9606080651/653/654 Ultrasound Combined With Nanomaterials For Cancer Therapy
Ultrasound (US) waves refer to wave frequencies beyond 20 kHz. For many years, US have been effectively employed for clinical imaging because of its economical, simplicity, and safety. Several US contrast agents, including micro bubbles were developed to increase image quality by modifying the acoustic characteristics of tissues locally).
US is a safe method which not only can penetrate deeper tissue but also minimizes harmful effects on normal tissues in the neigh- boring area Recently, US with mechanical and thermal effects is emerging in the field of cancer therapy.
US is a safe method which not only can penetrate deeper tissue but also minimizes harmful effects on normal tissues in the neigh- boring area Recently, US with mechanical and thermal effects is emerging in the field of cancer therapy.
They cause cell membranes and organelles to break, which can be employed to directly destroy cancer cells or increase membrane permeability for anticancer medication administration. For cancer therapy, there are two types of US: high-intensity focused ultrasound (HIFU) and low-intensity ultrasound (LIUS).
Because of its selectivity and different biological effects on cancer tissue, HIFU has become a viable therapeutic option for cancer therapy. LIUS together with the sonosensitizers has been used for the sonodynamic therapy (SDT) of cancers, which is able to treat deeply located tumors.
Nanomaterials Combined with HIFU for Cancer Therapy
High-Intensity Focused US (HIFU) is a safe treatment method that uses the US transmission to affect cellular micro- and macro environments. HIFU has been utilized to treat prostate, hepatobiliary, and breast cancers. The technology uses US waves usually in range with high intensities from 0.1 to 10 kW/cm2. HIFU transducers are built such that US beams converge at a focal point to create localized biological effects. As the nanotechnology develops, the nano materials have been designed to improve the HIFU therapy efficiency while lowering the US irradiation dosage.
Nano-Sonosensitizers Combined with LIU for Cancer Therapy
Compared with the HIFU, low intensity US (LIU) often has a much lower intensity. Instead of reaching a high temperature for direct tumor ablation under the HIFU irradiation, ROS species containing hydrogen peroxide (H2O2), superoxide anion (02-), hydroxyl radical (OH) and singlet oxygen (102) are formed for killing cancers under LIU irradiation and in the presence of sonosensitizer (SSs). It is known as SDT. Due to its great therapeutic effectiveness, deep penetration, noninvasiveness, and minimum lateral harm, due to the unique properties and the facile surface modification of the nanomaterials. The nano sensitizers can be designed with the capacities of oxygen generation, oxygen delivery and GSH depletion to alleviate the hypoxia microenvironment and to decrease the ROS consumption. They have also been endowed with acidic PH sensitivity to increase the SDT efficiency. In this section, the SDT mechanism and the nano systems designed to enhance its cancer therapy efficiency have been introduced.
US Triggered Drug Delivery
Sonoporation, also known as sonication mixed with US contrast agents (UCAs), is the temporary formation of holes in the cell membrane that may be repaired. It offers a pathway for molecules entering the cell from outside through the cell membrane. The micro-streaming generated and the corresponding shear stresses and the ROS generated by the cavitation of the UCAS under the US irradiation can deform the cell membrane. Micro bubbles are the most widely used and FDA approved UCAs. But their relatively large size causes a short retention time and their unavoidable retention in the lungs also limited the practical applications. The so-called Enhanced Permeation and Retention (EPR) effect of nano- materials, on the other hand, allows medications to accumulate in tumors while protecting from deterioration and improving pharmacokinetics
HIFU Triggered Drug Delivery
HIFU can induce both thermal and mechanical effects, so it can directly destroy the nanocapsules to release the encapsulated drugs. On the other hand, HIFU can combine with the phase transitional molecules which can transit from liquid to gas under the high temperature, thus to destroy the nanocapsules for the drug release.
Nanobubbles (NBs)
It is one of the nanocarriers, which have become more and more well-known in US drug delivery. It contained liposomal or polymeric shell with the gas or droplets cores.
LIU Triggered Drug Delivery
Low intensity ultrasound can trigger ultrasound targeted microbubble destruction (UTMD) to destruct directly the structure of the nanocapsules for releasing the loaded drugs. Nanobubbles can also be destructed by LIU, constructed the nanobubble by poly (lactide-co-gly- colic acid) (PLGA) shell encapsulating perfluoropropane (C3F8) inside to deliver paclitaxel and gene. They were further modified with A10e3.2 aptamer to specifically target prostate cancer.
Challenge and Perspectives
USG is a noninvasive and efficient stimulus, including HIFU and LIU. It can generate cavitation effect, thermal effect and ROS, thus it can be applied for cancer therapy. US had a greater advantage than the other external stimuli which could produce the ROS. It possessed deeper penetration than light such as the light. It provided a noninvasive therapy modality, compare to the micro- wave induced dynamic therapy and it was safer without the radiation damage than the X-ray.
There still remain many challenges-
1. Most US responsive carriers need a US- responsive core, which consume a lot of space. It leads to lower drug/gene loading efficiency and thus limited therapeutic efficacy.
2. NMs have lower reactivity than micro- bubbles, which need stronger US to cause cavitation for efficient drug/gene release. High intensity US, however, can harm nearby healthy tissues.
3. The controllable, scalable and cost-effective synthesis of the complex nanostructures is also challenging to achieve the high stability and performance for clinical applications.
4. The effects of US combined with US-responsive NMs on the tumor tissues are complicated. Many bio-effects including the thermal effect, sonochemical effect, sonoporation and mechanical forces can be induced.
As a result, a comprehensive understanding of the mechanism how US-responsive NMs enhance the cancer therapy efficiency will lay a foundation to drive the progress of US-responsive NMs in US triggered cancer therapy.