Ultrasound for the delivery of a nanocarrier across biological barriers in tumors: impact of cavitation and acoustic radiation force

Abstract

Ultrasound for the delivery of a nanocarrier across biological barriers in tumors: impact of cavitation and acoustic radiation force Although conventional chemotherapy is the still one of the most important treatment modalities, it is often insufficient resulting in limited efficacy and systemic off-target effects. Ultrasound (US) alone and in combination with microbubbles (MBs) have been shown to produce a variety ofbiological effects on tissue that can result in transiently enhanced permeability of biological barriers such as blood vessel walls, the extracellular matrix (ECM), cell membranes, and the blood-brain barrier, leading to enhanced accumulation of co-injected drug molecules at the target site. However, a full understanding of how US alone and combined with injected MBs improves thee therapeutic effect of drugs against tumors is lacking. In this thesis, a nano-carrier delivery study assessing the performance of the combination of US with nanoparticles (NPs), and NPs-stabilized MBs or commercial contrast agents (SonoVue) in overcoming the biological barriers, including blood vessel walls and the ECM to the extravasation and transport of NPs as a model therapeutic agents is conducted. US combined with injected MBs induced cavitation in the vasculature were observed in real time using optical microscope and found significant extravasation and penetration of the NPs under the range of pressures applied. Majority of the extravasation took place at vessel branching points, and a higher pressure is required to achieve extravasation from the smaller blood vessels than from larger vessels. US alters nanoparticle flow velocity and blood flow direction. In addition, we investigated the impact of US and MBs on the ECM and found insignificant changes in the collagen content and structure for the acoustic pressures applied. In addition, we found that the mechanical effect of US through acoustic radiation force (ARF) and acoustic streaming improved the transport of NPs in the tumor ECM. This penetration of the NPs might facilitate enhanced therapeutic efficacy against tumor sites. However, we found no effect of ARF on the transport of NPs in the tissue-mimicking collagen phantom, whereas a large deformation of the collagen gel was found for the acoustic pressures tested. ARF could play an important role in overcoming the barriers created by vasculature and ECM if the US parameters are well optimized. Using several experimental investigations, important insights were gained concerning the mechanisms involved in the non-thermal effect of US (cavitation and ARF) on enhancing drug delivery. Interestingly, the results are highly useful for understanding the mechanisms, optimizing the US-mediated delivery of NPs and supplying important insights for future studies. It is also noted that the US-induced drug delivery of nano-carriers across biological barriers can enhanced cancer treatment