Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts

Abstract

Compared with conventional chemotherapy, encapsulation of drugs in nanoparticles can improve efficacy and reduce toxicity. However, delivery of nanoparticles is often insufficient and heterogeneous because of various biological barriers and uneven tumor perfusion. We investigated a unique multifunctional drug delivery system consisting of microbubbles stabilized by polymeric nanoparticles (NPMBs), enabling ultrasound-mediated drug delivery. The aim was to examine mechanisms of ultrasound-mediated delivery and to determine if increased tumor uptake had a therapeutic benefit. Cellular uptake and toxicity, circulation and biodistribution were characterized. After intravenous injection of NPMBs into mice, tumors were treated with ultrasound of various pressures and pulse lengths, and distribution of nanoparticles was imaged on tumor sections. No effects of low pressures were observed, whereas complete bubble destruction at higher pressures improved tumor uptake 2.3 times, without tissue damage. An enhanced therapeutic effect was illustrated in a promising proof-of-concept study, in which all tumors exhibited regression into complete remission.

The Role of Ultrasound-Driven Microbubble Dynamics in Drug Delivery: From Microbubble Fundamentals to Clinical Translation

“…Yet, different evaluation methods are often required, which complicates the interpretation of results. To increase the knowledge on microbubbleassisted drug delivery in vivo, methods to estimate the tissue distribution of the drug in small animals have been described, either on the entire animal using near-infrared fluorescence imaging 15,166 , or by harvesting the organs and extracting the drug separately 167 . MRI has been widely used to monitor blood-brain barrier opening, with the aid of MR contrast agents 97,165,[168][169][170] .…”

“…Using this approach, positive results have been obtained for numerous of microbubble-drug formulations and ultrasound in comparison to the delivery of drugs or nanoparticles alone 10,15,167,[174][175][176] . Nevertheless, a number of adverse effects have also been reported, including hemorrhage 15,171,175 , local burns 16 , necrosis due to vascular shut-down, formation of thrombi 148,177 as well as drug accumulation in lungs, liver and kidney. Furthermore, immunohistochemistry has confirmed the down-regulation of P-glycoprotein in endothelial cells and astrocytes that make up the blood-brain barrier due to microbubble-assisted ultrasound treatment 170,178 .…”

Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes

“…[16][17][18][19][20][21] In this strategy, chemotherapeutics are incorporated into MB shells by hydrophobic interactions, or attached to MB shells by various approaches, such as nanoparticles. [20][21][22][23][24] Thereafter, the MB-loaded chemotherapeutics are then released from MBs that flow through the targeted tumor tissues by high-intensity focused US. The US-controlled release of chemotherapeutics can greatly improve the intracellular uptake of drugs at target tumor tissues, because high-intensity US causes inertial acoustic cavitation effects, such as bubble implosion, shock waves, microstreaming, and microjets.…”

The alkyl side chain of PACA nanoparticles dictates the impact on cellular stress responses and the mode of particle-induced cell death

“…Ferroptosis-inducing drugs have been shown to cooperate with chemotherapeutics such as cisplatin [43], doxorubicin [44], and gemcitabine [45]. Interestingly, PEBCA particles loaded with doxorubicin are currently in clinical trials for hepatocellular carcinoma (ClinicalTrials.gov NCT01655693), and since PACA particles accumulate in the liver [46], they may influence the redox status of the tumor cells and contribute to cell killing by ferroptosis. Our data also suggests that exchanging the PEBCA monomer with PBCA could potentially prove even more efficient in cell killing of drug-resistant cancers.…”