Layer-by-layer assembly of nanotheranostic particles for simultaneous delivery of docetaxel and doxorubicin to target osteosarcoma.

Osteosarcoma (OS) is a rare form of primary bone cancer, impacting approximately 3.4 × 106 individuals worldwide each year, primarily afflicting children. Given the limitations of existing cancer therapies, the emergence of nanotheranostic platforms has generated considerable research interest in recent decades. These platforms seamlessly integrate therapeutic potential of drug compounds with the diagnostic capabilities of imaging probes within a single construct. This innovation has opened avenues for enhanced drug delivery to targeted sites while concurrently enabling real-time monitoring of the vehicle's trajectory. In this study, we developed a nanotheranostic system employing the layer-by-layer (LbL) technique on a core containing doxorubicin (DOXO) and in-house synthesized carbon quantum dots. By utilizing chitosan and chondroitin sulfate as polyelectrolytes, we constructed a multilayered coating to encapsulate DOXO and docetaxel, achieving a coordinated co-delivery of both drugs. The LbL-functionalized nanoparticles exhibited an approximate size of 150 nm, manifesting a predominantly uniform and spherical morphology, with an encapsulation efficiency of 48% for both drugs. The presence of seven layers in these systems facilitated controlled drug release over time, as evidenced by in vitro release tests. Finally, the impact of the LbL-functionalized nanoparticles was evaluated on U2OS and Saos-2 osteosarcoma cells. The synergistic effect of the two drugs was found to be crucial in inducing cell death, particularly in Saos-2 cells treated with nanoparticles at concentrations higher than 10 µg/ml. Transmission electron microscopy analysis confirmed the internalization of the nanoparticles into both cell types through endocytic mechanisms, revealing an underlying mechanism of necrosis-induced cell death.

Modelling smart drug release with functionally graded materials.

Functionally graded materials (FGMs), possessing properties that vary smoothly from one region to another, have been receiving increasing attention in recent years, particularly in the aerospace, automotive and biomedical sectors. However, they have yet to reach their full potential. In this paper, we explore the potential of FGMs in the context of drug delivery, where the unique material characteristics offer the potential of fine-tuning drug-release for the desired application. Specifically, we develop a mathematical model of drug release from a thin film FGM, based upon a spatially-varying drug diffusivity. We demonstrate that, depending on the functional form of the diffusivity (related to the material properties) a wide range of drug release profiles may be obtained. Interestingly, the shape of these release profiles are not, in general, achievable from a homogeneous medium with a constant diffusivity.

Controlling release from encapsulated drug-loaded devices: insights from modeling the dissolution front propagation.

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile.

Oral Viscous Budesonide in Children With Eosinophilic Esophagitis After Repaired Esophageal Atresia: A Clinical Trial.

OBJECTIVES: A high prevalence of eosinophilic esophagitis (EoE) has been reported in children with repaired esophageal atresia (EA). Topical steroids proved to be an effective and safe therapy in EoE, although not approved in pediatrics. We report the results of the first clinical trial of oral viscous budesonide (OVB) performed in children with EoE after repaired esophageal atresia (EoE-EA). METHODS: This open-label, single-arm, phase 2 clinical trial with randomized pharmacokinetic sampling, was conducted at the Bambino Gesù Children's Hospital between September 2019 and June 2021. EoE-EA patients received an age-banded dose of OVB twice daily for 12 weeks and were endoscopically evaluated. The primary endpoint was the rate of patients achieving histological remission. Secondary endpoints included clinical and endoscopic benefit after treatment, and safety assessments. RESULTS: Eight consecutive EA-EoE patients were enrolled (median age 9.1 years, interquartile range 5.5). Of these, 5 received 0.8 mg and 3 received 1.0 mg twice daily of OVB. Histological remission was obtained in all but 1 patient (87.5%). The clinical score showed significant improvement at the end of treatment in all patients. No endoscopic features of EoE were found after treatment. No treatment-emergent adverse event occurred. CONCLUSION: OVB is an effective, safe, and well-tolerated formulation of budesonide for use in pediatric patients with EoE-EA.

Participant Recruitment Issues in Child and Adolescent Psychiatry Clinical Trials with a Focus on Prevention Programs: A Meta-Analytic Review of the Literature.

Introduction: There is a strong need to conduct rigorous and robust trials for children and adolescents in mental health settings. One of the main barriers to meeting this requirement is the poor recruitment rate. Effective recruitment strategies are crucial for the success of a clinical trial, and therefore, we reviewed recruitment strategies in clinical trials on children and adolescents in mental health with a focus on prevention programs. Methods: We reviewed the literature by searching PubMed/Medline, the Cochrane Library database, and Web of Science through December 2022 as well as the reference lists of relevant articles. We included only studies describing recruitment strategies for pediatric clinical trials in mental health settings and extracted data on recruitment and completion rates. Results: The search yielded 13 studies that enrolled a total of 14,452 participants. Overall, studies mainly used social networks or clinical settings to recruit participants. Half of the studies used only one recruitment method. Using multiple recruitment methods (56.6%, 95%CI: 24.5-86.0) resulted in higher recruitment. The use of monetary incentives (47.0%, 95%CI: 24.6-70.0) enhanced the recruitment rate but not significantly (32.6%, 95%CI: 15.7-52.1). All types of recruitment methods showed high completion rates (82.9%, 95%CI: 61.7-97.5) even though prevention programs showed the smallest recruitment rate (76.1%, 95%CI: 50.9-94.4). Conclusions: Pediatric mental health clinical trials face many difficulties in recruitment. We found that these trials could benefit from faster and more efficient recruitment of participants when more than one method is implemented. Social networks can be helpful where ethically possible. We hope the description of these strategies will help foster innovation in recruitment for pediatric studies in mental health.

Modeling Dual Drug Delivery from Eluting Stents: The Influence of Non-Linear Binding Competition and Non-Uniform Drug Loading.

OBJECTIVE: There is increasing interest in simultaneous endovascular delivery of more than one drug from a drug-loaded stent into a diseased artery. There may be an opportunity to obtain a therapeutically desirable uptake profile of the two drugs over time by appropriate design of the initial drug distribution in the stent. Due to the non-linear, coupled nature of diffusion and reversible specific/non-specific binding of both drugs as well as competition between the drugs for a fixed binding site density, a comprehensive numerical investigation of this problem is critically needed. METHODS: This paper presents numerical computation of dual drug delivery in a stent-artery system, accounting for diffusion as well as specific and non-specific reversible binding. The governing differential equations are discretized in space, followed by integration over time using a stiff numerical solver. Three different cases of initial dual drug distribution are considered. RESULTS: For the particular case of sirolimus and paclitaxel, results show that competition for a limited non-specific binding site density and the significant difference in the forward/backward reaction coefficients play a key role in determining the nature of drug uptake. The nature of initial distribution of the two drugs in the stent is also found to influence the binding process, which can potentially be used to engineer a desirable dual drug uptake profile. CONCLUSIONS: These results help improve the fundamental understanding of endovascular dual drug delivery. In addition, the numerical technique and results presented here may be helpful for designing and optimizing other drug delivery problems as well.

Heart rate reduction as a marker to optimize carvedilol treatment and enhance myocardial recovery in pediatric dilated cardiomyopathy.

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children. Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol. Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged <18 years) between 2013 and 2020, with LVEF <40% and treated with carvedilol. Carvedilol was up titrated to the maximal tolerated dose or to 1 mg/kg/day. Echocardiographic data on left ventricular function and dimension were collected. The relationship between HRR and LVEF, left ventricular end-diastolic (LVEDd) and end-systolic diameter (LVESd) was assessed before and after HRR with carvedilol, using regression analysis. Results: 100 patients were enrolled (M: 51%; age 7 ± 8 years). The mean LVEF was 30.2 ± 10% before treatment and 43.7 ± 9.6% after treatment, at the maximum therapeutic dose (p < 0.0001). There was a positive relationship between HRR and increase in LVEF (R 2 = 0.06, p = 0.014). A HRR of >20% correlated with an improvement in LVEF >13%. At 3 years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% (p < 0.0001). No deaths or heart transplant occurred during follow-up. Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children.

Optimization of Initial Drug Distribution in Spherical Capsules for Personalized Release.

OBJECTIVE: Customization of the rate of drug delivered based on individual patient requirements is of paramount importance in the design of drug delivery devices. Advances in manufacturing may enable multilayer drug delivery devices with different initial drug distributions in each layer. However, a robust mathematical understanding of how to optimize such capabilities is critically needed. The objective of this work is to determine the initial drug distribution needed in a spherical drug delivery device such as a capsule in order to obtain a desired drug release profile. METHODS: This optimization problem is posed as an inverse mass transfer problem, and optimization is carried out using the solution of the forward problem. Both non-erodible and erodible multilayer spheres are analyzed. Cases with polynomial forms of initial drug distribution are also analyzed. Optimization is also carried out for a case where an initial burst in drug release rate is desired, followed by a constant drug release rate. RESULTS: More than 60% reduction in root-mean-square deviation of the actual drug release rate from the ideal constant drug release rate is reported. Typically, the optimized initial drug distribution in these cases prevents or minimizes large drug release rate at early times, leading to a much more uniform drug release overall. CONCLUSIONS: Results demonstrate potential for obtaining a desired drug delivery profile over time by carefully engineering the drug distribution in the drug delivery device. These results may help engineer devices that offer customized drug delivery by combining advanced manufacturing with mathematical optimization.

Modeling ATP-mediated endothelial cell elongation on line patterns.

Endothelial cell (EC) migration is crucial for a wide range of processes including vascular wound healing, tumor angiogenesis, and the development of viable endovascular implants. We have previously demonstrated that ECs cultured on 15-µm wide adhesive line patterns exhibit three distinct migration phenotypes: (a) "running" cells that are polarized and migrate continuously and persistently on the adhesive lines with possible spontaneous directional changes, (b) "undecided" cells that are highly elongated and exhibit periodic changes in the direction of their polarization while maintaining minimal net migration, and (c) "tumbling-like" cells that migrate persistently for a certain amount of time but then stop and round up for a few hours before spreading again and resuming migration. Importantly, the three migration patterns are associated with distinct profiles of cell length. Because of the impact of adenosine triphosphate (ATP) on cytoskeletal organization and cell polarization, we hypothesize that the observed differences in EC length among the three different migration phenotypes are driven by differences in intracellular ATP levels. In the present work, we develop a mathematical model that incorporates the interactions between cell length, cytoskeletal (F-actin) organization, and intracellular ATP concentration. An optimization procedure is used to obtain the model parameter values that best fit the experimental data on EC lengths. The results indicate that a minimalist model based on differences in intracellular ATP levels is capable of capturing the different cell length profiles observed experimentally.

Mass diffusion in multi-layer systems: an electrical analogue modelling approach.

We develop a lumped parameter model to describe and predict the mass release of (absorption from) an arbitrary shaped body of any dimension in a large environment. Through the one-to-one analogy between diffusion-dominated mass transfer systems and electrical circuits we provide exact solutions in terms of averaged concentrations and mass released. An estimate of the equivalent resistance and of the release time is also given, and shown to be inversely proportional to the diffusivity. The proposed electrical analogue approach allows a time constant to be defined and provides an easy extension to a multi-layer and multi-phase cases in planar and spherical geometries. The simulation results are compared with those obtained from the solution of the corresponding analytical, numerical and experimental solutions, showing a satisfactory accuracy and a good agreement.

Drug diffusion and release from a bioerodible spherical capsule.

Controlled release of a drug contained in a spherical polymer capsule is of significant interest in many fields of medicine. There is growing interest in tailoring the erosion properties of the drug to help control and optimize the drug release process. Theoretical understanding of the nature of drug release from a bioerodible capsule is, therefore, important for designing effective drug delivery systems. While drug release from a fixed-radius capsule is relatively easier to model, the shrinking nature of a bioerodible capsule due to surface erosion presents several difficulties in theoretical modeling. This work presents a closed-form solution for the drug concentration distribution and drug delivery characteristics from a spherical capsule undergoing linear surface erosion. This problem is solved by a transformation that converts the moving boundary problem into a fixed boundary problem. For uniform initial drug distribution, the solution is shown to depend on a single non-dimensional parameter. The theoretical model is used to develop an understanding of the impact of varying the drug diffusion coefficient and rate of erosion on drug delivery characteristics. It is found that, in general, the nature of drug release in a bioerodible sphere is determined by a delicate balance between two simultaneously occurring processes - erosion and diffusion. This work improves the theoretical understanding of diffusion in drug delivery systems by accounting for the practical erosion phenomena, and may contribute towards the design and optimization of drug delivery systems.

Diagnosis of COVID-19 in children guided by lack of fever and exposure to SARS-CoV-2.

BACKGROUND: The objective of this study is to test how certain signs and symptoms related to COVID-19 in children predict the positivity or negativity of the SARS-CoV-2 nasopharyngeal swab in children. METHODS: We review the data of children who were tested for SARS-CoV-2 for a suspected infection. We compared the clinical characteristics of the subjects who tested positive and negative, including the sensibility, positive and negative predictive value of different combination of signs and symptoms. RESULTS: Of all the suspected infected, 2596 tested negative (96.2%) and 103 tested positive (3.8%). The median age was 7.0 and 5.3 years for the positive and negative ones, respectively. The female to male ratio was ~1:1.3. Fever and respiratory symptoms were mostly reported. Most positive children had a prior exposure to SARS-CoV-2-infected subjects (59.2%). A total of 99.3% of patients without fever nor exposure to the virus proved negative to the SARS-CoV-2 test. CONCLUSIONS: Our study suggests that a child without fever or contact with infected subjects is SARS-CoV-2 negative. If this were to be confirmed, many resources would be spared, with improved care of both COVID-19 and not COVID-19-affected children. IMPACT: Key message: lack of fever and exposure to SARS-CoV-2-infected people highly predicts a negative results of the SARS-CoV-2 nasopharyngeal swab in the paediatric population. Added value to the current literature: this is the first article to prove this point. IMPACT: reduction of emergency department accesses of children with suspected SARS-CoV-2 infection; increased outpatient management of children with cough or other common respiratory symptoms of infancy; sparing of many human and material health resources.

Model of drug delivery to populations composed of two cell types.

The rate of drug delivery to cells and the subsequent rate of drug metabolism are dependent on the cell membrane permeability to the drug. In some cases, tissue may be composed of different types of cells that exhibit order of magnitude differences in their membrane permeabilities. This paper presents a brief review of the components of the tissue scale three-compartment pharmacokinetic model of drug delivery to single-cell-type populations. The existing model is extended to consider tissue composed of two different cell types. A case study is presented of infusion mediated delivery of doxorubicin to a tumor that is composed of a drug reactive cell type and of a drug resistive cell type. The membrane permeabilities of the two cell types differ by an order of magnitude. A parametric investigation of the population composition is conducted and it is shown that the drug metabolism of the low permeability cells are negatively influenced by the fraction of the tissue composed of the permeable drug reactive cells. This is because when the population is composed mostly of drug permeable cells, the extracellular space is rapidly depleted of the drug. This has two compounding effects: (i) locally there is simply less drug available to the neighboring drug resistant cells, and (ii) the depletion of the drug from the extracellular space near the vessel-tissue interface leaves less drug to be transported to both cell types farther away from the vessel.

Prioritizing the First Doses of SARS-CoV-2 Vaccine to Save the Elderly: The Case Study of Italy.

SARS-CoV-2 is currently causing hundreds of deaths every day in European countries, mostly in not yet vaccinated elderly. Vaccine shortage poses relevant challenges to health authorities, called to act promptly with a scarcity of data. We modeled the mortality reduction of the elderly according to a schedule of mRNA SARS-CoV-2 vaccine that prioritized first dose administration. For the case study of Italy, we show an increase in protected individuals up to 53.4% and a decrease in deaths up to 19.8% in the cohort of over 80's compared with the standard vaccine recalls after 3 or 4 weeks. This model supports the adoption of vaccination campaigns that prioritize the administration of the first doses in the elderly.

The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.

Acute Exposure to European Viper Bite in Children: Advocating for a Pediatric Approach.

Viper bite is an uncommon but serious cause of envenoming in Europe, especially in children. Our study aim is to better describe and analyze the clinical course and treatment of viper bite envenoming in a pediatric population. We retrospectively reviewed 24 cases of pediatric viper bites that were admitted to the Pediatric Emergency Department and the Pediatric Intensive Care Unit of the Bambino Gesù Children Hospital in Rome between 2000 and 2020. Epidemiological characteristics of the children, localization of the bite, clinical and laboratory findings, and treatment approaches were evaluated. The median age of the patients was 4.2 years, with male predominance. Most cases of viper bite occurred in the late summer. Most patients required admission to the ward for prolonged observation. The most common presenting signs were pain, local oedema, and swelling. Patients with a high severity score also had a significantly higher white blood cell count and an increase of INR, LDH, and CRP levels. No fatality was reported. Viper bite envenomation is a rare pediatric medical emergency in Italy but may sometimes be severe. A new pediatric severity score may be implemented in the screening of children with viper bites to favor a selective and prompt administration of antivenom.

Macrophage membrane functionalized biomimetic nanoparticles for targeted anti-atherosclerosis applications.

Atherosclerosis (AS), the underlying cause of most cardiovascular events, is one of the most common causes of human morbidity and mortality worldwide due to the lack of an efficient strategy for targeted therapy. In this work, we aimed to develop an ideal biomimetic nanoparticle for targeted AS therapy. Methods: Based on macrophage "homing" into atherosclerotic lesions and cell membrane coating nanotechnology, biomimetic nanoparticles (MM/RAPNPs) were fabricated with a macrophage membrane (MM) coating on the surface of rapamycin-loaded poly (lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (RAPNPs). Subsequently, the physical properties of the MM/RAPNPs were characterized. The biocompatibility and biological functions of MM/RAPNPs were determined in vitro. Finally, in AS mouse models, the targeting characteristics, therapeutic efficacy and safety of the MM/RAPNPs were examined. Results: The advanced MM/RAPNPs demonstrated good biocompatibility. Due to the MM coating, the nanoparticles effectively inhibited the phagocytosis by macrophages and targeted activated endothelial cells in vitro. In addition, MM-coated nanoparticles effectively targeted and accumulated in atherosclerotic lesions in vivo. After a 4-week treatment program, MM/RAPNPs were shown to significantly delay the progression of AS. Furthermore, MM/RAPNPs displayed favorable safety performance after long-term administration. Conclusion: These results demonstrate that MM/RAPNPs could efficiently and safely inhibit the progression of AS. These biomimetic nanoparticles may be potential drug delivery systems for safe and effective anti-AS applications.

A Langevin dynamics approach for multi-layer mass transfer problems.

We use Langevin dynamics simulations to study the mass diffusion problem across two adjacent porous layers of different transport properties. At the interface between the layers, we impose the Kedem-Katchalsky (KK) interfacial boundary condition that is well suited in a general situation. A detailed algorithm for the implementation of the KK interfacial condition in the Langevin dynamics framework is presented. As a case study, we consider a two-layer diffusion model of a drug-eluting stent. The simulation results are compared with those obtained from the solution of the corresponding continuum diffusion equation, and an excellent agreement is shown.