The Synergistic Effect of Nanocrystals Combined With Ultrasound in the Generation of Reactive Oxygen Species for Biomedical Applications

Reactive oxygen species (ROS) effects on living cells and tissues is multifaceted and their level or dose can considerably affect cell proliferation and viability. It is therefore necessary understand their role also designing ways able to regulate their amount inside cells, i.e., using engineered nanomaterials with either antioxidant properties or, for cancer therapy applications, capable to induce oxidative stress and cell death, through tunable ROS production. In this paper, we report on the use of single-crystalline zinc oxide (ZnO) round-shaped nanoparticles, yet ZnO nanocrystals (NCs) functionalized with amino-propyl groups (ZnO-NH2 NCs), combined with pulsed ultrasound (US). We show the synergistic effects produced by NC-assisted US which are able to produce different amount of ROS, as a result of inertial cavitation under the pulsed US exposure. Using Passive Cavitation Detection (PCD) and Electron Paramagnetic Resonance (EPR) spectroscopy, we systematically study which are the key parameters, monitoring, and influencing the amount of generated ROS measuring their concentration in water media and comparing all the results with pure water batches. We thus propose a ROS generation mechanism based on the selective application of US to the ZnO nanocrystals in water solutions. Ultrasound B-mode imaging is also applied, proving in respect to pure water, the enhanced ecographic signal generation of the aqueous solution containing ZnO-NH2 NCs when exposed to pulsed ultrasound. Furthermore, to evaluate the applicability of ZnO-NH2 NCs in the biomedical field, the ROS generation is studied by interposing different tissue mimicking materials, like phantoms and ex vivo tissues, between the US transducer and the sample well. As a whole, we clearly proof the enhanced capability to produce ROS and to control their amount when using ZnO-NH2 NCs in combination with pulsed ultrasound anticipating their applicability in the fields of biology and health care

Improving dispersal of therapeutic nanoparticles in the human body

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Smart Shockwave Responsive Titania-Based Nanoparticles for Cancer Treatment

Nanomedicine is an emerging treatment approach for many cancers, characterized by having high sensitivity and selectivity for tumor cells and minimal toxic effects induced by the conventional chemotherapeutics. In these context, smart nanoparticles (NPs) are getting increasingly relevant in the development of new therapies. NPs with specific chemical composition and/or structure and being stimuli-responsive to magnetic, light or ultrasound waves are new promising tools. In the present work, amorphous-titania propyl-amine functionalized (a-TiO2-NH2) NPs, coated with bovine serum albumin (BSA), are stimulated with high energy shock waves to induce cytotoxic effects in cancer cells. First, a new method to coat a-TiO2-NH2 NPs with BSA (a-TiO2-NH2/BSA) was proposed, allowing for a high dispersion and colloidal stability in a cell culture media. The a-TiO2-NH2/BSA NPs showed no cancer cell cytotoxicity. In a second step, the use of shock waves to stimulate a-TiO2-NH2/BSA NPs, was evaluated and optimized. A systematic study was performed in in vitro cell culture aiming to impair the cancer cell viability: NP concentrations, time steps and single versus multiple shock waves treatments were studied. The obtained results highlighted the relevance of NPs design and administration time point with respect to the shock wave treatment and allow to hypothesize mechanical damages to cells

Dual Drug Loaded Nanotheranostic Platforms as a Novel Synergistic Approach to Improve Pancreatic Cancer Treatment

This study focuses on the development of theranostic, dual drug-loaded nanocarriers to propose a proof-of-principle therapeutic approach in the treatment of pancreatic ductal adenocarcinoma (PDAC). The nanoconstructs consist of a core of zinc oxide nanocrystals doped with gadolinium, useful as a potential contrast agent in magnetic resonance imaging applications. After functionalizing their surface with amino-propyl groups, the physical adsorption of two hydrophobic drugs is performed: Vismodegib and Sorafenib. Their synergistic use might improve PDAC treatment and stroma depletion when co-delivered in the tumor microenvironment for future in vivo applications. To enhance the nanoconstructs’ biostability, the ensemble is coated by a lipid bilayer and a tumor targeting peptide is incorporated on the outer shell surface. As a first proof of concept, the resulting nanoconstructs are tested against two pancreatic cancer cell lines, showing a modest increase in treatment efficacy compared to the free drug counterparts and proving to spare healthy pancreatic cells. In a second testing set, the dual-drug loaded nanoconstructs are tested on both cell lines previously sensitized to a firstline chemotherapeutic drug, Gemcitabine, showing an improved treatment response. From these preliminary results, the nanotheranostic platforms might constitute a good starting point for future PDAC therapy and diagnosis studies

Enhanced selective sonosensitizing efficacy of ultrasound-based anticancer treatment by targeted gold nanoparticles

partially_open9noThis study investigates cancer targeted gold nanoparticles as ultrasound sensitizers for the treatment of cancer.his study investigates cancer targeted gold nanoparticles as ultrasound sensitizers for the treatment of cancer. Methods: The ultrasound sensitizer activity of folate-PEG decorated gold nanoparticles (FA-PEG-GNP) has been studied on human cancer cell lines that overexpress folate receptors (KB and HCT-116) and another that does not (MCF7), at two ultrasound energy densities (8 × 10-6 J cm-2 and 8 × 10-5 J cm-2, for 5 min at 1.866 MHz). Results: FA-PEG-GNP selectively targeted KB and HCT-116 cells and a remarkable reduction in cancer cell growth was observed upon ultrasound exposure, along with significant reactive oxygen species generation and increase in necrotic cells. Conclusion: The combined use of targeting capacity and the ultrasound sensitizing effect, make FA-PEG-GNP promising candidates for the site-specific cancer treatment. © 2016 Future Medicine Ltd.partially_openBrazzale, Chiara; Canaparo, Roberto; Racca, Luisa; Foglietta, Federica; Durando, Giovanni; Fantozzi, Roberto; Caliceti, Paolo; Salmaso, Stefano; Serpe, LoredanaBrazzale, Chiara; Canaparo, Roberto; Racca, Luisa; Foglietta, Federica; Durando, Giovanni; Fantozzi, Roberto; Caliceti, Paolo; Salmaso, Stefano; Serpe, Loredan

BIOMIMETIC NON - IMMUNOGENIC NANOASSEMBLY FOR THE ANTITUMOR THERAPY

Nanoassembly ( 1 ) for inducing apoptosis in cancer cells comprising : a core ( 2 ) comprising at least a nanoparticle of a nano structured and semiconductor metal oxide , said nanoparticle being monocrystalline or polycrystalline ; a shell ( 3 ) formed by a double phospholipid layer and proteins derived from an extracellular biovesicole chosen between an exosome , an ectosome , a connectosome , an oncosome and an apoptotic body , and an oncosome , said core ( 2 ) being enclosed inside said shell ( 3 ) ; and a plurality of targeting molecules ( 4 , 4 ' , 4 " ) of said cancer cells , preferably mono clonal antibodies ( 4 , 4 ' , 4 " ) , said molecules ( 4 , 4 , 4 " ) being anchored to the external surface of said biovesicole

Nanoparticle-assisted ultrasound: a special focus on sonodynamic therapy against cancer

At present, ultrasound radiation is broadly employed in medicine for both diagnostic and therapeutic purposes at various frequencies and intensities. In this review article, we focus on therapeutically-active nanoparticles (NPs) when stimulated by ultrasound. We first introduce the different ultrasound-based therapies with special attention to the techniques involved in oncological field, then we summarize the different NPs used, ranging from soft materials, like liposomes or micro/nano-bubbles, to metal and metal oxide NPs. We therefore focus on the sonodynamic therapy and on the possible working mechanisms under debate of NPs-assisted sonodynamic treatments. We support the idea that various, complex and synergistics physical-chemical processes take place during acoustic cavitation and NP activation. Different mechanisms are therefore responsible for the final cancer cell death and strongly depends on not only the type and structure of NPs or nanocarriers, but also on the way they interact with the ultrasonic pressure waves. We conclude with a brief overview of the clinical applications of the various ultrasound therapies and the related use of NPs-assisted ultrasound in clinics, showing that this very innovative and promising approach is however still at its infancy in the clinical cancer treatment