The primary goal of image guided drug delivery (IGDD) is to increase the therapeutic index of potent, often toxic treatments through personalized image-guided treatment, ultimately decreasing adverse effects of drugs by better controlling the pharmacokinetics (PK) and pharmacodynamics (PD) of therapy.

High frequency sound waves can lead to local tissue heating, cavitation, and radiation force in tissue, which can be used for 1) local drug release from nanocarriers circulating in the blood, 2) increased extravasation and crossing of the Blood-Brain-Barrier, 3) increased cellular uptake of drugs and/or carriers, and 4) enhanced diffusivity of drugs. Ultrasound can be focused within a region with a diameter of about 1 mm. Nanocarriers sensitive to mechanical forces, and/or sensitive to temperature can be used to release the content of the nanocarriers locally. Real-time imaging methods, such as MRI, optical and ultrasound imaging have led to novel insights and methods for ultrasound triggered drug delivery. Image guidance of ultrasound therapy can be used for: 1) target identification and characterization; 2) spatio-temporal guidance of actions to release or activate the drugs and/or permeabilize membranes; 3) evaluation of biodistribution, pharmacokinetics and pharmacodynamics; 4) Physiological read-outs to evaluate the therapeutic efficacy.

Magnetic resonance guided high-intensity focused ultrasound (MR-HIFU) is a versatile technology platform for noninvasive thermal therapies. Since MR-HIFU allows heating of deep-seated tissue to well defined temperatures under MR image guidance, this novel technology has great potential for local heat mediated drug delivery from temperature-sensitive liposomes (TSLs). MRI also allows imaging the drug release when an MRI contrast agent is co-encapsulated with the drug in the aqueous lumen of the liposomes. This review describes MR-HIFU as a noninvasive technology platform,which in combination with temperature sensitive liposomal formulations provide a means for image-guided local drug delivery. The effects of HIFU induced hyperthermia on the TSL and drug distribution will be demonstrated. The opportunities and challenges of localized MR-HIFU-mediated drug delivery by using temperature-sensitive liposomes are discussed. In addition, it is described how MRI can be used to monitor the ultrasound triggered drug delivery.

Thermosensitive liposomes have been suggested for local drug release in combination with local hyperthermia more than 25 years ago. Liposomes may carry both hydrophilic and hydrophobic drugs, together with contrast agents, in their aqueous interior and lipid bilayer membrane, respectively. Iron oxide particles and/or conventional Gd based contrast agents can be used to track the particles with MRI, and monitor the release of the contents.

Microbubbles are used clinically to increase contrast in ultrasound imaging. They can also be used therapeutically in IGDD. Drugs and imaging agents can be attached to the shell surrounding the microbubble, they can be imbedded within the shell itself, they can be bound non-covalently to the surface of the microbubble. Optical contrast agents can be used as model drugs that allow monitoring of extravasation and internalization in the cells. Labelling with radioactive nuclei allows the evolution of the biodistribution of particles and drugs.

Sonoporation can be used to facilitate transport of drugs to its target. One of the most intriguing therapeutic possibilities of HIFU arising from these types of therapy is the ability of HIFU to temporarily disrupt the blood-brain barrier (BBB) with a combination of MR-HIFU and (clinically approved) ultrasound contrast agents. Conventional MR contrast agents can be used to demonstrate that the BBB has been opened before drugs are administered.The recently published examples of the use of MR-HIFU for local drug delivery illustrate the important role of multi-modal molecular imaging in the various aspects of ultrasound triggered IGDD. Ultrasound triggered IGDD has been shown to be feasible (1,2), and initial clinical applications have started. (Real-time) molecular imaging methods based on MRI, optical and ultrasound, are used for guidance of actions to release or activate drugs and/or permeabilize membranes, and for evaluation of biodistribution, PK/PD. MRI offers many advantages in this field such as: excellent target definition, temperature monitoring, nanoparticle monitoring, biomarkers for drug release, and biomarkers for BBB opening.