Green synthesis of anti-cancer drug-loaded gold nanoparticles for low-intensity pulsed ultrasound targeted drug release.

In the present work, we have designed a one-pot green protocol in which anti-cancer drugs (curcumin and doxorubicin) can be directly loaded on the surface of gold nanoparticles during their formation. We have further demonstrated that low-intensity pulsed ultrasound (LIPUS) can be used to effectively induce the release of anti-cancer drugs from the surface of gold nanoparticles in an ex vivo tissue model. With this protocol, gold nanoparticles can be easily loaded with different types of anticancer drugs, irrespective of their affinity towards water, and even hydrophobic molecules, like curcumin, can be attached onto the gold nanoparticles in an aqueous medium. The method is very simple and straightforward and does not require stirring or mechanical shaking. The drug molecules interact with the gold seeds formed during the reduction and growth process and modulate the final morphology into a spherical shape. A black-colored colloidal solution of gold nanowire networks is formed in the absence of these anti-cancer drug molecules in the reaction mixture. We used hyperspectral-enhanced dark field microscopy to examine the uptake of gold nanoparticles by breast cancer cells. Upon exposure to LIPUS, the release of the anti-cancer drug from the particle surface can be quantified by fluorescence measurements. This release of drug molecules along with trisodium citrate from the surface of gold nanoparticles by ultrasound resulted in their destabilization and subsequent aggregation, which could be visually observed through the change in the color of colloidal sol. Cancer cell viability was studied by MTT assay to examine the efficacy of this nanoparticle-based drug delivery system. Ultraviolet-visible spectroscopy, dynamic light scattering (DLS), and transmission electron microscope (TEM) analysis were used to characterize the nanoparticles and quantify anti-cancer drug release.

Ultrasound-mediated nano-sized drug delivery systems for cancer treatment: Multi-scale and multi-physics computational modeling.

Computational modeling enables researchers to study and understand various complex biological phenomena in anticancer drug delivery systems (DDSs), especially nano-sized DDSs (NSDDSs). The combination of NSDDSs and therapeutic ultrasound (TUS), that is, focused ultrasound and low-intensity pulsed ultrasound, has made significant progress in recent years, opening many opportunities for cancer treatment. Multiple parameters require tuning and optimization to develop effective DDSs, such as NSDDSs, in which mathematical modeling can prove advantageous. In silico computational modeling of ultrasound-responsive DDS typically involves a complex framework of acoustic interactions, heat transfer, drug release from nanoparticles, fluid flow, mass transport, and pharmacodynamic governing equations. Owing to the rapid development of computational tools, modeling the different phenomena in multi-scale complex problems involved in drug delivery to tumors has become possible. In the present study, we present an in-depth review of recent advances in the mathematical modeling of TUS-mediated DDSs for cancer treatment. A detailed discussion is also provided on applying these computational models to improve the clinical translation for applications in cancer treatment. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Kinetic modelling of ultrasound-triggered chemotherapeutic drug release from the surface of gold nanoparticles.

Therapeutic ultrasound can be used to trigger the on-demand release of chemotherapeutic drugs from gold nanoparticles (GNPs). In the previous work, our group achieved doxorubicin (DOX) release from the surface of GNPS under low-intensity pulsed ultrasound (LIPUS) exposure. However, the specific release kinetics of ultrasound-triggered DOX release from GNPs is not known. Here, we present a release kinetics study of DOX from GNPs under ultrasound exposure for the first time. A novel dialysis membrane setup was designed to quantify DOX release from LIPUS-activated GNPs at 37.0 °C and 43.4 °C (hyperthermia temperature range). Contributions of thermal and non-thermal mechanisms of LIPUS-triggered DOX release were also quantified. Non-thermal mechanisms accounted for 40 ± 7% and 34 ± 5% of DOX release for 37.0 °C and 43.4 °C trials, respectively. DOX release under LIPUS exposure was found to follow Korsmeyer-Peppas (K-P) kinetics, suggesting a shift from a Fickian (static) to a non-Fickian (dynamic) release profile with the addition of non-thermal interactions. DOX release was attributed to an anomalous diffusion release mechanism from the GNP surface. A finite element model was also developed to quantify the acoustic radiation force, believed to be the driving force of non-thermal DOX release inside the dialysis bag.

Integrating Therapeutic Ultrasound With Nanosized Drug Delivery Systems in the Battle Against Cancer.

Controlled, localized, and timely activation of nanosized drug delivery systems (NSDDSs), using an external stimulus such as therapeutic ultrasound (TUS), can improve the efficacy of cancer treatments compared to either conventional chemotherapy methods or passive NSDDSs alone. Specifically, TUS induces thermal and mechanical effects that trigger drug release from NSDDSs and overcomes drug delivery barriers in tumor microenvironments to allow nanoparticle drug carriers to penetrate more deeply into tumor tissue while minimizing side effects. This review highlights recent advancements, contemplates future prospects, and addresses challenges in using TUS-mediated NSDDSs for cancer treatment, encompassing preclinical and clinical applications.

A Quantitative Study of Thermal and Non-thermal Mechanisms in Ultrasound-Induced Nano-drug Delivery.

OBJECTIVE: The primary objective of this study was to quantify the contributions to drug release for thermal and non-thermal mechanisms in ultrasound-induced release from gold nanoparticles (GNPs) for the first time. METHODS: We studied doxorubicin (DOX) and curcumin release from the surface of GNPs using two different methods to induce drug release in an ex vivo tissue model: (i) localized tissue heating with a water bath and (ii) low-intensity pulsed ultrasound (LIPUS) exposure. Both methods have similar temperature profiles and can induce the release of both hydrophobic (curcumin) and hydrophilic (DOX) drugs from the surface of GNPs. Quantitative drug release in both cases was compared via fluorescence measurements. DISCUSSION: The water bath heating method induced drug release using thermal effects only, whereas LIPUS exposure induced drug release used a combination of thermal and non-thermal mechanisms. It was found that there were increases of 70 ± 16% (curcumin) and 127 ± 20% (DOX) in drug release when LIPUS was used to induce drug release (both thermal and non-thermal mechanisms) as compared with the water bath (thermal mechanisms only) mediated release. CONCLUSION: We determined that non-thermal mechanisms account for 41 ± 3% of curcumin release and 56 ± 4% of DOX release. It was concluded that in our ex vivo tissue model, the non-thermal mechanisms play a significant role in LIPUS-induced drug release from GNP drug carriers and that the contributions of non-thermal mechanisms to drug release depend on the type of anticancer drug loaded on the GNP surface.

Ultrasound-mediated nano drug delivery for treating cancer: Fundamental physics to future directions.

The application of biocompatible nanocarriers in medicine has provided several benefits over conventional treatment methods. However, achieving high treatment efficacy and deep penetration of nanocarriers in tumor tissue is still challenging. To address this, stimuli-responsive nano-sized drug delivery systems (DDSs) are an active area of investigation in delivering anticancer drugs. While ultrasound is mainly used for diagnostic purposes, it can also be applied to affect cellular function and the delivery/release of anticancer drugs. Therapeutic ultrasound (TUS) has shown potential as both a stand-alone anticancer treatment and a method to induce targeted drug release from nanocarrier systems. TUS approaches have been used to overcome various physiological obstacles, including endothelial barriers, the tumor microenvironment (TME), and immunological hurdles. Combining nanomedicine and ultrasound as a smart DDS can increase in situ drug delivery and improve access to impermeable tissues. Furthermore, smart DDSs can perform targeted drug release in response to distinctive TMEs, external triggers, or dual/multi-stimulus. This results in enhanced treatment efficacy and reduced damage to surrounding healthy tissue or organs at risk. Integrating DDSs and ultrasound is still in its early stages. More research and clinical trials are required to fully understand ultrasound's underlying physical mechanisms and interactions with various types of nanocarriers and different types of cells and tissues. In the present review, ultrasound-mediated nano-sized DDS, specifically focused on cancer treatment, is presented and discussed. Ultrasound interaction with nanoparticles (NPs), drug release mechanisms, and various types of ultrasound-sensitive NPs are examined. Additionally, in vitro, in vivo, and clinical applications of TUS are reviewed in light of the critical challenges that need to be considered to advance TUS toward an efficient, secure, straightforward, and accessible cancer treatment. This study also presents effective TUS parameters and safety considerations for this treatment modality and gives recommendations about system design and operation. Finally, future perspectives are considered, and different TUS approaches are examined and discussed in detail. This review investigates drug release and delivery through ultrasound-mediated nano-sized cancer treatment, both pre-clinically and clinically.

Multiphysics Modeling of Low-Intensity Pulsed Ultrasound Induced Chemotherapeutic Drug Release from the Surface of Gold Nanoparticles.

Currently, no numerical model for low-intensity pulsed ultrasound (LIPUS)-triggered anticancer drug release from gold nanoparticle (GNP) drug carriers exists in the literature. In this work, LIPUS-induced doxorubicin (DOX) release from GNPs was achieved in an ex vivo tissue model. Transmission electronic microscopy (TEM) imaging was performed before and after LIPUS exposure, and significant aggregation of the GNPs was observed upon DOX release. Subsequently, GNP surface potential was determined before and after LIPUS-induced DOX release, using a Zetasizer. A numerical model was then created to predict GNP aggregation, and the subsequent DOX release, via combining a thermal field simulation by solving the bioheat transfer equation (in COMSOL) and the Derjaguin, Landau, Verwey, and Overbeek (DLVO) total interaction potential (in MATLAB). The DLVO model was applied to the colloidal DOX-loaded GNPs by summing the attractive van der Waals and electrostatic repulsion interaction potentials for any given GNP pair. DLVO total interaction potential was found before and after LIPUS exposure, and an energy barrier for aggregation was determined. The DLVO interaction potential peak amplitude was found to drop from 1.36 kBT to 0.24 kBT after LIPUS exposure, translating to an 82.4% decrease in peak amplitude value. It was concluded that the interaction potential energy threshold for GNP aggregation (and, as a result, DOX release) was equal to 0.24 kBT.