Engineering Approaches for Exosome Cargo Loading and Targeted Delivery: Biological versus Chemical Perspectives.

Exosomes are nanoscale membrane bound vesicles secreted by almost all types of cells. Their unique attributes, such as minimal immunogenicity and compatibility with biological systems, make them novel carriers for drug delivery. These native exosomes harbor proteins, nucleic acids, small molecule compounds, and fluorogenic agents. Moreover, through a combination of chemical and bioengineering methodologies, exosomes are tailored to transport precise therapeutic payloads to designated cells or tissues. In this review, we summarize the strategies for exosome modification and drug loading modalities in engineered exosomes. In addition, we provide an overview of the advances in the use of engineered exosomes for targeted drug delivery. Lastly, we discuss the merits and limitations of chemically engineered versus bioengineered exosome-mediated target therapies. These insights offer additional options for refining engineered exosomes in pharmaceutical development and hold promise for expediting the successful translation of engineered exosomes from the bench to the bedside.

Targeted Nanoparticles Based on Alendronate Polyethylene Glycol Conjugated Chitosan for the Delivery of siRNA and Curcumin for Bone Metastasized Breast Cancer Applications.

Bone metastasized breast cancer reduces the quality of life and median survival. Targeted delivery of small interfering RNA (siRNA) and chemotherapeutic drugs using nanoparticles (NPs) is a promising strategy to overcome current limitations in treating these metastatic breast cancers. This research develops alendronate conjugated polyethylene glycol functionalized chitosan (ALD-PEG-CHI) NP for the delivery of cell death siRNA (CD-siRNA) and curcumin (CUR) and explores its targeting ability and in vitro cell cytotoxicity. Polyethylene glycol functionalized CHI (mPEG-CHI) NPs serve as control. The size of CD-siRNA loaded NPs is below 100 nm while CUR loaded NPs is below 200 nm, with near neutral zeta potential for all NPs. The CUR encapsulation efficiency (EE) is 70% and 88% for targeted and control NPs, respectively, while complete encapsulation of CD-siRNA is achieved in both NP systems. The bone targeting ability of CY5-dsDNA loaded ALD-PEG-CHI NPs using hydroxyapatite discs is fivefold compared to control indicating ALD presentation at the targeting NP surface. Delivery of CD-siRNA loaded NPs and CUR loaded NPs show synergistic and additive growth inhibition effects against MCF-7 cells by mPEG-CHI and ALD-PEG-CHI NPs, respectively. Overall, these in vitro results illustrate the potential of the targeted NPs as an effective therapeutic system toward bone metastasized breast cancer.

Early palliative care referral may improve end-of-life care in end-stage liver disease patients: A retrospective analysis from a non-transplant center.

BACKGROUND: Patients with end-stage liver disease (ESLD) who are not transplant candidates often have a trajectory of rapid decline and death similar to patients with stage IV cancer. Palliative care (PC) services have been shown to be underutilized for such patients. Most studies examining the role of PC in ESLD have been done at transplant centers. Thus, determining the utilization and benefit of PC at a non-transplant tertiary center may help establish a standard of care in the management of patients with ESLD not eligible for transplant. METHODS: We conducted a retrospective analysis of adult (>18 years) patients with ESLD admitted to Rochester Regional Health (RRH) system hospitals from 2012 to 2021. Patients were divided into groups based on the presence or absence of PC involvement. Baseline characteristics were recorded. The impact of PC was assessed by comparing the number of hospitalizations before and after the involvement of PC, comparing code status changes, health care proxy (HCP) assignments, Aspira catheter placements, and frequency of repeated paracentesis. RESULTS: In our analysis of 576 patients, 41.1% (237 patients) received a PC consult (PC group), while 58.9% (339 patients) did not (no-PC group). Baseline characteristics were comparable. However, their mean number of admissions significantly decreased (15.66 vs. 3.49, p < 0.001) after PC involvement. Full code status was more prevalent in the no-PC group (67.8% vs. 18.6%, p < 0.001), while comfort care code status was more common in the PC group (59.9% vs. 20.6%, p < 0.001). Changes in code status were significantly higher in the PC group (77.6% vs. 29.2%, p < 0.001). The PC group had a significantly higher mortality rate (83.1% vs. 46.4%, p < 0.01). Patients in the PC group had a higher likelihood of having an assigned HCP (63.7% vs. 37.5%, p < 0.001). PC referral was associated with more frequent use of an Aspira catheter (5.9% vs. 0.9%, p < 0.001) and more frequent paracentesis (30.8% vs. 16.8%, p < 0.001). CONCLUSIONS: In conclusion, our study provides compelling evidence of the diverse advantages of palliative care for patients with end-stage liver disease, including reduced admissions, improved goals of care, code status modifications, enhanced healthcare proxy assignments, and targeted interventions. These findings highlight the potential significance of early integration of palliative care in the disease trajectory to provide comprehensive, patient-centered care that addresses the unique needs and preferences of individuals with advanced liver disease.

Characterisation of products from EDC-mediated PEG substitution of chitosan allows optimisation of reaction conditions.

PEGylation is a common method use to modify the physiochemical properties and increase the solubility of chitosan (CHI). Knowledge of optimal reaction conditions for PEGylation of CHI underpins its ongoing use in nanomedicine. This study synthesised methoxy polyethyleneglycol grafted CHI (mPEG-CHI) using carbodiimide-mediated coupling. The effect of reagent concentrations and pH on the degree of substitution (DS) and the PEGylation yield (conversion of free PEG to conjugated PEG) was evaluated through detailed chemical characterisation. Within the parameter space investigated, optimised reaction conditions (NH2: COOH:NHS:EDC of 3.5:1:1:10, pH = 5) resulted in a DS of 24 % and a PEGylation yield of 84 %. An EDC-derived adduct formed at pH ≥ 5.5 and at a 15-fold excess of EDC relative to COOH. The adduct was evaluated to be a guanidine derivative formed by the reaction of the amine group of CHI directly with EDC. DS ≥ 12 % imparted water solubility to CHI at physiological pH and mPEG-CHI (0.2-1.0 mg/mL) was not cytotoxic against the breast cancer cell lines MCF-7 and MDA-MB-231, indicating its suitability for medical applications.

pH-Responsive Au@Pd bimetallic core-shell nanorods for enhanced synergistic targeted photothermal-augmented nanocatalytic therapy in the second near-infrared window.

Nanotheranostic agents based on plasmonic nanostructures with their resonance wavelengths located in the second near-infrared window (NIR-II) have gained significant attention in profound tumor photothermal therapy. However, the modulation of localized surface plasmon resonance of gold nanomaterials from the first near-infrared (NIR-I) window to the NIR-II window is still challenging. The structures and compositions of the plasmonic nanomaterials have demonstrated promising characteristics in controlling the optical properties of plasmonic nanostructures. Here, gold nanorod (Au NR) coated with an ultrathin palladium (Pd) shell was developed for tumor-targeted NIR-II photothermal-augmented nanocatalytic therapy through the combination of compositional manipulation and structural evolution strategies. These Au@Pd core-shell hybrid NRs (HNRs) were functionalized with biocompatible chitosan (CS) to acquire lower toxicity and higher stability in physiological systems. Further, Au@Pd-CS HNRs were endowed with an excellent targeting ability by conjugating with folic acid (FA). The as-synthesized Au@Pd-CS-FA HNRs show efficient and complete photothermal ablation of tumor cells upon 1064 nm laser irradiation. The remarkable photothermal conversion efficiency of 69.0% was achieved, which is superior to many reported photothermal agents activated in the NIR-II region. Excitingly, Au@Pd-CS-FA HNRs have peroxidase and catalase activities, simultaneously producing ˙OH for catalytic therapy and O2 for relieving tumor hypoxia and photodynamic therapy. Additionally, in vivo tumor photothermal therapy was carried out, where the biocompatible Au@Pd-CS-FA HNRs penetrate intensely into the tumor cells and consequently show remarkable therapeutic effects. The idea about plasmonic modulation behind the bimetallic core-shell nanostructure in this report can be extended to construct new classes of metal-based nanotheranostic agents with dual-modal combined therapy as an alternative to traditional chemotherapy.

Antiviral effects of coinage metal-based nanomaterials to combat COVID-19 and its variants.

The world has been suffering from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, and millions of people have been infected through human-to-human transmission and lost their lives within months. Although multidisciplinary scientific approaches have been employed to fight against this deadly pandemic, various mutations and diverse environments keep producing constraints in treating SARS-CoV-2. Indeed, the efficacy of the developed vaccines has been limited, and inoculation with the vaccines does not guarantee complete protection even though multiple doses are required, which is a frustrating process. Historically, coinage metals (Cu, Ag, and Au) have been well-known for their effectiveness in antiviral action as well as good biocompatibility, binding receptor inhibition, reactive oxygen species, and phototherapy properties. Thus, this review highlights the diagnostic and therapeutic mechanisms of SARS-CoV-2 using the antivirus ability and mode of action of coinage metals such as viral entry mechanisms into host cells and the NP-inhibition process, which are explained in detail. This article also draws attention to coinage metal nanomaterial-based approaches to treat other contagious viruses. In addition, coinage metal-based biosensors and an overview of some other biocompatible metal-based nanomaterials to fight against SARS-CoV-2 variants are discussed. Finally, the advantages, perspectives and challenges of coinage metal nanoparticles are given to fight against viral infections in the future.

Facile Synthesis of Multifunctional Magnetoplasmonic Au-MnO Hybrid Nanocomposites for Cancer Theranostics.

Significant attention is paid to the design of magnetoplasmonic nanohybrids, which exploit synergistic properties for biomedical applications. Here, a facile method was employed to prepare plasmonic magnetic Au-MnO heterostructured hybrid nanoparticles for imaging-guided photothermal therapy of cancers in vitro, with the view to reducing the serious drawbacks of chemotherapy and gadolinium-based contrast agents. The biocompatibility of the prepared Au-MnO nanocomposites was further enhanced by Food and Drug Administration (FDA)-approved triblock copolymers Pluronic® F-127 and chitosan oligosaccharide (COS), with complementary support to enhance the absorption in the near-infrared (NIR) region. In addition, synthesized COS-PF127@Au-MnO nanocomposites exhibited promising contrast enhancement in T1 MR imaging with a good r1 relaxivity value (1.2 mM-1 s-1), demonstrating a capable substitute to Gd-based toxic contrast agents. In addition, prepared COS-PF127@Au-MnO hybrid nanoparticles (HNPs) produced sufficient heat (62 °C at 200 µg/mL) to ablate cancerous cells upon 808 nm laser irradiation, inducing cell toxicity, and apoptosis. The promising diagnostic and photothermal therapeutic performance demonstrated the appropriateness of the COS-PF127@Au-MnO HNPs as a potential theranostic agent.

Silk Fibroin/Collagen Blended Membrane Fabricated via a Green Papermaking Method for Potential Guided Bone Regeneration Application: In Vitro and In Vivo Evaluation.

Guided bone regeneration (GBR) technology is a commonly used surgical procedure for the repair of damaged periodontal tissues. Poor mechanical property and rapid degradation rate are the major reasons for GBR membrane failure in clinical applications. Herein, we applied a green papermaking method to fabricate silk fibroin (SF) membranes blended with collagen and tested their performance. The results showed that the blended SF75 (SF and collagen in a weight ratio of 75:25) membranes are biocompatible with good mechanical properties in the wet condition and appropriate biodegradation rate. MC3T3-E1 osteoblast cell adhesion and proliferation on the membranes were improved by the hybrid biological functions of SF and collagen. Subcutaneous implantation in rats for 9 weeks demonstrated that the membranes induced a less severe inflammatory response. The biodegradation time of the SF75 membranes was appropriate for tissue regeneration. This research, for the first time, reports a blended membrane prepared from silk fibroin and collagen with an ecofriendly method, which shows promise for application in guided bone regeneration.

Facile synthesis of biocompatible magnetic titania nanorods for T1-magnetic resonance imaging and enhanced phototherapy of cancers.

Cancer treatment has been recently energized by nanomaterials that simultaneously offer diagnostic and therapeutic effects. Among the imaging and treatment modalities in frontline research today, magnetic resonance imaging (MRI) and phototherapy have gained significant interest due to their noninvasiveness among other intriguing benefits. Herein, Fe(iii) was adsorbed on titanium dioxide to develop magnetic Fe-TiO2 nanocomposites (NCs) which leverage the Fe moiety in a double-edge-sword approach to: (i) achieve T1-weighted MRI contrast enhancement, and (ii) improve the well-established photodynamic therapeutic efficacy of TiO2 nanoparticles. Interestingly, the proposed NCs exhibit classic T1 MRI contrast agent properties (r1 = 1.16 mM-1 s-1) that are comparable to those of clinically available contrast agents. Moreover, the NCs induce negligible cytotoxicity in traditional methods and show remarkable support to the proliferation of intestine organoids, an advanced toxicity evaluation system based on three-dimensional organoids, which could benefit their potential safe application for in vivo cancer theranostics. Aided by the Fenton reaction contribution of the Fe component of the Fe-TiO2 NCs, considerable photo-killing of cancer cells is achieved upon UV irradiation at very low (2.5 mW cm-2) intensity in typical cancer PDT. It is therefore expected that this study will guide the engineering of other biocompatible magnetic titania-based nanosystems with multi-faceted properties for biomedical applications.

Chitosan Nanomedicine in Cancer Therapy: Targeted Delivery and Cellular Uptake.

Nanomedicine has gained much attention for the management and treatment of cancers due to the distinctive physicochemical properties of the drug-loaded particles. Chitosan's cationic nature is attractive for the development of such particles for drug delivery, transfection, and controlled release. The particle properties can be improved by modification of the polymer or the particle themselves. The physicochemical properties of chitosan particles are analyzed in 126 recent studies, which allows to highlight their impact on passive and active targeted drug delivery, cellular uptake, and tumor growth inhibition (TGI). From 2012 to 2019, out of 40 in vivo studies, only 4 studies are found reporting a reduction in tumor size by using chitosan particles while all other studies reported tumor growth inhibition relative to controls. A total of 23 studies are analyzed for cellular uptake including 12 studies reporting cellular uptake mechanisms. Understanding and exploiting the processes involved in targeted delivery, endocytosis, and exocytosis by controlling the physicochemical properties of chitosan particles are important for the development of safe and efficient nanomedicine. It is concluded based on the recent literature available on chitosan particles that combination therapies can play a pivotal role in transformation of chitosan nanomedicine from bench to bedside.

Gram-scale synthesis of splat-shaped Ag-TiO2 nanocomposites for enhanced antimicrobial properties.

The control over contagious diseases caused by pathogenic organisms has become a serious health issue. The extensive usage of antibiotics has led to the development of multidrug-resistant bacterial strains. In this regard, metal-oxide-based antibacterial nanomaterials have received potential research interest due to the efficient prevention of microorganism growth. In this study, splat-shaped Ag-TiO2 nanocomposites (NCs) were synthesized on the gram scale and the enhanced antibacterial properties of TiO2 in the presence of silver were examined. The formation of Ag-TiO2 NCs was analyzed through various characterization techniques. The cell viability experimental results demonstrated that the Ag-TiO2 NCs have good biocompatibility. The antibacterial activity of the prepared Ag-TiO2 NCs was tested against the Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) bacterial strains. The Ag-TiO2 NCs exhibited promising and superior antibacterial properties compared to TiO2 nanospheres as confirmed by the bacterial growth and inhibition zone. The improvement in the antibacterial activity was attributed to the synergistic effect of the hybrid nature of TiO2 nanoparticles in the presence of Ag.

Polio in Pakistan: Social constraints and travel implications.

The Global Polio Eradication Initiative (GPEI) in Pakistan has faced failure despite being implemented successfully. Polio cases were successfully reduced by 99% until 2005. However, thereafter, new polio cases were registered, which continue to rise annually. This repeat polio outbreak has placed the country on watch by the World Health Organization (WHO) due to travelers, and Hajj and Umrah pilgrims. The present report reviews the published literature for determining the social constraints to the polio eradication initiative in Pakistan. Religion, politics, awareness, insecurity, inequity, governance, and social responsibility have been identified as key social factors in the failure of any vaccination campaign. Possible interventions have been proposed, which include effectively using modern mass media and educating vaccinators on the social and cultural background of the target community.

Multiple intracranial capillary hemangiomas and transient cerebrovascular insufficiency.

Hemangiomas constitute a heterogeneous group of benign vascular proliferations of skin and mucous membranes and very rarely known to develop in the brain or spinal cord. We report here a case of multiple intracranial capillary hemangiomas presenting with transient neurological deficit. The patient underwent stealth MRI brain utilizing 15 ml of Magnevist for stereotactic localization and biopsy was done to establish the diagnosis. It is pivotal to differentiate benign hemangiomas from primary cerebral vascular tumors including hemangioblastoma, hemangioendothelioma and hemangiopericytoma, as later are known for more aggressive biologic behavior.

Preoperative anxiety before elective surgery.

OBJECTIVE: To ascertain the preoperative anxiety level and different factors responsible in patients admitted for an elective surgical procedure in a tertiary care public hospital. METHODS: Anxiety levels were measured in admitted patients of the Civil Hospital, Karachi, Pakistan awaiting elective surgery from October to January 2006. In the afternoon preceding surgery, patients were asked to complete 2 visual analogue scales (VAS) regarding anxiety about the proposed surgery and anesthesia (range, 0 = `not anxious at all` to 100 = `extremely anxious`). They were then asked to select different factors responsible for their anxiety from a list. RESULTS: Mean anxiety score for surgery was 57.65+/-25.1 and for anesthesia was 38.14+/-26.05. There was a statistically significant high level of pre-operative anxiety in females as compared to males (p<0.01). The most common factors contributing to anxiety were concern about family in 173 (89.6%) patients, fear of complications in 168 (87%), results of operation in 159 (82.4%), and postoperative pain in 152 (78.8%). Fifty-six percent of patients thought that their anxiety would be lessened by a detailed explanation regarding the operation and anesthesia. CONCLUSION: Our patients experience very high levels of preoperative anxiety. This can be easily measured in the preoperative period and allows detection of patients with high anxiety, encouraging appropriate steps to ameliorate this. Establishment of preoperative counseling clinics and properly informed consent taken before surgery will help in reducing preoperative anxiety.