Magnetic hyperthermia (MH) based on magnetic nanoparticles (MNPs) is a promising adjuvant therapy for cancer treatment. Particle clustering leading to complex magnetic interactions affects the heat ...generated by MNPs during MH. The heat efficiencies, theoretically predicted, are still poorly understood because of a lack of control of the fabrication of such clusters with defined geometries and thus their functionality. This study aims to correlate the heating efficiency under MH of individually coated iron oxide nanocubes (IONCs) versus soft colloidal nanoclusters made of small groupings of nanocubes arranged in different geometries. The controlled clustering of alkyl-stabilized IONCs is achieved here during the water transfer procedure by tuning the fraction of the amphiphilic copolymer, poly(styrene-co-maleic anhydride) cumene-terminated, to the nanoparticle surface. It is found that increasing the polymer-to-nanoparticle surface ratio leads to the formation of increasingly large nanoclusters with defined geometries. When compared to the individual nanocubes, we show here that controlled grouping of nanoparticlesso-called “dimers” and “trimers” composed of two and three nanocubes, respectivelyincreases specific absorption rate (SAR) values, while conversely, forming centrosymmetric clusters having more than four nanocubes leads to lower SAR values. Magnetization measurements and Monte Carlo-based simulations support the observed SAR trend and reveal the importance of the dipolar interaction effect and its dependence on the details of the particle arrangements within the different clusters.
Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for ...studying personalized medicine and pre-clinical tests. Despite recent advances, models that reproduce both tissue complexity and maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating human cardiac microtissues in vitro from hiPSCs-namely human organotypic cardiac microtissues (hOCMTs)-that show some degree of self-organization and can be cultured for long term. This is achieved by the differentiation of hiPSC in 2D monolayer culture towards cardiovascular lineage, followed by further aggregation on low-attachment culture dishes in 3D. The generated hOCMTs contain multiple cell types that physiologically compose the heart and beat without external stimuli for more than 100 days. We have shown that 3D hOCMTs display improved cardiac specification, survival and metabolic maturation as compared to standard monolayer cardiac differentiation. We also confirmed the functionality of hOCMTs by their response to cardioactive drugs in long-term culture. Furthermore, we demonstrated that they could be used to study chemotherapy-induced cardiotoxicity. Due to showing a tendency for self-organization, cellular heterogeneity, and functionality in our 3D microtissues over extended culture time, we could also confirm these constructs as human cardiac organoids (hCOs). This study could help to develop more physiologically-relevant cardiac tissue models, and represent a powerful platform for future translational research in cardiovascular biology.
The application of lipid‐based nanoparticles for COVID‐19 vaccines and transthyretin‐mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their ...use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid‐based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid‐based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid‐based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes.
The implementation of advanced preclinical models such as tumor organoids, incorporating immune system cells and tumor extracellular matrix, will contribute to the development of innovative antitumor therapies such as mechanotherapy‐assisted lipid‐based immunotherapy.
The research for heart therapies is challenged by the limited intrinsic regenerative capacity of the adult heart. Moreover, it has been hampered by the poor results obtained by tissue engineering and ...regenerative medicine attempts at generating functional beating constructs able to integrate with the host tissue. For this reason, organ transplantation remains the elective treatment for end-stage heart failure, while novel strategies aiming to promote cardiac regeneration or repair lag behind. The recent discovery that adult cardiomyocytes can be ectopically induced to enter the cell cycle and proliferate by a combination of microRNAs and cardioprotective drugs, like anti-oxidant, anti-inflammatory, anti-coagulants and anti-platelets agents, fueled the quest for new strategies suited to foster cardiac repair. While proposing a revolutionary approach for heart regeneration, these studies raised serious issues regarding the efficient controlled delivery of the therapeutic cargo, as well as its timely removal or metabolic inactivation from the site of action. Especially, there is need for innovative treatment because of evidence of severe side effects caused by pleiotropic drugs. Biocompatible nanoparticles possess unique physico-chemical properties that have been extensively exploited for overcoming the limitations of standard medical therapies. Researchers have put great efforts into the optimization of the nanoparticles synthesis and functionalization, to control their interactions with the biological milieu and use as a viable alternative to traditional approaches. Nanoparticles can be used for diagnosis and deliver therapies in a personalized and targeted fashion. Regarding the treatment of cardiovascular diseases, nanoparticles-based strategies have provided very promising outcomes, in preclinical studies, during the last years. Efficient encapsulation of a large variety of cargos, specific release at the desired site and improvement of cardiac function are some of the main achievements reached so far by nanoparticle-based treatments in animal models. This work offers an overview on the recent nanomedical applications for cardiac regeneration and highlights how the versatility of nanomaterials can be combined with the newest molecular biology discoveries to advance cardiac regeneration therapies.
Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main ...features able to control the fate of cell‐nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell‐nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell‐nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes‐associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple‐negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP‐dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple‐negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.
The inhibition of Yeas‐associated protein (YAP) in TNBC cells affects the organization of plasma membrane, reduces the extracellular matrix (ECM) deposition, impacts their adhesion ability, and increases the endocytosis rate. Thus, targeting cell mechanobiology may be leveraged to optimize cell‐nanoparticle interactions. Ultimately, these changes contribute cooperatively to promote the delivery of nanomedicines to cancer cells and improve the therapeutic efficiency.
Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clinical trials for the treatment ...of brain and prostate tumors, iron oxide nanoparticles are employed as intra-tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific physical-chemical properties in terms of magneto-energy conversion, heat dose production, surface chemistry and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced
different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temperature at the tumor, we focus on the studies that have optimized MNPs to maintain gold-standard MHT performance and are also tackling MNP imaging with the aim to quantitatively assess the amount of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided.
Background
Sella turcica bridging (STB), or calcification of the interclinoid ligament of sella turcica, has been reported to be associated with some dental anomalies (palatal canine impaction and ...transposition).
Hypothesis or Aim
The aim of the study was to find any association between canine impaction, hyperdontia or hypodontia and sellar dimensions or bridging.
Design
Lateral cephalometric radiographs from 78 patients with impacted canines, 68 with dental agenesis and 17 with hyperdontia were collected. Linear dimensions of sella turcica were calculated and compared to those of a control group (47 individuals). A standardize scoring scale was used to quantify the extent of STB from each radiographs.
Results
The frequency of partial and complete calcifications of sella in patients with dental anomalies is increased when compared to controls. STB can influence the interclinoid distance but does not affect other linear dimensions of sella. No statistically significant difference has been found in sellar dimensions and STB expression when evaluating radiographs at different ages.
Conclusions
STB is frequently found in patients with dental abnormalities.
Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor‐selective drugs. Here, as a proof‐of‐concept, the use of high‐frequency ...sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self‐aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug‐resistant cell lines. Only marginal cytotoxicity (80–100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25–40 µg mL−1). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor‐mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell‐collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono‐active moieties.
The ultrasonic transformation of doxorubicin into a tumor selective nanodrug is presented. The nanodrug maintains the antiproliferative activity against several cancer cell lines without being toxic to healthy cells as verified in 2D/3D coculture. The nanodrug associates with lipid rafts on mitochondria membranes to produce cytotoxic reactive oxygen species. In vivo study reveals accumulation of the nanodrug in the lung.
Herein, by studying a stepwise phase transformation of 23 nm FeO–Fe3O4 core–shell nanocubes into Fe3O4, we identify a composition at which the magnetic heating performance of the nanocubes is not ...affected by the medium viscosity and aggregation. Structural and magnetic characterizations reveal the transformation of the FeO–Fe3O4 nanocubes from having stoichiometric phase compositions into Fe2+-deficient Fe3O4 phases. The resultant nanocubes contain tiny compressed and randomly distributed FeO subdomains as well as structural defects. This phase transformation causes a 10-fold increase in the magnetic losses of the nanocubes, which remain exceptionally insensitive to the medium viscosity as well as aggregation unlike similarly sized single-phase magnetite nanocubes. We observe that the dominant relaxation mechanism switches from Néel in fresh core–shell nanocubes to Brownian in partially oxidized nanocubes and once again to Néel in completely treated nanocubes. The Fe2+ deficiencies and structural defects appear to reduce the magnetic energy barrier and anisotropy field, thereby driving the overall relaxation into Néel process. The magnetic losses of these nanoparticles remain unchanged through a progressive internalization/association to ovarian cancer cells. Moreover, the particles induce a significant cell death after being exposed to hyperthermia treatment. Here, we present the largest heating performance that has been reported to date for 23 nm iron oxide nanoparticles under intracellular conditions. Our findings clearly demonstrate the positive impacts of the Fe2+ deficiencies and structural defects in the Fe3O4 structure on the heating performance into intracellular environment.
Magnetic nanoparticles (MNPs) provide new opportunities for enzyme-free biosensing of nucleic acid biomarkers and magnetic actuation by patterning on DNA origami, yet how the DNA grafting density ...affects their dynamics and accessibility remains poorly understood. Here, we performed surface functionalization of MNPs with single-stranded DNA (ssDNA)
click chemistry with a tunable grafting density, which enables the encapsulation of single MNPs inside a functional polymeric layer. We used several complementary methods to show that particle translational and rotational dynamics exhibit a sigmoidal dependence on the ssDNA grafting density. At low densities, ssDNA strands adopt a coiled conformation that results in minor alterations to particle dynamics, while at high densities, they organize into polymer brushes that collectively influence particle dynamics. Intermediate ssDNA densities, where the dynamics are most sensitive to changes, show the highest magnetic biosensing sensitivity for the detection of target nucleic acids. Finally, we demonstrate that MNPs with high ssDNA grafting densities are required to efficiently couple to DNA origami. Our results establish ssDNA grafting density as a critical parameter for the functionalization of MNPs for magnetic biosensing and functionalization of DNA nanostructures.
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