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Cardiovascular diseases (CVDs) stand as the leading cause of death worldwide, posing a significant global health challenge. Consequently, the development of innovative therapeutic ...strategies to enhance CVDs treatment is imperative. RNA-based therapies, encompassing non-coding RNAs, mRNA, aptamers, and CRISPR/Cas9 technology, have emerged as promising tools for addressing CVDs. However, inherent challenges associated with RNA, such as poor cellular uptake, susceptibility to RNase degradation, and capture by the reticuloendothelial system, underscore the necessity of combining these therapies with effective drug delivery systems.
Various non-viral delivery systems, including extracellular vesicles, lipid-based carriers, polymeric and inorganic nanoparticles, as well as hydrogels, have shown promise in enhancing the efficacy of RNA therapeutics. In this review, we offer an overview of the most relevant RNA-based therapeutic strategies explored for addressing CVDs and emphasize the pivotal role of delivery systems in augmenting their effectiveness. Additionally, we discuss the current status of these therapies and the challenges that hinder their clinical translation.
Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. ...Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.
The co-administration of glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged as a powerful strategy to enhance the efficient ...integration of transplanted cells in Parkinson’s disease (PD). This strategy could be improved by controlling the cellular microenvironment and biomolecule release and better mimicking the complex properties of the brain tissue. Here, we develop and characterize a drug delivery system for brain repair where MSCs and GDNF are included in a nanoparticle-modified supramolecular guest–host HA HG. In this system, the nanoparticles act as both carriers for the GDNF and active physical crosslinkers of the HG. The multifunctional HG is mechanically compatible with brain tissue and easily injectable. It also protects GDNF from degradation and achieves its controlled release over time. The cytocompatibility studies show that the developed biomaterial provides a friendly environment for MSCs and presents good compatibility with PC12 cells. Finally, using RNA-sequencing (RNA-seq), we investigated how the three-dimensional (3D) environment, provided by the nanostructured HG, impacted the encapsulated cells. The transcriptome analysis supports the beneficial effect of including MSCs in the nanoreinforced HG. An enhancement in the anti-inflammatory effect of MSCs was observed, as well as a differentiation of the MSCs toward a neuron-like cell type. In summary, the suitable strength, excellent self-healing properties, good biocompatibility, and ability to boost MSC regenerative potential make this nanoreinforced HG a good candidate for drug and cell administration to the brain.
Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene‐based ...nanomedicine with bone affinity and retention capacity. A squalenyl‐hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1‐hydroxyl‐1,1‐bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl‐gemcitabine nanoparticles using the nanoprecipitation method. The co‐assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl‐hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient‐treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas.
Precision nanomedicines can improve osteosarcoma treatments by enhancing the action of cytostatic agents through selective targeting to the bone tumor area. HbisP−Sq, a lipid molecule with high affinity for calcium ions present in HA has been successfully synthetized. Its amphiphilic nature makes this bone targeting moiety suitable for insertion into anticancer dFdC−Sq NPs. Their combination led to the formation of multilamellar monodisperse dFdC−Sq|HbisP−Sq NPs of 75 nm size with bone binding affinity skills.
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Tetronics are X-shaped block-copolymers of polyethylene oxide and polypropylene oxide, which self-assemble into micelles and can undergo a sol-gel transition; these transitions are ...dependent on temperature, concentration but also pH, due to the central diamine group of the tetrablock. We report the nanoscale morphologies underlying these different phases and the rheology of the systems for a very large, highly hydrophilic block copolymer, Tetronic 908, through the combined use of oscillatory rheology, steadyblock-state and time-resolved fluorescence, small-angle neutron scattering (SANS), dynamic light scattering (DLS) and Fourier transform infrared attenuated total reflectance (FTIR-ATR). At low concentrations, SANS reveal core-shell micelles of ca. 10 nm radius, presenting a dehydrated core and a highly hydrated shell, with relatively small aggregation numbers (Nagg ≈ 13). The micelles are notably affected by the pH, due to the protonation of the central amine spacer at low pH (pH ≈ 2), which shifts micellization to higher temperature, with smaller micelles than at natural pH. In the intermediate concentration regime (10–15%), micelles become smaller (Nagg ≈ 5), and present a higher hydration of the core. In the high concentration regime, Tetronic 908 undergoes a sol-gel transition above a threshold temperature, which is fully inhibited at acidic pH. SANS data from the gel phase reveal a BCC order of tightly packed spheres. Temperature sweeps in oscillatory rheology show a shift of the onset of gelation towards lower temperatures as concentration increases, an increase in the elastic modulus G′ and an expansion of gel region over a larger range of temperatures. SANS and rheology reveal that at pH below the natural pH (ca. 8), gelation is shifted to higher temperatures, but the morphology of the gels is similar, while under highly acidic conditions the gelation is fully suppresed.
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•An alginate-collagen hydrogel (HG) was developed as an extracellular vesicle (EV) delivery system for increasing EV exposure in the heart after myocardial infarction (MI).•The ...combination of alginate and collagen allowed for the development of an in-situ jellifying HG compatible with EV delivery via catheter-based technology.•The HG developed possessed an internal gel structure, weak mechanical properties and low viscosity, facilitating easy administration.•The alginate-collagen HG showed long-term retention in the heart and allowed sustained release of EVs for at least 7 days in a rat model of MI.
Extracellular vesicles (EVs) are nanosized particles with attractive therapeutic potential for cardiac repair. However, low retention and stability after systemic administration limit their clinical translation. As an alternative, the combination of EVs with biomaterial-based hydrogels (HGs) is being investigated to increase their exposure in the myocardium and achieve an optimal therapeutic effect. In this study, we developed and characterized a novel injectable in-situ forming HG based on alginate and collagen as a cardiac delivery vehicle for EVs. Different concentrations of alginate and collagen crosslinked with calcium gluconate were tested. Based on injectability studies, 1% alginate, 0.5 mg/mL collagen and 0.25% calcium gluconate HG was selected as the idoneous combination for cardiac administration using catheter-based systems. Rheological examination revealed that the HG possessed an internal gel structure, weak mechanical properties and low viscosity, facilitating an easy administration. In addition, EVs were successfully incorporated and homogeneously distributed in the HG. After administration in a rat model of myocardial infarction, the HG showed long-term retention in the heart and allowed for a sustained release of EVs for at least 7 days. Thus, the combination of HGs and EVs represents a promising therapeutic strategy for myocardial repair. Besides EVs delivery, the developed HG could represent a useful platform for cardiac delivery of multiple therapeutic agents.
RNA-based therapies, and siRNAs in particular, have attractive therapeutic potential for cancer treatment due to their ability to silence genes that are imperative for tumor progression. To be ...effective and solve issues related to their poor half-life and poor pharmacokinetic properties, siRNAs require adequate drug delivery systems that protect them from degradation and allow intracellular delivery. Among the various delivery vehicles available, lipid nanoparticles have emerged as the leading choice. These nanoparticles consist of cholesterol, phospholipids, PEG-lipids and most importantly ionizable cationic lipids. These ionizable lipids enable the binding of negatively charged siRNA, resulting in the formation of stable and neutral lipid nanoparticles with exceptionally high encapsulation efficiency. Lipid nanoparticles have demonstrated their effectiveness and versatility in delivering not only siRNAs but also multiple RNA molecules, contributing to their remarkable success. Furthermore, the advancement of efficient manufacturing techniques such as microfluidics, enables the rapid mixing of two miscible solvents without the need for shear forces. This facilitates the reproducible production of lipid nanoparticles and holds enormous potential for scalability. This is shown by the increasing number of preclinical and clinical trials evaluating the potential use of siRNA-LNPs for the treatment of solid and hematological tumors as well as in cancer immunotherapy. In this review, we provide an overview of the progress made on siRNA-LNP development for cancer treatment and outline the current preclinical and clinical landscape in this area. Finally, the translational challenges required to bring siRNA-LNPs further into the clinic are also discussed.
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•RNA-based cancer therapy modifies the genetic signature of tumor cells, surrounding cells and the immune system causing tumor reduction.•siRNA represents a promising strategy within RNA-based therapy for cancer.•siRNAs face some obstacles including rapid elimination by nucleases and hindrances to internalization by cells due to their negative charge.•Lipid nanoparticles containing ionizable lipids can deliver siRNA to tumor cells by the endosomal escape pathway.•siRNA-lipid nanoparticles have still some challenges to overcome, mostly regarding long term storage stability.
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•Nanomedicine shows potential to improve brain drug delivery.•Chemotherapeutics have been encapsulated into nanocarriers for glioblastoma treatment.•Doxorubicin and liposomes are the ...most frequent drug and carrier tested preclinically.•Several nanocarriers have entered clinical trials for glioblastoma treatment.
Even though substantial advances in understanding glioma pathogenesis have prompted a more rational design of potential therapeutic strategies, glioblastoma multiforme remains an incurable disease with the lowest median overall survival among all malignant brain tumours. Therefore, there is a dire need to find novel drug delivery strategies to improve the current dismal survival outcomes. In this context, nanomedicine offers an appealing alternative as it shows potential to improve brain drug delivery. Accordingly, we here review nanomedicine-based drug delivery strategies tested in orthotopic animal models of glioblastoma intended to improve the efficacy of the drug candidates that are currently used in the clinical setting or that have entered clinical trials for the treatment of glioblastoma multiforme. We also outline the future perspectives of nanotechnology to provide emerging glioblastoma treatment with broad translational clinical potential based on the nanocarriers that have already entered the clinical trials stage for the treatment of malignant glioma.
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