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Ultrasound activiated nanoencapsulated targetted drug delivery and tumous cell poration

Final Report Summary - NANOPORATION (Ultrasound activiated nanoencapsulated targetted drug delivery and tumous cell poration)

Executive Summary:

Nanoporation was a Marie Curie Industry-Academia Partnership Pathways (IAPP) Project funded by the FP7 people programme. Nanoporation aimed to overcome challenges in current chemotherapy-related treatment, by developing new methods which directed drug delivery exclusively to tumours, thus reducing the harmful side effects of chemotherapy such as bone-marrow suppression and hair loss, and increasing the effectiveness of the treatment.

The aim of this type of project was to develop collaborations between public research organisations and private commercial enterprises, in particular SMEs, with the potential to increase knowledge-sharing and mutual understanding of different cultural settings and skill requirements of both sectors. Nanoporation exchanged researchers and transferred knowledge between three partners; the University of Dundee (UNIVDUN), InSightec Ltd (INS) and CapsuTech Ltd (CAP), which is an SME. The project focused on the exchange of expertise in Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS), drug nano-capsules, nano-scale sonication research, cell biology and pre-clinical oncology research for targeted drug delivery of generic chemotherapy drugs. The objectives of the research activities included the development of a new integrated treatment protocol, characterised by reduced systemic dosage of existing anti-cancer drugs with more effective tumour cell uptake and therefore enhanced objective tumour response.

Conventional chemotherapy involves administering toxic chemical substances that damage rapidly dividing cells, a characteristic of cancer cells. These substances can permeate the whole body and can also damage healthy cells that divide rapidly. The project has proved that using the developed Nanoporation technique, anti-cancer substances are placed inside advanced nano-capsules that then deliver the substances only when focused ultrasound is applied. This carries the potential of the harmful side effects of chemotherapy being reduced, if not eliminated, whilst the efficacy is increased; which may lead to higher survival rates and enhanced quality of life for patients. The project work continues with preclinical trials.

Achievements in the project include:

• Development of an experimental platform

CAP drug delivery vehicles were successfully utilised at UNIVDUN in the ultrasound system supplied by INS. Extensive, ground-breaking studies were completed for a laser-nucleated acoustic cavitation technique for investigation of bubble and bubble cloud dynamics and for optical / acoustic / hybrid trapping. Microscopy techniques showed that conventional microscopy was inappropriate. In-vitro multi focal sonication was developed as a novel modality of using the INS Conformal Bone System. In vivo procedures for using the INS clinical system on mice has been developed, approved and validated. Robotic positioning of Focused Ultrasound has been tested on Thiel soft embalmed human cadavers so as to establish an alternative preclinical validation platform.

• Optimisation of sonication effects and ultrasonic device development

The research at INS focused on the development and optimisation of ultrasound systems technology for improved data acquisition, monitoring and analysis. INS developed an ExAblate2100 Conformal Bone System cell culture sonication setup and experimental procedure. To further study the effect of focused ultrasound on cell lines, a multi-focal beam pattern was developed and characterized. The pattern allows simultaneous generation of 16 focal points for more reliable in-vitro results. Very advanced experimental studies have been performed including modelling and simulation of the ultrasound beam resulting in various publications and the abilities of sonication 96 wellplates using the clinical MRgFUS system.

• Optimisation of Nano-capsule response to sonication and cytotoxic drug loading

CAP researched the optimization of different nano-drug carriers to improve specific encapsulation properties for different anti-cancer drugs: Doxorubicin (DOX), Taxol, Camptothecin (CPT) and Mitoxantrone (MITOX). The result of optimization was verified thorough in-vitro release under hyperthermia and sonication conditions, in-vivo uptake, a kinetics study and finally in the approved set up of an in-vivo study for drug delivery mediated by ultrasound under MRI guidance.

• Convergence of developing technologies. In-vitro studies of efficacy and toxicology

In-vitro experiments were performed for researching the kinetics of uptake of the drug by human carcinoma cell lines (MCF7, A375M, PANC-1, PC-3 and KB). Also the cytotoxicity was measured using standard techniques and the separation of thermal and mechanical (bubble mediated) effects were investigated. A high-throughput device was developed and experimental methods were optimized towards standardization of in-vitro US-mediated Targeted Drug Delivery experiments using 96 wellplates.

• Pre-clinical and experimental in-vivo oncology of nano-particle encapsulated compounds

After a significant amount of prerequisites were met, sonication protocols (most suitable US parameters that can be used with nano-carriers for drug release) for small animals were explored with in-vivo mice. Moreover nude immune-compromise with human xenograft tumours (colon cancerous cells HCT116) was monitored and tumour growth rate documented. MR imaging was performed ex-vivo and then the best MRI parameters were verified in-vivo. Thus two key components of the MRgFUS treatment, the US and MRI parameters were identified in two separate experiments in the absence of drug or microbubbles. The animal trials are on-going.

In Nanoporation there have been 23 (twenty three) Marie Curie Early Stage and Experienced Research Fellows working on the project. Seven of which were recruited and the rest of the Fellows undertook inter-sectoral secondments, the lengths of which ranged from two to twenty-four months. All partners recruited and seconded an even mix of men and women at all career levels, with each partner adhering to their appropriate Equal Opportunities policies for their country and organisation. The Fellows had varying levels of expertise in their fields and their knowledge was regularly exchanged through monthly technical web-based conferences. All fellows were actively encouraged to participate fully in the project and attend other technical conferences, training events and conferences to publicise the project scientifically and to the general public.

To encourage and strengthen the transfer of knowledge, two summer schools were scheduled for the project. The first summer school was hosted by INS in March 2011 and the second was hosted by UNIVDUN in September 2012. The schools offered both theoretical and hands-on practical training sessions in the field of targeted drug delivery; with invited world-leading scientists as chairs and speakers to each day. The schools were widely advertised internationally to attract a large number of external participants. The summer schools were very well attended by numerous participants from all over the world along with all Nanoporation fellows.

The project has exceeded expectations of progress and has made many scientific achievements alongside recruiting and seconding highly talented researchers. Both the academic and industrial partners have gained immensely from the skills exchanges which have taken place. The consortium has developed long-term collaborations and relationships which will continue in the future. The consortium has been widely recognized in the international community resulting in the election of Professor Andreas Melzer as co-chairman of the European Working group on Focused Ultrasound Therapy and co-organizer of the 2nd European FUS Therapy Symposium, 10-12 October 2013.