Large-Pore Functionalized Mesoporous Silica Nanoparticles as Drug Delivery Vector for a Highly Cytotoxic Hybrid Platinum-Acridine Anticancer Agent.

Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40 wt % drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions.

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic. At the recent conference workshop "Mechanisms and Barriers in Nanomedicine" in May 2023 in Colorado, U.S.A., leading experts discussed the formulation, physiological, immunological, regulatory, clinical, and educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, and students to trigger ideas and concepts to move the field forward.

Significance of 4D printing for dentistry: Materials, process, and potentials.

Every industry need helps to modify its working style quickly with the improvement of existing technology. New developing technologies improve production speed, reduce industrial process costs, etc. Technical specialists carry out continuous research and development to increase efficiency. A significant advance in 4D printing over 3D Printing is its capacity to alter shape over time because external elements such as pressure, air, heat, water, etc., use controlled impact. 4D Printing has one "D" instead of 3D Printing, and the fourth aspect is time. Therefore, its capacity to alter shape over time is a significant advancement of 4D printing over 3D printing technologies. It is evident that 4D printing will be of tremendous value to manufacturers regarding features and advances in dentistry. Its applications cover medical modelling, surgical guides manufacture, prosthodontics, dentistry, orthodontics, implantology, and dentistry instruments. This paper is brief about 4D printing and its printing of smart materials through 4D printing. Process workflow and Bio-Oriented 4D printable smart materials for dentistry are presented diagrammatically. Further, the paper identifies and discusses the significant potential of 4D printing for dentistry. 4D printing is an innovative technology that uses the inputs from smart materials, and the 3D printed item becomes another structure via the impact of external energy sources such as temperature, light, or other environmental stimuli. The objective is to integrate technology and design to create self-assembly and programmable material technologies that better design, production, and performance.

Pedagogy and innovative care tenets in COVID-19 pandemic: An enhancive way through Dentistry 4.0.

The global oral healthcare sector has now woken to implement Dentistry 4.0. The implementation of this revolution is feasible with extensive digital and advanced technologies applications and the adoption of new sets of processes in dentistry & its support areas. COVID-19 has bought new challenges to dental professionals and patients towards their customised requirements, regular dental health checkups, fast-paced and safe procedures. People are not visiting the dentist even for mild cases as they fear COVID-19 infection. We see that this set of technologies will help improve health education and treatment process and materials and minimise the infection. During the COVID-19 pandemic, there is a need to understand the possible impact of Dentistry 4.0 for education and innovative care. This paper discusses the significant benefits of Dentistry 4.0 technologies for the smart education platform and dentistry treatment. Finally, this article identifies twenty significant enhancements in dental education and effective care platforms during the COVID-19 pandemic by employing Dentistry 4.0 technologies. Thus, proper implementation of these technologies will improve the process efficiency in healthcare during the COVID-19 pandemic. Dentistry 4.0 technologies drive innovations to improve the quality of internet-connected healthcare devices. It creates automation and exchanges data to make a smart health care system. Therefore, helps better healthcare services, planning, monitoring, teaching, learning, treatment, and innovation capability. These technologies moved to smart transportation systems in the hospital during the COVID-19 Pandemic. Modern manufacturing technologies create digital transformation in manufacturing, optimises the operational processes and enhances productivity.

Semiconducting polymer nanoparticles for photothermal ablation of colorectal cancer organoids.

Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant. Targeted theranostic nanoparticles (NPs) that can produce heat for ablation and enable tumor visualization via their fluorescence offer advantages for detection and treatment of disseminated small nodules. A major hurdle in clinical translation of nanoparticles is their interaction with the 3D tumor microenvironment. To address this problem tumor organoid technology was used to evaluate the ablative potential of CD44-targeted polymer nanoparticles using hyaluronic acid (HA) as the targeting agent and coating it onto hybrid donor acceptor polymer particles (HDAPPs) to form HA-HDAPPs. Additionally, nanoparticles composed from only the photothermal polymer, poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b']dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe), were also coated with HA, to form HA-BSe NPs, and evaluated in 3D. Monitoring of nanoparticle transport in 3D organoids revealed uniform diffusion of non-targeted HDAPPs in comparison to attenuated diffusion of HA-HDAPPs due to nanoparticle-matrix interactions. Computational diffusion profiles suggested that HA-HDAPPs transport may not be accounted for by diffusion alone, which is indicative of nanoparticle/cell matrix interactions. Photothermal activation revealed that only HA-BSe NPs were able to significantly reduce tumor cell viability in the organoids. Despite limited transport of the CD44-targeted theranostic nanoparticles, their targeted retention provides increased heat for enhanced photothermal ablation in 3D, which is beneficial for assessing nanoparticle therapies prior to in vivo testing.

Ultrasonic Atomizer-Driven Development of Biocompatible and Biodegradable Poly(d,l-lactide-co-glycolide) Nanocarrier-Encapsulated Suberoylanilide Hydroxamic Acid to Combat Brain Cancer.

The path to the discovery of anticancer drugs and investigating their potential activity has remained a quest for several decades. Suberoylanilide hydroxamic acid (SAHA), also known as "Vorinostat", is a well-known histone deacetylase inhibitor (HDACi) and has the potential to act as a therapeutic agent against tumorigenesis. Herein, we have fabricated SAHA incorporated into biocompatible and biodegradable poly(d,l-lactide-co-glycolide) PLGA nanoparticles (NPs) using a facile method of ultrasonic atomization and evaluated their anticancer property. We have explored their characteristics using dynamic light scattering (DLS), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), encapsulation efficiency, and in vitro drug release and have investigated their efficacy on U87 glioblastoma (GBM) cells. SAHA-PLGA NPs synthesized were of average mean size of 80 ± 23 and 105 ± 6.0 nm observed through cryo-field-emission gun SEM and HR-TEM with a polydispersity index of 0.068 and a ζ-potential value of -13.26 mV. The encapsulation efficiency was 53%, with a sustained in vitro release up to 48 h. The in vitro assessment of SAHA-PLGA NPs for their anticancer activity on U87 GBM cells showed cellular cytotoxicity with an IC50 of 19.91 µM. SAHA-PLGA NP-treated cells also showed suppression in migration with 8.77 µM concentration, and cell growth inhibition was observed in the wound scratch assay for up to 24 h. The cellular uptake studies have been utilized by time-dependent experiments, revealing their cellular internalization. Taking this into account, our present experimental findings indicate that SAHA-PLGA NPs could play a significant role in enhancing the effectiveness and bioavailability and reducing adverse effects of cancer chemotherapy. It also highlights the inherent potential of these biocompatible entities for chemotherapeutic applications in biomedical and pharmaceutics.

A randomized controlled trial comparing everting sutures with everting sutures and a lateral tarsal strip for involutional entropion.

OBJECTIVE: To determine whether there is a statistically significant difference in the surgical outcome of everting sutures (ES) alone versus everting sutures with a lateral tarsal strip (ES+LTS) in the treatment of involutional entropion. DESIGN: Prospective randomized comparative trial. PARTICIPANTS: Sixty-three patients with primary involutional lower eyelid entropion were enrolled in the study. The age range was 54 to 94 years, with a mean age of 77 years. Baseline characteristics of the comparative groups were similar. METHODS: Patients requiring primary surgical repair for involutional entropion were selected, and those providing informed consent were randomized for surgery. Thirty-six patients were randomized to ES alone, and 27 patients were randomized to ES+LTS. Patients were evaluated at 3 weeks and 6, 12, and 18 months postoperatively. MAIN OUTCOME MEASURES: Successful surgery was defined as a normal eyelid position at rest and inability to induce entropion on tetracaine provocation testing at or before the 18-month follow-up visit. RESULTS: Eight patients were lost to follow-up (7 had ES alone). Of the 55 patients with complete follow-up data, there were 6 failed procedures in the patients who underwent ES alone and no failed procedures in the patients who underwent ES+LTS (P = 0.02). CONCLUSIONS: These data provide strong evidence that success rates at 18 months are higher in patients treated with ES+LTS procedure compared with ES alone.

P-Glycoprotein-Targeted Photothermal Therapy of Drug-Resistant Cancer Cells Using Antibody-Conjugated Carbon Nanotubes.

P-Glycoprotein (Pgp)-medicated multidrug resistance (MDR) remains a formidable challenge to cancer therapy. As conventional approaches using small-molecule inhibitors failed in clinical development because of the lack of cancer specificity, we develop Pgp-targeted carbon nanotubes to achieve highly cancer-specific therapy through combining antibody-based cancer targeting and locoregional tumor ablation with photothermal therapy. Through a dense coating with phospholipid-poly(ethylene glycol), we have engineered multiwalled carbon nanotubes (MWCNTs) which show minimum nonspecific cell interactions and maximum intercellular diffusion. After chemically modifying with an anti-Pgp antibody, these MWCNTs showed highly Pgp-specific cellular uptake. Treatment of the targeted MWCNTs caused dramatic cytotoxicity in MDR cancer cells upon photoirradiation, whereas they did not cause any toxicity in the dark or phototoxicity toward normal cells that do not express Pgp. Because of excellent intratumor diffusion and Pgp-specific cellular uptake, the targeted MWCNTs produced strong phototoxicity in tumor spheroids of MDR cancer cells, a 3-D tumor model for studying tumor penetration and therapy. In conclusion, we have developed highly Pgp-specific MWCNTs that may provide an effective therapy for MDR cancers where other approaches have failed.

Evaluation of multiwalled carbon nanotube cytotoxicity in cultures of human brain microvascular endothelial cells grown on plastic or basement membrane.

There is a growing interest in the use of multiwalled carbon nanotubes (MWCNTs) to treat diseases of the brain. Little is known about the effects of MWCNTs on human brain microvascular endothelial cells (HBMECs), which make up the blood vessels in the brain. In our studies, we evaluate the cytotoxicity of MWCNTs and acid oxidized MWNCTs, with or without a phospholipid-polyethylene glycol coating. We determined the cytotoxic effects of MWCNTs on both tissue-mimicking cultures of HBMECs grown on basement membrane and on monolayer cultures of HBMECs grown on plastic. We also evaluated the effects of MWCNT exposure on the capacity of HBMECs to form rings after plating on basement membrane, a commonly used assay to evaluate angiogenesis. We show that tissue-mimicking cultures of HBMECs are less sensitive to all types of MWCNTs than monolayer cultures of HBMECs. Furthermore, we found that MWCNTs have little impact on the capacity of HBMECs to form rings. Our results indicate that relative cytotoxicity of MWCNTs is significantly affected by the type of cell culture model used for testing, and supports further research into the use of tissue-mimicking endothelial cell culture models to help bridge the gap between in vitro and in vivo toxicology.

Liposome-Protamine-DNA Nanoparticle-Mediated Delivery of Short Hairpin RNA Targeting Brachyury Inhibits Chordoma Cell Growth.

Recent evidence suggests that brachyury is a crucial molecular driver in the initiation and propagation of chordoma. However, no small molecules have been used to specifically target brachyury. Short hairpin RNA (shRNA) has therapeutic promise for the genetic treatment of cancer, but the usage of shRNA therapeutics is limited by obstacles related to effective delivery into the nuclei of target cancer cells due to their inherent sensitivity to nucleases and large polyanionic characteristics. To overcome instability and low transfection efficiency, liposome-protamine-DNA (LPD) nanoparticles were synthesized and investigated as a non-viral carrier of shRNA targeting brachyury in chordoma cells. The size, zeta potential, affinity and transfection efficiency of LPD-shRNA complexes were characterized, and their biological functions in chordoma cells were evaluated. The transfection efficiency of LPD-shRNA was significant higher than naked shRNA. LPD delivered brachyury shRNA into chordoma cells and inhibited brachyury expression, induced apoptosis, upregulated the epithelial biomarker, E-cadherin, downregulated the mesenchymal biomarker, Snail and Slug, and suppressed cell growth. These data indicate that LPD might be a promising non-viral carrier for shRNA in gene targeted therapy of chordoma.

Prostate-specific membrane antigen-targeted liposomes specifically deliver the Zn(2+) chelator TPEN inducing oxidative stress in prostate cancer cells.

AIM: To evaluate the potential use of zinc chelation for prostate cancer therapy using a new liposomal formulation of the zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN). MATERIALS & METHODS: TPEN was encapsulated in nontargeted liposomes or liposomes displaying an aptamer to target prostate cancer cells overexpression prostate-specific membrane antigen. The prostate cancer selectivity and therapeutic efficacy of liposomal (targeted and nontargeted) and free TPEN were evaluated in vitro and in tumor-bearing mice. RESULTS & CONCLUSION: TPEN chelates zinc and results in reactive oxygen species imbalance leading to cell death. Delivery of TPEN using aptamer-targeted liposomes results in specific delivery to targeted cells. In vivo experiments show that TPEN-loaded, aptamer-targeted liposomes reduce tumor growth in a human prostate cancer xenograft model.

Pre-procedural fasting for coronary interventions: is it time to change practice?

INTRODUCTION: Traditionally, patients are kept nil-per-os/nil-by-mouth (NPO/NBM) prior to invasive cardiac procedures, yet there exists neither evidence nor clear guidance about the benefits of this practice. OBJECTIVES: To demonstrate that percutaneous cardiac catheterisation does not require prior fasting. METHODS: The data source is a retrospective analysis of data registry of consecutive patients who underwent percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and stable angina at two district general hospitals in the UK with no on-site cardiac surgery services. RESULTS: A total of 1916 PCI procedures were performed over a 3-year period. None of the patients were kept NPO/NBM prior to their coronary procedures. The mean age was 67±16 years. 1349 (70%) were men; 38.5% (738/1916) had chronic stable angina, while the rest had ACS. 21% (398/1916) were diabetics while 53% (1017/1916) were hypertensive. PCI was technically successful in 95% (1821/1916) patients. 88.5% (1697/1916) had transradial approach. 77% (570/738) of elective PCI patients were discharged within 6 h postprocedure. No patients required emergency endotracheal intubation and there were no occurrences of intraprocedural or postprocedural aspiration pneumonia. CONCLUSIONS: Our observational study demonstrates that patients undergoing PCI do not need to be fasted prior to their procedures.

The suitability of an uncemented hydroxyapatite coated (HAC) hip hemiarthroplasty stem for intra-capsular femoral neck fractures in osteoporotic elderly patients: the Metaphyseal-Diaphyseal Index, a solution to preventing intra-operative periprosthetic fracture.

This study will seek to identify a measurable radiographic index, the Metaphyseal-Diaphyseal Index (MDI) score to determine whether intra-operative fracture in osteoporotic bone can be predicted.A 5 year prospective cohort of 560 consecutive patients, undergoing hemiarthroplasty (cemented or uncemented), was evaluated. A nested case-control study to determine risk factors affecting intra-operative fracture was carried out. The Vancouver Classification was used to classify periprosthetic fracture. The MDI score was calculated using radiographs from the uncemented group. As a control (gold standard), Yeung et al's Canal Bone Ratio (CBR) score was also calculated. From this, a receiver operating characteristic (ROC) curve was formulated for both scores and area under the curve (AUC) compared. Intra and inter-observer correlations were determined. Cost analysis was also worked out for adverse outcomes. Four hundred and seven uncemented and one hundred and fifty-three cemented stems were implanted. The use of uncemented implants was the main risk factor for intra-operative periprosthetic fracture. Sixty-two periprosthetic fractures occurred in the uncemented group (15.2%), nine occurred in the cemented group (5.9%), P < 0.001. The revision rate for sustaining a periprosthetic fracture (uncemented group) was 17.7%, P < 0.001 and 90 day mortality 19.7%, P < 0.03. MDI's AUC was 0.985 compared to CBR's 0.948, P < 0.001. The MDI score cut-off to predict fracture was 21, sensitivity 98.3%, specificity 99.8%, positive predictive value 90.5% and negative predictive value 98%. Multivariate regression analysis ruled out any other confounding factors as being significant. The intra and inter-observer Pearson correlation scores were r = 0.99, P < 0.001. JRI uncemented hemiarthroplasty has a significantly higher intra-operative fracture rate. We recommend cemented arthroplasty for hip fractures. We propose a radiographic system that may allow surgeons to select patients who are good candidates for uncemented arthroplasty, but it needs prospective validation.

Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina.

The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying the ratio between NIPAAm and Dex-lactateHEMA and altering the physical size of the hydrogels. The hydrogels are not toxic to R28 retinal neuron cells in culture medium with 100% cell viability. The hydrogels can be implanted under the conjunctiva without causing adverse effects to the retina based on hematoxylin and eosin stain, immunostaining for microglial cell activation, and electroretinography. These subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases.

Nanoengineering artificial lipid envelopes around adenovirus by self-assembly.

We have developed a novel, reproducible, and facile methodology for the construction of artificial lipid envelopes for adenoviruses (Ad) by self-assembly of lipid molecules around the viral capsid. No alteration of the viral genome or conjugation surface chemistry at the virus capsid was necessary, therefore difficulties in production and purification associated with generating most surface-modified viruses can be eliminated. Different lipid bilayer compositions produced artificially enveloped Ad with physicochemical and biological characteristics determined by the type of lipid used. Physicochemical characteristics such as vector size, degree of aggregation, stability, and surface charge of the artificially enveloped Ad were correlated to their biological (gene transfer) function. In monolayer cell cultures, binding to the coxsackie and adenovirus receptor (CAR) was blocked using a zwitterionic envelope, whereas enhanced binding to the cell membrane was achieved using a cationic envelope. Envelopment of Ad by both zwitterionic and cationic lipid bilayers led to almost complete ablation of gene expression in cell monolayers, due to blockage of virion endosomal escape. Alternatively, artificial Ad envelopes built from lipid bilayers at the fluid phase in physiological conditions led to enhanced penetration of the vectors inside a three-dimensional tumor spheroid cell culture model and delayed gene expression in the tumor spheroid compared to nonenveloped adenovirus. These results indicate that construction of artificial envelopes for nonenveloped viruses by lipid bilayer wrapping of the viral capsids constitutes a general strategy to rationally engineer viruses at the nanoscale with control over their biological properties.