrasound beam is transmitted from an applicator 2–3 cm in diameter, the ultrasound intensity at the millimetre-sized focal spot can be several hundred times higher than in the overlying tissues. The ultrasound exposure drops off rapidly across the area within the sonication path and focusing helps overcoming attenuation losses and to concentrate energy deep in the body avoiding the surrounding tissues.²⁷

The fact that focusing of ultrasound energy is so defined is important for the design of smart materials that can respond or transform to temperature change. Hyperthermia applied in a focused way could affect the phase transition of these materials and induce release of the therapeutic payload only at the heated site. Focussing can help the release of the drug only at the desired site.²⁸

Focusing of ultrasound energy is significantly improved with the use of transducer arrays that are driven by signals having the necessary phase difference to obtain a common focal point.²⁹ The advantage of phased transducer arrays is that the focal spot can be guided and controlled. In addition, the electronically focussed beam allows multiple focal points to be induced simultaneously or fast electronic scanning of the focal spot which increases the area of the focal region. This feature allows shorter treatment time.^30,31 Therefore when focused ultrasound is coupled with imaging and theranostics it could target treatments in areas inside the body independent of the size or location.

1.1.2 Image Guided Focused Ultrasound Mediated Drug Delivery

During the last 15 years emphasis has been given to nanosized carriers for cancer therapy. Nanomedicine is a topic that investigates the effects of nanotechnology in healthcare and has introduced a series of novel drug delivery systems, among which are multifunctional chemical entities called nanotheranostics.^32,33 These are designed to simultaneously detect, image and treat tumours due to the fact that nanoparticles preferably accumulate in tumours compared to other tissues. If these nanoparticles can provide contrast enhancement and deliver their therapeutic cargo then these nanoparticles act as theranostics.³⁴ These systems can be engineered using biocompatible and biodegradable materials and nanomaterials, or by “labelling” previously developed nanoparticles.³⁵ The recent advances of imaging modalities enable nanotheranostics to bind onto lesions or biomarkers on specific cells opening the doors to personalised cancer therapy. The concept of “scan and treat” at the same time can provide clinicians the opportunity to adapt treatments according to imaging data in real time. Nanotheranostics can be used to detect and treat metastases.^36,37 The ability of these drug carrying nanoparticles to reach small metastatic lesions and detect them can offer a substantial advantage to image guided treatments. Nanotheranostics were introduced in the field of nanomedicine research about a decade ago, however their clinical potential is yet to be seen.³⁸ Nanotheranostics can be specially designed to respond to focused ultrasound and an imaging modality.

1.2 Requirements of Image Guided FUS Triggered Drug Delivery Systems

The combination of high-intensity focused ultrasound together with high-resolution MR guidance has created a platform that can produce focussing of the ultrasound energy deep within solid organs without invasive steps. Being non-invasive, focused ultrasound gives several advantages to modify the temperature of deep tissues and in combination with smart temperature triggered nanotheranostics to create a powerful tool for killing cance...