Editorial for Special Issue 'Engineering and Characterisation of Novel Nanomedicine Formulations'.

Nanomedicine is the application of nanotechnology to achieve innovations in healthcare and involves the engineering of systems at the nanoscale (particle size < 1000 nm) with the aim of improving drug delivery [...].

[Phenotyping and genotyping in patients with inflammatory bowel disease in a reference center in Colombia]. / Fenotipificación y genotipificación en pacientes con enfermedad inflamatoria intestinal en un centro de referencia de Colombia.

INTRODUCTION: Attempts have been made to identify the genetic factors related to susceptibility to inflammatory bowel disease (IBD), and the current conclusions are in favor of a complex pathology model, without a clear hereditary pattern. OBJECTIVE: To perform phenotypic and genotypic characterization of patients with IBD in Colombian population and to describe its possible association with predisposition. MATERIALS AND METHODS: case series, 16 patients with IBD according to clinical and pathological criteria, onset of gastrointestinal symptoms after 18 years of age. All had pre-test genetic counseling and family trees of at least three generations were made. Also, genotyping, using a multi-gene panel that included genes related to IBD and some autoimmune disorders. Finally, a genomic analysis of variants was performed. RESULTS: 9 women and 7 men, with mean age of diagnosis of IBD of 35 years, and gastrointestinal symptoms appearance of 32 years. 11/16 (68.75%) required biological therapy. 10/16 (62.5%) were refractory to standard therapy. 3/16 (18.75%) had positive family history of IBD. 100% cases presented at least one single nucleotide polymorphism related to IBD risk in more than one gene. The genes most related to ulcerative colitis (UC) were CD48, CD6, and TYK2 for UC, and CD6 and ITGAM for Crohn's disease. The most frequent gene was CD6. It was found presence of up to 5 genes in 3/16 (18.75%), 4 in 3/16 (18.75%), and three in 5/16 (31.25%). CONCLUSION: In IBD there is the presence of genetic variants with associated predisposition, but without confirmed pathogenicity, and whose sum seems to contribute to its pathophysiology.

A Prospective, Observational Study of the Effect of a High-Calorie, High-Protein Oral Nutritional Supplement with HMB in an Old and Malnourished or at-Risk-of-Malnutrition Population with Hip Fractures: A FracNut Study.

BACKGROUND: Hip fractures are prevalent among older people, often leading to reduced mobility, muscle loss, and bone density decline. Malnutrition exacerbates the prognosis post surgery. This study aimed to evaluate the impact of a 12-week regimen of a high-calorie, high-protein oral supplement with ß-hydroxy-ß-methylbutyrate (HC-HP-HMB-ONS) on nutritional status, daily activities, and compliance in malnourished or at-risk older patients with hip fractures receiving standard care. SUBJECTS AND METHODS: A total of 270 subjects ≥75 years of age, residing at home or in nursing homes, malnourished or at risk of malnutrition, and post hip fracture surgery, received HC-HP-HMB-ONS for 12 weeks. Various scales and questionnaires assessed outcomes. RESULTS: During the 12 weeks of follow-up, 82.8% consumed ≥75% of HC-HP-HMB-ONS. By week 12, 62.4% gained or maintained weight (+0.3 kg), 29.2% achieved normal nutritional status (mean MNA score +2.8), and 46.8% improved nutritional status. Biochemical parameters improved significantly. Subjects reported good tolerability (mean score 8.5/10), with 87.1% of healthcare providers concurring. CONCLUSIONS: The administration of HC-HP-HMB-ONS markedly enhanced nutritional status and biochemical parameters in older hip-fracture patients, with high compliance and tolerability. Both patients and healthcare professionals expressed satisfaction with HC-HP-HMB-ONS.

Pharmacist's role in the management of drug-drug interactions caused by nirmatrelvir/ritonavir in COVID-19 oncohematology patients.

OBJECTIVE: New drugs developed for SARS-CoV-2 infection, such as nirmatrelvir/ritonavir (NMV/r), represent a potential for oncohematology patients, but also pose a challenge in managing the potential clinically relevant drug-drug interactions (pDDIs) that may arise. The aim of this study is to assess the frequency, severity, and pharmacist detection of pDDIs. METHODS: This prospective, observational, study spanned 8 months, involving 42 oncohematology patients prescribed NMV/r in a tertiary-level hospital. A Board Certified oncology pharmacist assessed pDDIs using three databases and made recommendations to prescribing physicians. Linear and logistic regression analyses were employed to explore the relationship between prescribed drugs and pDDIs. RESULTS: Clinically relevant pDDIs were detected in 76.2% of patients, with 18.1% of all medications involved in drug-drug interactions (DDIs). The most common drugs implicated were atorvastatin and imatinib. Micromedex® identified 63.3% of interactions as major severity, while Lexicomp® and University of Liverpool classifications were less restrictive. Pharmacists prevented most DDIs from reaching patients through different interventions, including treatment monitoring (44.2%), discontinuation (36.5%), and dose reduction (17.3%). CONCLUSION: This study highlights the high prevalence of clinically significant pDDIs in oncohematology patients receiving NMV/r for COVID-19. Pharmacists, as integral members of the healthcare team, played a crucial role in detecting, categorizing, and mitigating these interactions. The results underscore the need for comprehensive studies to evaluate the impact of pharmacist-led interventions in optimizing drug therapy and enhancing patient safety in this vulnerable population.

Is the Combination of Robot-Assisted Therapy and Transcranial Direct Current Stimulation Useful for Upper Limb Motor Recovery? A Systematic Review with Meta-Analysis.

Stroke is the third leading cause of disability in the world, and effective rehabilitation is needed to improve lost functionality post-stroke. In this regard, robot-assisted therapy (RAT) and transcranial direct current stimulation (tDCS) are promising rehabilitative approaches that have been shown to be effective in motor recovery. In the past decade, they have been combined to study whether their combination produces adjuvant and greater effects on stroke recovery. The aim of this study was to estimate the effectiveness of the combined use of RATs and tDCS in the motor recovery of the upper extremities after stroke. After reviewing 227 studies, we included nine randomised clinical trials (RCTs) in this study. We analysed the methodological quality of all nine RCTs in the meta-analysis. The analysed outcomes were deficit severity, hand dexterity, spasticity, and activity. The addition of tDCS to RAT produced a negligible additional benefit on the effects of upper limb function (SMD -0.09, 95% CI -0.31 to 0.12), hand dexterity (SMD 0.12, 95% CI -0.22 to 0.46), spasticity (SMD 0.04, 95% CI -0.24 to 0.32), and activity (SMD 0.66, 95% CI -1.82 to 3.14). There is no evidence of an additional effect when adding tDCS to RAT for upper limb recovery after stroke. Combining tDCS with RAT does not improve upper limb motor function, spasticity, and/or hand dexterity. Future research should focus on the use of RAT protocols in which the patient is given an active role, focusing on the intensity and dosage, and determining how certain variables influence the success of RAT.

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.

Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.

Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release.

Cannabidiol (CBD) has become a highly attractive entity in therapeutics. However, its low aqueous solubility, instability and handling problems limit the development of effective CBD formulations. Subcutaneously administered CBD-loaded polycaprolactone microparticles (MP) represent an interesting strategy to overcome these challenges. This work focuses on evaluating the pharmacokinetics of CBD formulated in polymer microparticles for subcutaneous administration and characterising its release. The mean release time (MRLT) parameter is used to compare the release of CBD from two microparticle formulations in vitro and in a mouse model. After the administration of CBD in solution, a bicompartmental distribution is observed due to the extensive diffusion to the brain, being the brain/blood AUC ratio 1.29. The blood and brain mean residence time (MRT) are 0.507 ± 0.04 and 0.257 ± 0.0004 days, respectively. MP prepared with two drug/polymer ratios (15/150-MP and 30/150-MP) are designed, showing similar in vitro dissolution profiles (similarity factor (f2) is 63.21), without statistically significant differences between MRLTin vitro values (4.68 ± 0.63 and 4.32 ± 0.05 days). However, considerable differences in blood and brain profiles between both formulations are detected. The blood and brain MRT values of 15/150-MP are 6.44 ± 0.3 days and 6.15 ± 0.25 days, respectively, whereas significantly lower values 3.91 ± 0.29 days and 2.24 ± 0.64 days are obtained with 30/150-MP. The extended release of CBD during 10 days after a single subcutaneous administration is achieved.

Real-world data of atezolizumab in patients with previously treated locally advanced or metastatic urothelial bladder cancer.

BACKGROUND: Clinical trials of atezolizumab for locally advanced or metastatic urothelial bladder cancer (mUBC) report controversial efficacy data. Furthermore, real-world evidence about this use is limited. AIM: We aimed to evaluate the effectiveness of atezolizumab in a real-world population with mUBC, to explore effectiveness with regard to selected poor prognostic criteria such as performance status by Eastern Oncology Cooperative Group (ECOG), hemoglobin levels and liver metastases, and to determine the safety profile of atezolizumab. METHOD: Multicenter, retrospective real-world study including previously treated mUBC patients who received atezolizumab. The primary endpoint was overall survival (OS). Additionally, progression-free survival (PFS), best response reached and safety data were analyzed. A descriptive analysis was performed, while OS and PFS were estimated by Kaplan-Meier method. RESULTS: A total of 185 patients (84.9% men, median age 69 years) were included. Median PFS was 4.8 months [95% confidence interval (CI) 3.6-6.0], and median OS was 20.0 months (95% CI 11.8-28.5), with an objective response rate of 28.1%. OS was higher for patients with ECOG 0-1 versus 2-3 [24.5 months (95% CI 14.5-34.6) vs. 5.2 (95% CI 4.4-6.0), p = 0.004]; and for patients without liver metastases [25.4 months (95% CI 16.2-34.6) vs. 6.4 months (95% CI 4.0-8.1), p = 0.006]. Regarding hemoglobin levels, no survival differences were detected. Adverse events were registered in 55.1% of patients. CONCLUSION: In a real-world population with previously treated mUBC, atezolizumab seems to provide clinically relevant benefit, which is even higher for patients with ECOG 0-1 and without liver metastases, with an acceptable safety profile.

Evaluation of DiaSorin Liaison® calprotectin fecal assay adapted for pleural effusion.

Objectives: Calprotectin (CP) is a calcium and zinc binding protein that is widely measured on faecal samples but its determination in other biological fluids might be of interest. The aim of this work was to validate the measurement of CP in pleural fluid by chemiluminescence. Methods: LIAISON®XL, a fully automated chemiluminescence analyzer, was used for CP quantification on pleural fluid. A validation protocol was designed using both quality control materials provided by the manufacturer and pools of pleural fluid samples. Stability, imprecision, bias, linearity, detection capability and carry over effect were evaluated. Results: CP was stable on pleural fluid at least one week, under refrigerated conditions, and four weeks at -80 °C. The observed intra- and inter-day imprecision was between 2.2 and 6.49 %, with a negative bias under 5.51 %. The linearity of the method was verified up to 2,000 ng/mL. The LoQ for the assay was 48.52 ng/mL. A statistically significant carry-over effect was observed after measuring CP concentrations above the upper limit of linearity, but given the observed magnitude, a clinically relevant impact should not be expected. Conclusions: DiaSorin Liaison® calprotectin assay allows reliable measurement of CP in pleural fluid.

Liver Transplant With Double Portal Anastomose: A Case Report.

BACKGROUND: Reno-portal reconstruction is a surgical alternative to achieve enough portal flow in liver transplant when there is a complete portal thrombosis, provided there are collaterals or portosystemic shunt, with or without spleno-renal shunt. METHODS: We present the case of a 58-year-old man with enolic cirrhosis and a history of gastrointestinal hemorrhage due to esophageal varices and portal thrombosis. The clinical case was discussed in the Transplant Committee, and the patient was included in the surgical waiting list with a Model for End-Stage Liver Disease score of 17 and Child-Pugh score of A6. The preoperative computer tomography scan showed significant collateral circulation with esophageal varices, varices dependent on the inferior mesenteric vein (IMV) and hypoplasic portal vein. During the operation, a large shunt from the IMV to the iliac territory and type II portal thrombosis were observed, which was managed with eversion thrombectomy. A temporary portocaval shunt was performed, showing minimal flow in the portal vein, which did not improve after ligation of the systemic shunt. It was decided to perform a reno-portal anastomosis, after which the portal flow measurement was 600 cc per minute; because of this, it was decided to supplement portal flow with an end-to-side portoportal anastomosis, obtaining a flow of 1300 cc per minute with low resistance (R0.5). RESULTS: The postoperative period was favorable, with good evolution of liver analytical parameters, with permeability of the porto-portal venous anastomoses, reno-portal, arterial, and suprahepatic anastomoses in the imaging tests. CONCLUSION: If the portal flow is insufficient with a hypoplasic portal vein, a double anastomosis, portoportal, and reno-portal would be a technical resource.

Ganancia de peso y modificación de la composición corporal después de un trasplante renal / Weight gain and changes in body composition after a kidney transplant

Introducción: Esta constatado un aumento de peso postrasplante renal, entre otros factores, por una reducción de la actividad física en los primeros meses, aumento del apetito y toma de inmunosupresores y corticoides. Objetivo: Conocer la ganancia de peso postrasplante. Determinar relación entre ganancia de peso y comorbilidades. Evaluar la modificación de la composición corporal. Material y Método: Estudio prospectivo, septiembre 2020-abril 2023. Se realizaron mediciones de peso a los 0, 3, 6, 12 meses. Resultados: Se analizaron 92 pacientes, 68,5% varones, edad 58±18,5 años. Peso pretrasplante 72,5 (±5,8), a los 12 meses: 75,10 (±15,7) kg. Se encontraron diferencias entre primero y trasplantes previos (p=0,020). En el análisis de las varianzas de medidas repetidas de peso (p=0,022), las diferencias se mostraron entre el mes 0 y el tercero, el mes 0 y el año y, entre el tercer mes y el año.En la masa muscular (p<0,001), se vieron al comparar el mes 0 con 3º, con 6º y con 12 meses. La masa grasa al comparar 3er mes con 12 meses y la grasa visceral (p=0,032), al comparar 3er mes con 6º y con 12 meses. Conclusión: Tras el trasplante renal se produce un aumento de peso, especialmente a partir del 6º mes, situándose en un 5% al año. La masa muscular aumenta en mayor medida que la masa grasa. Las personas trasplantadas de donante vivo, trasplante previos, con hipertensión y/o enfermedad cardiovascular tienen mayor ganancia de peso. (AU)

Introduction: Weight gain after kidney transplant has been documented, among other factors, due to reduced physical activity in the early months, increased appetite, and the use of immunosuppressants and corticosteroids. Objetives: To understand post-transplant weight gain. Indeed, to determine the relationship between weight gain and comorbidities, as well as, to evaluate changes in body composition. Material and Method: Prospective study, September 2020 to April 2023. Weight measurements were taken at 0, 3, 6, and 12 months. Results: Ninety-two patients were analyzed, 68.5% male, with an average age of 58±18.5 years. Pre-transplant weight was 72.5 (±5.8) kg, and at 12 months, it was 75.10 (±15.7) kg. Differences were found between first-time and repeat transplants (p=0.020). In the analysis of repeated measures of weight (p=0.022), differences were observed between month 0 and the third month, month 0 and one year, and between the third month and one year.In muscle mass (p<0.001), differences were seen when comparing month 0 with the third, sixth, and twelfth months. Fat mass differed when comparing the third month with the twelfth month, and visceral fat (p=0.032) differed when comparing the third month with the sixth and twelfth months. Conclusion: After a kidney transplant, weight gain occurs, especially after the sixth month, reaching 5% per year. Muscle mass increases more than fat mass. People who received kidneys from living donors, those with previous transplants, and those with hypertension and/or cardiovascular disease experience greater weight gain. (AU)

Can specific virtual reality combined with conventional rehabilitation improve poststroke hand motor function? A randomized clinical trial.

TRIAL OBJECTIVE: To verify whether conventional rehabilitation combined with specific virtual reality is more effective than conventional therapy alone in restoring hand motor function and muscle tone after stroke. TRIAL DESIGN: This prospective single-blind randomized controlled trial compared conventional rehabilitation based on physiotherapy and occupational therapy (control group) with the combination of conventional rehabilitation and specific virtual reality technology (experimental group). Participants were allocated to these groups in a ratio of 1:1. The conventional rehabilitation therapists were blinded to the study, but neither the participants nor the therapist who applied the virtual reality-based therapy could be blinded to the intervention. PARTICIPANTS: Forty-six patients (43 of whom completed the intervention period and follow-up evaluation) were recruited from the Neurology and Rehabilitation units of the Hospital General Universitario of Talavera de la Reina, Spain. INTERVENTION: Each participant completed 15 treatment sessions lasting 150 min/session; the sessions took place five consecutive days/week over the course of three weeks. The experimental group received conventional upper-limb strength and motor training (100 min/session) combined with specific virtual reality technology devices (50 min/session); the control group received only conventional training (150 min/session). RESULTS: As measured by the Ashworth Scale, a decrease in wrist muscle tone was observed in both groups (control and experimental), with a notably larger decrease in the experimental group (baseline mean/postintervention mean: 1.22/0.39; difference between baseline and follow-up: 0.78; 95% confidence interval: 0.38-1.18; effect size = 0.206). Fugl-Meyer Assessment scores were observed to increase in both groups, with a notably larger increase in the experimental group (total motor function: effect size = 0.300; mean: - 35.5; 95% confidence interval: - 38.9 to - 32.0; wrist: effect size = 0.290; mean: - 5.6; 95% confidence interval: - 6.4 to - 4.8; hand: effect size = 0.299; mean: - -8.9; 95% confidence interval: - 10.1 to - 7.6). On the Action Research Arm Test, the experimental group quadrupled its score after the combined intervention (effect size = 0.321; mean: - 32.8; 95% confidence interval: - 40.1 to - 25.5). CONCLUSION: The outcomes of the study suggest that conventional rehabilitation combined with a specific virtual reality technology system can be more effective than conventional programs alone in improving hand motor function and voluntary movement and in normalizing muscle tone in subacute stroke patients. With combined treatment, hand and wrist functionality and motion increase; resistance to movement (spasticity) decreases and remains at a reduced level. TRIALS REGISTRY: International Clinical Trials Registry Platform: ISRCTN27760662 (15/06/2020; retrospectively registered).

Seasonal influence on sleep apnoea recorded daily by pacemakers.

PURPOSE: Obstructive sleep apnoea (OSA) and cardiac conduction disorders are pathologies with a rising prevalence due to increased life expectancy. Upper airway patency is affected by environmental factors that may be associated with seasonal periods. The ability to record the degree of nocturnal apnoea on a daily basis may provide a more accurate picture of seasonal variability. METHODS: This study used an observational, cross-sectional design recruiting consecutive patients with Sorin/Livanova/Microport® pacemakers. The study assessed the seasonal influence on the daily degree of nocturnal apnoea over a minimum period of 180 days. The respiratory events were recorded using a pacemaker-integrated detection algorithm based on transthoracic impedance variation. A generalised linear repeated measure mixed model was used to study the seasonal effect. RESULTS: A sample of 101 subjects with a mean of 227 valid nights was compiled. Summer was associated with higher RDI (respiratory disturbance index) values and winter with lower values. The mean daily RDI ratio in summer was 1.099 times higher than in winter. CONCLUSIONS: Slight seasonal influences on the degree of nocturnal apnoea were detected through the daily observation of an unselected sample of pacemaker wearers. The degree of apnoea is higher in warmer months and lower in colder months.

Situación y actividad de las unidades de geriatría de enlace con residencias de mayores en la Comunidad de Madrid / Situation and activity of the liaison geriatrics units with nursing homes in the Community of Madrid

Introducción: En junio de 2020, tras la primera ola de la pandemia de COVID-19, se crearon unidades de geriatría de enlace hospitalaria y unidades de atención a residencia de atención primaria en la Comunidad de Madrid, para mejorar la atención sanitaria a los residentes de forma coordinada. Objetivo: Analizar la situación y la actividad realizada por las unidades de geriatría de enlace hospitalaria. Material y métodos: Estudio transversal realizado mediante una encuesta electrónica que se envió a los geriatras de enlace en marzo de 2022, incluyendo los siguientes apartados: recursos disponibles, áreas de atención sanitaria, motivos de consulta, intervenciones asistenciales, actividad investigadora y/o docente, perfiles de residentes atendidos y coordinación con otros profesionales hospitalarios en dicho momento. Se realizó un análisis descriptivo de los datos. Resultados: Respondieron 100% de las unidades de geriatría de enlace existentes, describiendo importantes diferencias en cuanto a los recursos humanos, el horario de atención y el volumen de pacientes atendidos. Respecto a la actividad asistencial de estas unidades, destacaron la consulta telemática, la valoración presencial durante la hospitalización y en el servicio de urgencias. Los principales motivos de valoración fueron la toma de decisiones, patología aguda y síndromes geriátricos y, entre las intervenciones, la gestión de fármacos de uso hospitalario y de material ortoprotésico. (AU)

Introduction: In June 2020, after the first wave of the COVID-19 pandemic, Hospital-Based Liaison Geriatrics units and Primary Care nursing care units were created in the Community of Madrid to improve health care for residents in a coordinated manner. Objective: To analyze the situation and the activity of the Hospital-Based Liaison Geriatrics units. Material and methods: A cross-sectional study was conducted using an electronic survey prepared and sent to the liaison geriatricians in March 2022, including the following sections: available resources, areas of health care, reasons for consultation, care interventions, research and teaching activity, profiles of residents attended and coordination with other health professionals at that time. A descriptive analysis of the data was performed. Results: 100% of the existing Liaison Geriatrics units responded, describing essential differences in human resources, hours of care and volume of patients attended. Regarding the care activity of these units, they highlighted the telematic consultation, and the face-to-face assessment during hospitalization and in the emergency department. The main reasons for assessment were decision-making, acute pathology and geriatric syndromes; and the in-hospital drug management or orthoprosthetic aids among the interventions. (AU)

[Situation and activity of the liaison geriatrics units with nursing homes in the Community of Madrid]. / Situación y actividad de las unidades de geriatría de enlace con residencias de mayores en la Comunidad de Madrid.

INTRODUCTION: In June 2020, after the first wave of the COVID-19 pandemic, Hospital-Based Liaison Geriatrics units and Primary Care nursing care units were created in the Community of Madrid to improve health care for residents in a coordinated manner. OBJECTIVE: To analyze the situation and the activity of the Hospital-Based Liaison Geriatrics units. MATERIAL AND METHODS: A cross-sectional study was conducted using an electronic survey prepared and sent to the liaison geriatricians in March 2022, including the following sections: available resources, areas of health care, reasons for consultation, care interventions, research and teaching activity, profiles of residents attended and coordination with other health professionals at that time. A descriptive analysis of the data was performed. RESULTS: 100% of the existing Liaison Geriatrics units responded, describing essential differences in human resources, hours of care and volume of patients attended. Regarding the care activity of these units, they highlighted the telematic consultation, and the face-to-face assessment during hospitalization and in the emergency department. The main reasons for assessment were decision-making, acute pathology and geriatric syndromes; and the in-hospital drug management or orthoprosthetic aids among the interventions. CONCLUSIONS: Despite the heterogeneity in the resources of the different Liaison Geriatric units, there is a similarity in their care activity and the use of telemedicine. It is common to request an assessment for decision-making, acute pathology or geriatric syndromes and interventions for managing in-hospital drugs and tests, orthoprosthetic aids and coordination with other specialists. Liaison Geriatrics units must continue leading quality health care coordinated with nursing homes, as well as continuity of care for residents.

Biological evaluation of integrin α3ß1-targeted 68Ga-labeled HEVNPs in HCT 116 colorectal tumor-bearing mice.

Integrins are cell surface receptors involved in multiple functions vital for cellular proliferation. Various tumor cells overexpress αß-integrins, making them ideal biomarkers for diagnostic imaging and tumor-targeted drug delivery. LXY30 is a peptide that can specifically recognize and interact with the integrin α3ß1, a molecule overexpressed in breast, ovarian and colorectal cancer. Hepatitis E virus nanoparticles (HEVNPs) are virus-like particles that have been investigated as drug delivery agents for the targeted delivery of nucleic acids and small proteins. HEVNPs can be a theranostic platform for monitoring and evaluating tumor-targeted therapies if tagged with a suitable diagnostic marker. Herein, we describe the radiolabeling and biological evaluation of integrin α3ß1-targeted HEVNPs. HEVNPs were conjugated with DOTA and radiolabeled with gallium-68 (t1/2 = 67.7 min), a short-lived positron emitter used in positron emission tomography (PET). The synthesized [68Ga]Ga-DOTA-HEVNPs were used to evaluate the efficacy of conjugated LXY30 peptide to improve HEVNPs binding and internalization to integrin α3ß1 expressing human colorectal HCT 116 cells. In vivo tumor accumulation of [68Ga]Ga-DOTA-HEVNP-LXY30 was evaluated in HCT 116 colorectal tumor-bearing mice. [68Ga]Ga-DOTA-HEVNP-LXY30 and non-targeted [68Ga]Ga-DOTA-HEVNP were radiolabeled with radiochemical yields (RCY) of 67.9 ± 3.3% and 73.7 ± 9.8%, respectively. [68Ga]Ga-DOTA-HEVNP-LXY30 exhibited significantly higher internalization in HCT 116 cells than the non-targeted [68Ga]Ga-DOTA-HEVNPs (21.0 ± 0.7% vs. 10.5 ± 0.3% at 3 h, ****P<0.0001). After intravenous administration to mice, accumulation of [68Ga]Ga-DOTA-HEVNP-LXY30 to HCT 116 xenograft tumors was at its highest rate of 0.8 ± 0.4%ID/g at 60 min. [68Ga]Ga-DOTA-HEVNP-LXY30 accumulated mainly in the liver and spleen (39.8 ± 13.0%%ID/g and 24.6 ± 24.1%ID/g, respectively). Despite the low targeting efficiency in vivo, we demonstrated that [68Ga]Ga-DOTA-HEVNP is a promising diagnostic platform for quantitative analysis of HEVNP distribution in vivo. This nanosystem can be utilized in future studies assessing the success of further engineered HEVNP structures with optimized targeting efficiency in vivo.

Quimioterapia nanométrica a base de cannabinoides para el tratamiento de tumores ginecológicos / Cannabinoid based chemo-nanotherapy for the treatment of gynecological malignancies

El cannabidiol está despertando un creciente interés como agente antitumoral. Sin embargo, no se ha estudiado su efecto en cáncer de ovario, uno de los tumores más agresivos en mujeres. En el presente trabajo se ha evaluado, por primera vez, el potencial uso del cannabidiol en solución y encapsulado en nanopartículas funcionalizadas con ácido fólico en cáncer de ovario, ya que estos tumores sobreexpresan los receptores de ácido fólico, permitiendo una acumulación selectiva de estas nanoformulaciones en las células tumorales. El cannabidiol en solución inhibe la proliferación y migración de las células SKOV-3. En terapia de combinación, aumenta significativamente la eficacia antitumoral del paclitaxel, presentando un efecto sensibilizador y sinérgico. En los modelos in ovo, la administración previa de cannabidiol en solución seguido de su coadministración con paclitaxel muestra un efecto inhibitorio sobre el crecimiento tumoral significativamente superior al paclitaxel en monoterapia. Las nanopartículas desarrolladas son eficazmente internalizadas por las células SKOV-3, presentando las nanopartículas con ácido fólico una captación más rápida. Aunque en los estudios de eficacia antitumoral in vitro las nanopartículas funcionalizadas no presentan una actividad antiproliferativa superior al cannabidiol en solución o a las nanopartículas no funcionalizadas, en los modelos in ovo su eficacia antitumoral es significativamente superior, indicando que el desarrollo de nanopartículas funcionalizadas con ácido fólico es una buena estrategia para vectorizar el cannabidiol a tumores de ovario. Por último, las nanopartículas de cannabidiol potencian el efecto antitumoral del paclitaxel, presentando las formulaciones funcionalizadas con ácido fólico una mayor eficacia que el cannabidiol en solución. (AU)

Cannabidiol has become in a potential anticancer agent. Nevertheless, it has not been evaluated in ovarian cancer, one of the most aggressive tumors in women. In this work, the potential use of cannabidiol in solution and encapsulated into polymeric nanoparticles coated with folic acid was evaluated for the first time for the treatment of ovarian cancer. Ovarian tumors over-express folic acid receptors and folic-acid-coated nanoformulations trend to be selectively accumulated at tumor site. Cannabidiol in solution administered as monotherapy inhibits the proliferation and migration of SKOV-3 cells. In combination therapy, it significantly increases the antitumor efficacy of paclitaxel, showing a sensitizer and synergistic effect. In ovo, the previous administration of cannabidiol in solution followed by its co-administration with paclitaxel, shows a significantly higher inhibitory effect on ovarian tumor growth than single paclitaxel. The developed nanoparticles are efficiently uptaken by SKOV-3 cells, showing folic acid coated formulations a faster internalization. Although coated formulations do not exhibit a higher in vitro antiproliferative effect compared to cannabidiol in solution or non-coated formulations, in ovo its antitumoral efficacy is significantly higher. This indicates thatfolic acid-coated nanoparticles represent a good strategy to target cannabidiol to ovarian tumors. Finally, cannabidiol-loaded nanoparticles improve the in vitro antiproliferative effect of paclitaxel, showing folic acid-coated-formulations a better efficacy than cannabidiol in solution. (AU)

Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood-brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration.