Smart nanoparticles for medical applications have gathered considerable attention due to an improved biocompatibility and multifunctional properties useful in several applications, including advanced ...drug delivery systems, nanotheranostics and in vivo imaging. Among nanomaterials, zinc oxide nanoparticles (ZnO NPs) were deeply investigated due to their peculiar physical and chemical properties. The large surface to volume ratio, coupled with a reduced size, antimicrobial activity, photocatalytic and semiconducting properties, allowed the use of ZnO NPs as anticancer drugs in new generation physical therapies, nanoantibiotics and osteoinductive agents for bone tissue regeneration. However, ZnO NPs also show a limited stability in biological environments and unpredictable cytotoxic effects thereof. To overcome the abovementioned limitations and further extend the use of ZnO NPs in nanomedicine, doping seems to represent a promising solution. This review covers the main achievements in the use of doped ZnO NPs for nanomedicine applications. Sol-gel, as well as hydrothermal and combustion methods are largely employed to prepare ZnO NPs doped with rare earth and transition metal elements. For both dopant typologies, biomedical applications were demonstrated, such as enhanced antimicrobial activities and contrast imaging properties, along with an improved biocompatibility and stability of the colloidal ZnO NPs in biological media. The obtained results confirm that the doping of ZnO NPs represents a valuable tool to improve the corresponding biomedical properties with respect to the undoped counterpart, and also suggest that a new application of ZnO NPs in nanomedicine can be envisioned.
Conventional technologies for ureteral stent fabrication suffer from major inconveniences such as the development of encrustations and bacteria biofilm formation. These drawbacks typically lead to ...the failure of the device, significant patient discomfort and an additional surgery to remove and replace the stent in the worst cases. This work focuses on the preparation of a new nanocomposite material able to show drug elution properties, biodegradation and eventually potential antibacterial activity. Poly(2-hydroxyethyl methacrylate) or the crosslinked poly(2-hydroxyethyl methacrylate)-co-poly(acrylic acid) hydrogels were prepared by the radical polymerization method and combined with a biodegradable and antibacterial filling agent, i.e., flower-like Zinc Oxide (ZnO) micropowders obtained via the hydrothermal route. The physico-chemical analyses revealed the correct incorporation of ZnO within the hydrogel matrix and its highly mesoporous structure and surface area, ideal for drug incorporation. Two different anti-inflammatory drugs (Ibuprofen and Diclofenac) were loaded within each composite and the release profile was monitored up to two weeks in artificial urine (AU) and even at different pH values in AU to simulate pathological conditions. The addition of mesoporous ZnO micropowders to the hydrogel did not negatively affect the drug loading properties of the hydrogel and it was successfully allowed to mitigate undesirable burst-release effects. Furthermore, the sustained release of the drugs over time was observed at neutral pH, with kinetic constants (k) as low as 0.05 h−1. By exploiting the pH-tunable swelling properties of the hydrogel, an even more sustained release was achieved in acidic and alkaline conditions especially at short release times, with a further reduction of burst effects (k ≈ 0.01–0.02 h−1). The nanocomposite system herein proposed represents a new material formulation for preparing innovative drug eluting stents with intrinsic antibacterial properties.
Recent advances in nanomedicine have led to the introduction and subsequent establishment of nanoparticles in cancer treatment and diagnosis. Nonetheless, their application is still hindered by a ...series of challenges related to their biocompatibility and biodistribution. In this paper, we take inspiration from the recently produced and widely spread COVID vaccines, based on the combinational use of ionizable solid lipid nanoparticles, cholesterol, PEGylated lipids, and neutral lipids able to incorporate mRNA fragments. Here, we focus on the implementation of a lipidic formulation meant to be used as a smart coating of solid-state nanoparticles. The composition of this formulation is finely tuned to ensure efficient and stable shielding of the cargo. The resulting shell is a highly customized tool that enables the possibility of further functionalizations with targeting agents, peptides, antibodies, and fluorescent moieties for future in vitro and in vivo tests and validations. Finally, as a proof of concept, zinc oxide nanoparticles doped with iron and successively coated with this lipidic formulation are tested in a pancreatic cancer cell line, BxPC-3. The results show an astonishing increase in cell viability with respect to the same uncoated nanoparticles. The preliminary results presented here pave the way towards many different therapeutic approaches based on the massive presence of highly biostable and well-tolerated nanoparticles in tumor tissues, such as sonodynamic therapy, photodynamic therapy, hyperthermia, and diagnosis by means of magnetic resonance imaging.
The horizon of nanomedicine research is moving toward the design of therapeutic tools able to be completely safe per se, and simultaneously be capable of becoming toxic when externally activated by ...stimuli of different nature. Among all the stimuli, ultrasounds come to the fore as an innovative approach to produce cytotoxicity on demand in presence of NPs, without invasiveness, with high biosafety and low cost. In this context, zinc oxide nanoparticles (NPs) are among the most promising metal oxide materials for theranostic application due to their optical and semi-conductor properties, high surface reactivity, and their response to ultrasound irradiation. Here, ZnO nanocrystals constitute the stimuli-responsive core with a customized biomimicking lipidic shielding, resembling the composition of natural extracellular vesicles. This core–shell hybrid structure provides high bio- and hemocompatibility towards healthy cells and is here proofed for the treatment of Burkitt’s Lymphoma. This is a very common haematological tumor, typically found in children, for which consolidated therapies are so far the combination of chemo-therapy drugs and targeted immunotherapy. In this work, the proposed safe-by-design antiCD38-targeted hybrid nanosystem exhibits an efficient selectivity toward cancerous cells, and an on-demand activation, leading to a significant killing efficacy due to the synergistic interaction between US and targeted hybrid NPs. Interestingly, this innovative treatment does not significantly affect healthy B lymphocytes nor a negative control cancer cell line, a CD38- acute myeloid leukemia, being thus highly specific and targeted. Different characterization and analyses confirmed indeed the effective formation of targeted hybrid ZnO NPs, their cellular internalization and the damages produced in Burkitt’s Lymphoma cells only with respect to the other cell lines. The presented work holds promises for future clinical applications, as well as translation to other tumor types.
Graphical abstract
Recent advances in nanomedicine toward cancer treatment have considered exploiting liposomes and extracellular vesicles as effective cargos to deliver therapeutic agents to tumor cells. Meanwhile, ...solid-state nanoparticles are continuing to attract interest for their great medical potential thanks to their countless properties and possible applications. However, possible drawbacks arising from the use of nanoparticles in nanomedicine, such as the nonspecific uptake of these materials in healthy organs, their aggregation in biological environments and their possible immunogenicity, must be taken into account. Considering these limitations and the intrinsic capability of phospholipidic bilayers to act as a biocompatible shield, their exploitation for effectively encasing solid-state nanoparticles seems a promising strategy to broaden the frontiers of cancer nanomedicine, also providing the possibility to engineer the lipid bilayers to further enhance the therapeutic potential of such nanotools. This work aims to give a comprehensive overview of the latest developments in the use of artificial liposomes and naturally derived extracellular vesicles for the coating of solid-state nanoparticles for cancer treatment, starting from in vitro works until the up-to-date advances and current limitations of these nanopharmaceutics in clinical applications, passing through in vivo and 3D cultures studies.
Background
Colorectal cancer (CRC) is the third most diagnosed tumor worldwide, with a very high mortality rate, second only to lung cancer. Current treatments, such as surgery, chemotherapy or ...radiotherapy, are not effective enough and show several limitations. Among the emerging strategies, nanomedicine offers very powerful tools in cancer treatment. Recently, the combination of nanoparticle antitumor effect with a triggering external stimulation was formulated to boost up the cytotoxic activity.
Results
In this work, we show the synergistic effect of oleic acid-capped zinc oxide nanocrystals (ZnO NCs) and mechanical high-energy shock waves (SW) in the treatment for CRC cells, in vitro. We tested two different types of ZnO NCs synthetized in our laboratory, the basal undoped ZnO NCs and the iron-doped ones (Fe:ZnO NCs). The presence of the oleic acid capping and the further amino-propyl functionalization guarantee a high colloidal stability to both NCs, while the iron doping confers to Fe:ZnO NCs interesting magnetic properties useful for imaging applications in a clinical perspective. Thus, the iron-doped ZnO NCs are very attractive as potentially theranostic nanoparticles, allowing both stimuli-responsive therapy and magnetic resonance imaging.
Importantly, two colon adenocarcinoma cell lines, the HT-29 and the Dukes’ type C Colo 320DM cells were tested, both showing a good bio-tolerance and internalization rates of NCs. With the aim of eradicating the CRC cells, the possible synergism between the undoped/iron-doped ZnO NCs and an external physical stimulus, i.e., high-energy SW, was then here investigated in vitro. We demonstrated that the combined treatment resulted in an augmentation of the antitumor activity, especially for Colo 320DM cells, when compared to controls. Moreover, a repeated and sequenced SW treatment (three times/day, 3SW) after ZnO NCs exposure resulted in a further increased mortality of CRC cells.
Conclusion
Our work proposes the combination of the cytotoxic activity of ZnO NCs with the SW external stimulation to obtain a booster of the antitumor activity, which warrants further investigation in vivo on CRC as well as on other tumors.
Graphical Abstract
Zinc oxide nanoparticles (ZnO NPs) are currently among the most promising nanomaterials for theranostics. However, they suffer from some drawbacks that could prevent their application in nanomedicine ...as theranostic agents. The doping of ZnO NPs can be effectively exploited to enhance the already-existing ZnO properties and introduce completely new functionalities in the doped material. Herein, we propose a novel synthetic approach for iron-doped ZnO (Fe:ZnO) NPs as a multifunctional theranostic nanoplatform aimed at cancer cell treatment. Pure ZnO and Fe:ZnO NPs, with two different levels of iron doping, were synthesized by a rapid wet-chemical method and analyzed in terms of morphology, crystal structure and chemical composition. Interestingly, Fe:ZnO NPs featured bioimaging potentialities thanks to superior optical properties and novel magnetic responsiveness. Moreover, iron doping provides a way to enhance the electromechanical behavior of the NPs, which are then expected to show enhanced therapeutic functionalities. Finally, the intrinsic therapeutic potentialities of the NPs were tested in terms of cytotoxicity and cellular uptake with both healthy B lymphocytes and cancerous Burkitt's lymphoma cells. Furthermore, their biocompatibility was tested with a pancreatic ductal adenocarcinoma cell line (BxPC-3), where the novel properties of the proposed iron-doped ZnO NPs can be potentially exploited for theranostics.
Despite different nanomaterials were developed so far against cancer, their potential drawbacks are still scarcely considered. The off-target delivery of a therapeutic compound, as well as the ...non-specific uptake of these nanomaterials by healthy tissues or organs, and their potential immunogenicity are some of the major issues that still have to be faced prior to a successful clinical translation. This work aims to develop an innovative theranostic, biocompatible, and drug-loaded nanoconstruct based on Gadolinium-doped Zinc Oxide (ZnO-Gd) nanocrystals (NCs), focusing on one of the most lethal diseases, i.e., pancreatic cancer. The use of zinc oxide is motivated by the huge potential of this nanomaterial already demonstrated for in vitro and in vivo applications, while the Gadolinium doping confers magnetic properties useful for diagnostics. Furthermore, an innovative biomimetic shell is here used to coat the NCs: it is composed of a lipid bilayer made from extracellular vesicles (EVs) combined with other synthetic lipids and a peptide targeting the pancreatic tumor microenvironment. To complete the nanoconstruct therapeutic function, Gemcitabine, a first-line drug for pancreatic cancer treatment, was adsorbed on the ZnO-Gd NCs prior to the coating with the above-mentioned lipidic shell. The aim of this work is thus to strongly enhance the therapeutic capability of the final nanoconstruct, providing it with high biocompatibility, colloidal stability in biological media, efficient cargo loading and release properties, as well as active targeting for site-selective drug delivery. Furthermore, the magnetic properties of the ZnO-Gd NCs core can in future allow efficient in situ bioimaging capabilities based on Magnetic Resonance Imaging technique. The obtained nanoconstructs were tested on two different pancreatic cancer cell lines, i.e., BxPC-3 and the metastatic AsPC-1, proving high cell internalization levels, mediated by the targeting peptide exposed on the nanoconstruct. Cellular cytotoxicity assay performed on both cell lines dictated ~ 20% increased cell killing efficacy of Gemcitabine when delivered through the nanoconstruct rather than as a free drug. Taken together, our designed theranostic nanoconstruct can have a significant impact on the standard treatment of pancreatic cancer.
Recent advances in optical imaging techniques rely on the use of nanosized contrast agents for in vitro and in vivo applications. We report on an imaging method based on the inertial cavitation of ...ultrasound-irradiated water solutions that lead to sonoluminescence (SL), here, newly proposed in combination with semiconductor nanoparticles, in particular, aminopropyl-functionalized zinc oxide nanocrystals. The obtained measurements confirm the ability of such nanocrystals to increase the sonoluminescence emission, together with the ability to modify the SL spectrum when compared to the pure water behavior. In particular, it is shown that the UV component of SL is absorbed by the semiconductor behavior that is also confirmed in different biologically relevant media. Finally, optical images of nanocrystal-assisted SL are acquired for the first time, in particular, in biological buffers, revealing that at low ultrasound intensities, SL is measurable only when the nanocrystals are present in solution. All of these results witness the role of amine-functionalized zinc oxide nanocrystals for sonoluminescence emission, which makes them very good candidates as efficient nanocontrast agents for SL imaging for biological and biomedical applications.
Rhodamine B (RhB) is a harmful dye released by industrial wastewaters, thus necessitating its urgent removal. Advanced oxidation processes constitute promising strategies to purify polluted water. ...Among others, photocatalysis relies on reactive oxygen species (ROS) produced by photocatalytic particles, typically semiconductors like titania or zinc oxide (ZnO), excited by solar or UV–Vis light. However, their wide band gap limits their catalytic capabilities within the absorption of the UV spectrum and causes fast electron–hole recombination. This study presents novel strategies to overcome these limitations: (i) doping semiconductors to increase photocatalytic efficiency; (ii) sensitization-mediated photocatalysis for visible light activation using chemical moieties to trap dye molecules; (iii) nanosizing the photocatalysts to enhance the surface area. ZnO nanoparticles, doped with iron or gadolinium and capped with oleic acid are here synthesized and tested in RhB dye solutions. Remarkably, the results demonstrate an ultra-fast RhB degradation, driven by oleic acid having crucial role in dye adsorption. The degradation mechanisms, including ROS-induced N-deethylation and xanthene group cleavage, are also unraveled. These findings underscore the efficacy of the proposed semiconductor photocatalyst design, highlighting a significant advancement with extensive potential applications in wastewater remediation. This innovative approach paves the way for more efficient and practical solutions to combat industrial dye pollution.
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