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Image Guided Local Drug Delivery from Nanocarriers using Focused Ultrasound

Final Report Summary - SOUND PHARMA (Image Guided Local Drug Delivery from Nanocarriers using Focused Ultrasound)

The principal objective of the Sound Pharma project was to increase the efficacy of drugs through personalized image-guided therapy, decreasing adverse effects of drugs by better controlling the pharmacokinetics (PK) and pharmacodynamics (PD) of therapy using ultrasound. For local disease, exogenous ultrasound energy was used to 1) release drugs entrapped within nanoparticles circulating through the tumor, and 2) to permeabilize local barriers in drug transport. This was achieved via a combination of Focused Ultrasound (FUS), and drug nanocarriers that are sensitive to bio-effects of ultrasound: either directly via the ultrasound pressure wave, or indirectly via a controlled local temperature increase.

As part of subproject 1, methodologies have been developed for well-controlled local hyperthermia by MRI guided FUS (MR-FUS) in which MRI is used for target identification (planning stage), as well as temperature mapping (during therapy, for real-time feedback control of FUS). For treatment of mobile organs (liver, kidney, pancreas), real-time tracking methods have been developed for precise targeting of FUS. The methods have been published, and made available to the community via our website.

Subproject 2 was devoted to technologies for pressure related drug delivery via cavitation effects. For this methods simultaneous MRI and ultrasound imaging have been developed and published. These methods have been applied to establish the spatial correlation of cavitation and (model) drug delivery.

Subproject 3 concerned real-time monitoring of drug release and drug uptake by Ultrasound/MRI/ Optical Imaging. Several new methods have been developed based on either pressure waves or temperature and applied in vitro resulting in several published papers. The use of intravital fluorescence microscopy to measure (model) drug uptake by cells following ultrasound induced sonoporation has been a true highlight in the Sound-Pharma project. The results allow the measurement of uptake kinetics in each individual cell. The results also show the importance of exocytosis as uptake mechanisms. Also, for temperature sensitive carriers it was shown that the use of liposomes filled with iron particles allow tracking of the intact liposomes as well as the local release upon temperature increase.

In subproject 4, protocols have been developed for ultrasound triggered cell-impermeant and cell permeant drugs using thermo-sensitive and pressure-sensitive agents. Of particular importance here is the evaluation of the duration of membrane permeabilization following FUS induced cavitation and ensuing sonoporation, the so-called temporal window. It has been shown that under moderate ultrasound pressures (400 KPa), this temporal window exceeds one hour. This finding should allow clinical protocols with sonoporation and addition of drugs separated by at least one hour. In addition, we have studied the effects of hyperthermia on PK and PD of high MW drugs (antibodies).

The translation aspects are part of subproject 5. Whereas we planned the use of hyperthermia and temperature sensitive nanocarriers in liver cancer, we have modified are plans as the Sound-Pharma project progressed. The current MR-FUS setup for the liver leads to excessive near-field heating for hyperthermia in the liver. Since in our MR-FUS setup for breast cancer this problem is avoided, and since we have identified a target breast cancer patient population with potential benefit, we have submitted the plan for a Phase 1 study to our Ethical Committe on breast cancer treatment combining MR-FUS induced hyperthermia and thermosensitive liposomes with doxorubicin. In addition, we are also panning the use of ultrasound induced sonoporation for local delivery of cisplatin for the treatment of Head&Neck tumors.

Overall, the project progressed as planned. Next to 33 published peer-reviewed, papers in international journals, 4 keynote lectures in international congresses, the organization of two international scientific conferences at the Host Institute, other highlights include the editing of special issue of Advanced Drug Delivery Reviews on ultrasound triggered drug delivery (with one of our papers being among the 1% most cited in Pharmacology), and the formation of special Study Groups at key international professional Societies, the World Molecular Imaging Society, and the European Society for Molecular Imaging.