טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentSchiopu Aresteanu Roana Noemi
SubjectNoninvasive Monitoring using MRI of Copper Oxide
Nanoparticles Controlled Release from
Nano Micelles Stimulated by Ultrasound
Hyperthermia
DepartmentDepartment of Biomedical Engineering
Supervisor Professor Haim Azhari
Full Thesis textFull thesis text - English Version


Abstract


Cancer remains among the greatest causes of mortality worldwide. Surgical procedures for tumor therapy are not always applicable while other conventional treatments such as chemotherapy and radiation therapy have undesirable side effects and may induce collateral damage to healthy tissues.

Hyperthermia is a complementary localized treatment used in cancer therapy which causes tissue sensitization thus improving treatment outcome. Therapeutic ultrasound can be used to induce local hyperthermia noninvasively.

Nanotechnology, on the other hand, can be utilized for controlled drug delivery and tumor targeting. Specifically, it has been shown that Copper-Oxide Nanoparticles (CuO NPs) demonstrate specific toxicity to tumor initiating cancer cells and can also serve as a contrast enhancing agent for both MRI and Ultrasound. However, CuO NPs toxicity may also induce possible side effects at high dosage. Thus, it is necessary to encapsulate them within nano carriers, which will enable their safe delivery to the target tissue and allow sufficient systemic circulation time in order to accumulate in the target.

The idea proposed here, is to combine ultrasound-induced hyperthermia with stimulated release of encapsulated CuO NPs in order to achieve a “double impact”, i.e. thermal treatment combined with stimulated local toxic drug release. Continuous monitoring of the treated area is critical in order to determine treatment effectiveness and safety. Magnetic resonance imaging (MRI) offers superior image quality and enables temperature mapping. The overall objective of this research was to suggest a new approach for tumor therapy based on a combination of ultrasound induced hyperthermia with stimulated CuO NPs release together with noninvasive MRI monitoring.

In stage I of the research, 200 nm PEG-b-PLA nano micelles loaded with 7nm CuO NPs were synthesized and characterized. A therapeutic ultrasonic transducer was used in order to induce hyperthermia. In stage II, water and saline-based samples containing the CuO NPs loaded micelles were sonicated and their temperature was elevated to about 60°C. Colorimetric methods were used to verify and quantify the copper release from the micelles as a function of time and temperature. In stage III, MRI images of NPs containing solutions and ex-vivo poultry liver samples were acquired. T1 weighted and T1 mapping images before and after ultrasonic treatment were produced.  

The results of stage I confirmed that CuO NPs can be encapsulated in PEG-b-PLA nano micelles. stage II confirmed that the combination of sonication by the therapeutic ultrasound and encapsulated CuO NPs substantially stimulates the NPs release from the micelles in comparison to non-treated samples. stage III confirmed that the samples containing the encapsulated NPs are detectible by T1-mapping, where substantial T1 shortening was measured. Furthermore, the NPs releasing effect was also visible by T1-weighted imaging where whitening of the samples containing the released NPs was clearly observed.

 In conclusion, this work has demonstrated the feasibility of encapsulating CuO NPs in PEG-b-PLA nano micelles, ultrasonically releasing them and monitoring the process by MRI. Considering the diagnostic and cytotoxic activities of the CuO NPs, this approach can potentially lead to the development of a new noninvasive strategy for cancer theranostics.