Successful Delivery Research Articles

ApoE—functionalization of nanoparticles for targeted brain delivery—a feasible method for polyplexes?

The blood–brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches. Graphical abstract

In Vivo mRNA CAR T Cell Engineering via Targeted Ionizable Lipid Nanoparticles with Extrahepatic Tropism.

With six therapies approved by the Food and Drug Association, chimeric antigen receptor (CAR) T cells have reshaped cancer immunotherapy. However, these therapies rely on ex vivo viral transduction to induce permanent CAR expression in T cells, which contributes to high production costs and long-term side effects. Thus, this work aims to develop an in vivo CAR T cell engineering platform to streamline production while using mRNA to induce transient, tunable CAR expression. Specifically, an ionizable lipid nanoparticle (LNP) is utilized as these platforms have demonstrated clinical success in nucleic acid delivery. Though LNPs often accumulate in the liver, the LNP platform used here achieves extrahepatic transfection with enhanced delivery to the spleen, and it is further modified via antibody conjugation (Ab-LNPs) to target pan-T cell markers. The in vivo evaluation of these Ab-LNPs confirms that targeting is necessary for potent T cell transfection. When using these Ab-LNPs for the delivery of CAR mRNA, antibody and dose-dependent CAR expression and cytokine release are observed along with B cell depletion of up to 90%. In all, this work conjugates antibodies to LNPs with extrahepatic tropism, evaluates pan-T cell markers, and develops Ab-LNPs capable of generating functional CAR T cells in vivo.

The management and clinical outcomes of pregnancies in women with urea cycle disorders: A review of the literature and results of an international survey

AbstractAn increasing number of women with urea cycle disorders (UCDs) are reaching child‐bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia—which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra‐ and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow‐up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

Multiple myeloma: a paradigm for blending community and academic care.

The care of the multiple myeloma (MM) patient is complex, with most patients requiring multiple lines of therapy over a span of many years to decades. Since the days when autologous stem cell transplantation became the standard of care for a large subset of patients, it was imperative that community practices and specialized academic centers work together to optimize the initial care of patients. Now, with the unprecedented number of treatment options and the introduction of chimeric antigen receptor T-cell therapies and bispecific T-cell engagers, that collaboration has become even more important and stretches from the upfront treatment to the relapsed and refractory disease setting. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the myeloma specialist, and the transplant or immune effector cell provider will be required to provide the optimal care longitudinally for each patient. This multidisciplinary approach to treating MM can serve as a paradigm for blending community and academic care.

Development of the cholestosome, a novel delivery system made exclusively from cholesteryl esters

AbstractA novel vesicular drug delivery system has been created using only cholesteryl esters. The uncharged nature of the esters requires a formulation process that uses energy, in the form of sonication, to facilitate the cholesteryl esters formation into vesicles. The nature of the material choices renders the vesicles resistant to pH degradation between a pH of 2 and 10. Storage condition at 4°C for 9 months shows a stability of encapsulated materials as well as vesicles. The formulation process is a modified reverse phase method in which the esters are dissolved in an organic solvent, which is then removed and the aqueous component is then added with sonication in a temperature‐controlled water bath. A wide variety of materials can be encapsulated in these vesicles, which are called cholestosomes. Delivery of the cholestosome‐encapsulated materials is a function of the ester component structure and not the encapsulated molecule. Once encapsulated, the vesicles deliver the materials into cells. The potential for oral availability was explored using chylomicrons. Successful delivery of the cholestosome encapsulated into chylomicrons has enhanced the effectiveness of delivery to cells. Analytical methods have been developed to analyze the materials chosen from the cholesteryl esters as well as the encapsulated materials.Practical Applications: The creation of the cholestosome vesicle opens up completely new areas for encapsulating and delivering materials. The cholesteryl ester structure that makes up the vesicles is impervious to pH and bile salts, making cholestosomes ideal for oral delivery of drugs, such as oral insulin. Intracellular delivery of cholestosome vesicles enables multiple applications, from killing latent infections to preventing viral replication (irrespective of the virus) and delivering nucleic acid therapeutics to cure genetic disease. These vesicles pass the blood–brain barrier and could be used for treatments of Alzheimer's and related neurodegenerative disease. Cholestosomes can also be used in cosmetic formulations as the vesicles pass the dermis. They even could be used in food applications as the materials are considered generally regarded as safe.

CdTe quantum dots as fluorescent nanotools for in vivo glioblastoma imaging

Glioblastoma (GBM) is the most aggressive and infiltrating primary tumor of the central nervous system (CNS), showing a variety of mutations and a high degree of vascularity, cell polymorphism, and nuclear atypia. GBM treatment often recurs to surgical resection, but such protocol lacks efficacy since complete tumor removal is not entirely successful due to invasive cells that cannot be detected at the moment of the surgery. Here, we describe a new in vivo targeting and imaging method for GBM detection in an orthotropic mouse model using fluorescent CdTe quantum dots (CdTe QDs) conjugated to anti-glial fibrillary acidic protein (anti-GFAP). We conjugated and optimized red-emitting CdTe QDs to anti-GFAP to label GBM (U87 cell line) in vivo. The in vivo tumor growth was visualized by the hematoxylin and eosin staining and showed the successful delivery of GBM cells into the mouse brain parenchyma. CdTe/anti-GFAP QDs were injected into the tumor region, and their uptake by tumor cells was visualized by fluorescence microscopy, showing a specific dual labeling with vimentin-immunoreactive GBM. The results reported here provide new perspectives for using CdTe QDs in GBM detection, suggesting their potential application in imaging-guided surgery and a potential fluorescent tool to be applied in the monitoring of 3D tumor glial cultures.

On Minimizing the Age of Information in NOMA-Based Vehicular Networks Using Markov Decision Process

Network sustainability relies on many important parameters where the timely dissemination of information has a prime role to improve network operations and henceforth the network sustainability. Age of Information is a critical metric in many applications of future networks including smart transportation systems as these networks require fresh updates from the various network entities for the successful delivery of their services. This paper considers smart vehicles in a vehicle-to-infrastructure network where each vehicle has a stream of data for transmission to the roadside unit (RSU). The information from vehicles is collected when they enter the communication range of an RSU and stay within the coverage area of that RSU for a particular time. During this time, the RSU attempts to receive information from each vehicle as timely as possible. This paper proposes a hybrid access mechanism consisting of both orthogonal and non-orthogonal multiple access that schedules the transmission of packets from vehicles to the RSU where each vehicle has a finite length queue. The transmission of the packets is modeled using a Markov decision process, where a specific cost function is optimized to collect maximum information from the vehicles in a minimum amount of time.

Spatial modeling and reliability analyzing of reconfigurable intelligent surfaces-assisted Fog-RAN with repulsion

Reconfigurable Intelligent Surface (RIS), fog computing, and Cell-Free (CF) network architecture are three promising technologies for application to the Ultra-Reliable Low Latency Communication (URLLC) scenario in 6G mobile communication systems. This paper considers a RIS-assisted FogRadio Access Network (Fog-RAN) architecture where a) the repulsively distributed Fog-Access Points (F-APs) communicate in a CF manner to suppress inter-cell interference, b) RISs are introduced into the CF network to avoid shadowing and enhance the system performance, and c) fog computing evolved as cloud services providers at the edge of the network and an enabler for constructing a multi-layer computing power RAN. Then, we derive and validate the integral form of the maximum F-AP offloading probability and Successful Delivery Probability (SDP) of this RIS-assisted Fog-RAN over composite Fisher-Snedecor F fading, where the spatial effects are reconsidered with the assumption that the F-APs are modelled as a Beta Ginibre Point Process (β-GPP). The numeric and simulation results indicate that for the investigated RIS-assisted Fog-RAN, the β-GPP-based deployment of F-APs can increase maximum of 8% of the SDP within the repulsion-effective range, compared with the Matern Cluster Process (MCP)-based ones. Also, deploying more RISs per F-AP offers more significant SDP improvements.

Groundwater Detection Using Resistivity at Nubutautau Village in Viti Levu in Fiji

A geophysical method, electrical resistivity tomography, was applied to identify potential groundwater-bearing zones around Nubutautau village on Viti Levu island, Fiji. Apparent resistivity data of the subsurface were collected through an electrode assembly along survey lines by injecting current into the subsurface using an ABEM Terrameter LS2. The apparent resistivity data were inverted using Res2DINVx64 software to produce the final electrical resistivity through an iterative process to compare the resistivity of layers and draw analogical hydrogeological results. Analysis revealed the presence of two potential groundwater-bearing zones as potential targets for future drilling. The two targets indicated the presence of potentially saturated vertical fractures through which infiltrating rainwater percolates through the volcanic rock towards a deeper basal aquifer. The identification of the two potential targets demonstrated great potential of this geophysical technique to effectively inform drilling operations. A scientific approach can increase the successful delivery of water security interventions in remote, drought-prone communities of the Pacific.

Unravelling the role of microneedles in drug delivery: Principle, perspectives, and practices.

In recent year, the research of transdermal drug delivery systems has got substantial attention towards the development of microneedles (MNs). This shift has occurred due to multifaceted advantages of MNs as they can be utilized to deliver the drug deeper to the skin with minimal invasion, offer successful delivery of drugs and biomolecules that are susceptible to degradation in gastrointestinal tract (GIT), act as biosensors, and help in monitoring the level of biomarkers in the body. These can be fabricated into different types based on their applications as well as material for fabrication. Some of their types include solid MNs, hollow MNs, coated MNs, hydrogel forming MNs, and dissolving MNs. These MNs deliver the therapeutics via microchannels deeper into the skin. The coated and hollow MNs have been found successful. However, they suffer from poor drug loading and blocking of pores. In contrast, dissolving MNs offer high drug loading. These MNs have also been utilized to deliver vaccines and biologicals. They have also been used in cosmetics. The current review covers the different types of MNs, materials used in their fabrication, properties of MNs, and various case studies related to their role in delivering therapeutics, monitoring level of biomarkers/hormones in body such as insulin. Various patents and clinical trials related to MNs are also covered. Covered are the major bottlenecks associated with their clinical translation and potential future perspectives.

Intrapartum transperineal ultrasound: angle of progression to evaluate and predict the mode of delivery and labor progression.

Intrapartum ultrasonography serves as a valuable tool for the objective evaluation of labor progression and effectively identifies underlying factors, such as asynclitism, in cases of abnormal labor progression. Among the various ultrasound measurement techniques, the angle of progression (AOP) demonstrates favorable reproducibility and accuracy in assessing fetal head descent. In the context of abnormal labor, interventions differ across different stages of labor, emphasizing the importance of investigating the utility of AOP according to labor stages in this review article. Pre-labor assessment of AOP can be beneficial in terms of counseling for the timing of induction of labor, while a wider AOP value during the prolonged first stage of labor has demonstrated a positive correlation with successful vaginal delivery and shorter time to delivery. In the second stage of labor, the AOP has exhibited efficacy in predicting the mode of delivery and complicated operative deliveries. Furthermore, it has assisted in predicting the duration of labor, thereby highlighting its potential as a decision-making model for labor progression. However, further research is needed to investigate aspects, such as the determination of cutoff values, of AOP, considering the multifaceted characteristics of labor progression, which are influenced by complex interactions among maternal, fetal, and other contributing factors.

Delivery of a community-based peer mentorship program for people with spinal cord injury at a rehabilitation center

IntroductionCommunity-based spinal cord injury (SCI) organizations deliver peer mentorship programs in rehabilitation settings. Little is known on how these programs are delivered through the collaboration between community-based SCI organizations and rehabilitation institutions. This study aimed to identify barriers, facilitators, and collaboration processes within a SCI peer mentorship program provided by a community-based organization at a rehabilitation center.MethodsA qualitative case study design was applied. Seven participants were recruited, including two mentees, two mentors, one program director of the community-based SCI organization, and two healthcare professionals of the rehabilitation center. Each participant completed a one-on-one interview. Data were analyzed inductively and deductively based on the Consolidated Framework for Implementation Research (CFIR).ResultsTen factors were identified to influence the delivery of the peer mentorship program, including nine CFIR constructs. Successful delivery of the program required strong, collaborative inter-professional relationships between health professionals and community organizational staff (e.g., peer mentors) as facilitators; whereas potential cost, minimal patient needs, and limited mentor resources were found to be barriers. Engaging health professionals by initiating communications, reflecting and evaluating the program collectively with health professionals were important collaboration processes for the community-based organization to maintain effective partnership with the rehabilitation center.DiscussionThe collaboration processes and strategies to addressing/leveraging the barriers and facilitators may inform evidence-based practice to establish and optimize the delivery of SCI peer mentorship programs in various rehabilitation settings.

Tenzing 7 delivery catheter with or without a leading microwire for single pass aspiration thrombectomy: A multicenter experience.

Aspiration mechanical thrombectomy traditionally includes use of an inner microcatheter and leading microwire to navigate an aspiration catheter (AC) to the site of occlusion. Early clinical experience suggests that a leading microwire is often not needed with the Tenzing 7 (T7, Route 92 Medical, San Mateo, CA), a soft tapered tip ledge-reducing delivery catheter. This multicenter experience aims to describe AC delivery success in single-pass thrombectomy using T7 with and without a leading microwire. A retrospective review was conducted of consecutive patients who underwent single-pass thrombectomy with T7 at six institutions between 2020 and 2022. We examined the percentage of successful AC delivery, puncture-to-revascularization time, and procedural complication rate. A leading microwire with T7 was used in 19/89 (21%) of patients, and it was not used with T7 in 70/89 (79%) of patients. Successful AC delivery was similar with and without microwires (97% vs. 90%, p = 0.15). Median puncture-to-revascularization times were similar (17 min microwire vs. 16 min no-microwire, p = 0.12). No complications were associated with microwire use; one (1.4%) patient had a T7-related vasospasm resolved with verapamil during thrombectomy without a leading microwire. Differences in complication rates were not statistically significant (p = 0.46). In our real-world clinical experience, leading microwire use was infrequently necessary with the T7 delivery catheter. Successful AC delivery and complication rates were similar with and without microwire use in single-pass T7 thrombectomies. Initial pass with T7 may be performed without use of leading microwire, reserving microwire use for refractory cases or known difficult-to-navigate vasculature.

Synoptic Analysis: Teachers’ Commitment in Nigeria

This study attempts to analyse the extent of teachers’ commitment among secondary schools of Zamfara State, Nigeria. The study was designed as descriptive research. Population of the study consisted of 28 Public Secondary Schools in Gusau Local Government Area of Zamfara State with a total number of 367 in-service teachers. From the population of the study, 19 Public Secondary Schools were sampled, wherein 190 teachers were extracted as participants in the study through simple random sampling technique using Morgan and Krejcie’s (1971) table of determining sample size. A structured questionnaire titled ‘Teacher Commitment Questionnaire’ with 15 items developed by Allen (1997) which was constructed on a 4-point Likert scale was employed as an instrument for data collection. Data analysis was made through descriptive statistics using mean and standard deviation. The paper portrayed that, teachers’ commitment towards teaching profession among public secondary schools of Zamfara State was on moderate extent with reference to its average mean value of (M=2.62, SD=1.61). This paper recommends that, in order to improve teachers’ commitment, more efforts should be offered by the stakeholders in education sector for ensuring a positive adjustment of successful course delivery of teachers and most importantly the academic achievement of the learners.

3D-printed TCP-HA scaffolds delivering MicroRNA-302a-3p improve bone regeneration in a mouse calvarial model

ObjectiveTo demonstrate hydroxyapatite nanoparticles modified with cationic functional molecules. 3-aminopropyltriethoxysilane (HA-NPs-APTES) carrying microRNA-302a-3p (miR) in the 3D-printed tricalcium phosphate/Hydroxyapatite (TCP/HA) scaffold can increase healing of the critical-sized bone defect.Materials and methods3D-printed TCP/HA were modified with HA-NPs-APTES by two methods (M1, M2). The dispersion of particles was visualized by fluorescent microscopy. Biocompatibility of the scaffolds was tested by alizarin assay. Delivery of miR to the cells and osteogenic gene expression were evaluated by qPCR. After selecting best method (M2), scaffolds, scaffolds+HA-NPs-APTES with or without miR were implanted in 4 mm mouse calvarium defect (n = 4 per group). After 2,4 and 6 weeks, bone regeneration were evaluated by microCT and histology sections.ResultsBoth M1 and M2 scaffolds were biocompatible with cell adhesion on its surface. M2 scaffold showed significant increase of miR, suggesting successful delivery, resulted in downregulation of its target mRNA COUP-TFII, and upregulation of RUNX2 mRNA. Calvarium defect with M2 scaffold also showed significantly higher BV/TV and higher number of filled spaces at all time points. Histomorphometry demonstrated new bone formed at the center of the HA-NPs-APTES-miR scaffold earlier than controls.ConclusionTCP/HA scaffold modified with HA-NPs-APTES facilitated delivery of miR and enhanced bone regeneration.

Rotational Atherectomy, Orbital Atherectomy, and Intravascular Lithotripsy Comparison for Calcified Coronary Lesions.

In order to improve the percutaneous treatment of coronary artery calcifications (CAC) before stent implantation, methods such as rotational atherectomy (RA), orbital atherectomy (OA), and coronary intravascular lithotripsy (IVL) were invented. These techniques use different mechanisms of action and therefore have various short- and long-term outcomes. IVL employs sonic waves to modify CAC, whereas RA and OA use a rapidly rotating burr or crown. These methods have specific advantages and limitations, regarding their cost-efficiency, the movement of the device, their usefulness given the individual anatomy of both the lesion and the vessel, and the risk of specified complications. This study reviews the key findings of peer-reviewed articles available on Google Scholar with the keywords RA, OA, and IVL. Based on the collected data, successful stent delivery was assessed as 97.7% for OA, 92.4% for IVL, and 92.5% for RA, and 30-day prevalence of MACE (Major Adverse Cardiac Events) in OA-10.4%, IVL-7.2%, and RA-5%. There were no significant differences in the 1-year MACE. Compared to RA, OA and IVL are cost-effective approaches, but this is substantially dependent on the reimbursement system of the particular country. There is no standard method of CAC modification; therefore, a tailor-made approach is required.

Thirty-day Outcomes of First-in-man Implantation of a Novel Transcatheter Edge-to-edge Mitral Repair System in Patients With Severe Mitral Regurgitation

Objectives: The aim of this multicenter, prospective, single-arm pilot study (ClinicalTrials.gov number: NCT05040074) was to observe the procedural and 30-day results of the novel transcatheter mitral valve repair system, SQ-Kyrin®-M Clip (Shenqi Medical, Shanghai, China), in patients with severe mitral regurgitation (MR). Methods: The heart team considered patients from 5 centers in China with clinically significant functional mitral regurgitation ≥3+ despite optimal medical therapy or degenerative mitral regurgitation ≥3+ with high surgical risk as candidates for transcatheter repair. All patients received transcatheter edge-to-edge mitral valve repair under general anesthesia. The primary outcome was technical success, which included all of the following measured at the exit from the catheterization laboratory: (1) absence of procedural mortality; (2) successful access, delivery, and retrieval of the device delivery system; (3) successful deployment and correct positioning of the first intended device; and (4) no emergency surgery or reintervention related to the device or access procedure. The secondary outcomes included all-cause mortality, serious adverse events, device success, and procedural success 30 d after the intervention. Results: From June 2021 to December 2021, 18 patients were enrolled in this study with age (75.7 ± 7.4) years. Fifteen patients had MR 4+, while 3 had MR 3+. Technical success was achieved in all patients, including 6 degenerative mitral regurgitation and 12 functional mitral regurgitation patients. There was no all-cause mortality at 30 d. One patient had single leaflet device attachment within 30 d, which was regarded as a serious adverse event, and the patient was successfully treated with reintervention by implanting another clip. Another patient’s transmitral gradient was 6 mmHg (>5 mmHg), with an effective orifice area of 2.57 cm2 after the procedure. Sixteen patients had device success and procedural success at 30 d postoperation. Fourteen patients had MR 1+, 3 had MR 2+, and only 1 patient had MR 3 + 30 d after the procedure. Conclusions: The results of this feasibility study showed the efficacy and safety of the SQ-Kyrin®-M device in the Chinese population with severe MR, laying a solid foundation for a subsequent large-scale confirmatory study.

Elasticity, an often-overseen parameter in the development of nanoscale drug delivery systems.

Nanoparticles have shown an enormous potential as drug delivery systems in the lab. However, translation to the clinics or even market approval often fails. So far, the reason for this discrepancy is manifold. Physicochemical properties such as size, surface potential, and surface chemistry are in focus of research for many years. Other equally important parameters, influencing whether a successful drug delivery can be achieved, are mechanical properties of nanoparticles. Even though this is often not even considered during formulation development, and it is not requested for approval, an increasing number of studies show that it is important to have knowledge about these characteristics. In this article, we discuss examples highlighting the influence of elasticity in nanoscale biological interactions focusing on mucosal delivery and on tumor targeting. Besides this, we discuss the influence of different measurement settings using atomic force microscopy for the determination of mechanical properties of drug carriers.

A Novel Port to Facilitate Magnetic Hyperthermia Therapy for Glioma.

High-grade gliomas (HGG) are the most common primary brain malignancy and continue to be associated with a dismal prognosis (median survival rate of 15-18 months) with standard of care therapy. Magnetic hyperthermia therapy (MHT) is an emerging intervention that leverages the ferromagnetic properties of magnetic iron-oxide nanoparticles (MIONPs) to target cancer cells that are otherwise left behind after resection. We report a novel port device to facilitate localization, delivery, and temperature measurement of MIONPs within a target lesion for MHT therapy. We conducted an in-depth literature and intellectual property review to define specifications of the conceived port device. After setting the design parameters, a thorough collaboration with neurological surgeons guided the iterative modeling process. A prototype was developed using Fusion 360 (Autodesk, San Rafael, CA) and printed on a Form 3 printer (Formlabs, Medford, MA) in Durable resin. The prototype was then tested in a phantom skull printed on a Pro-Jet 660Pro 3D printer (3D Systems, Rock Hill, SC) and a brain model based on mechanical and electrochemical properties of native brain tissue. This phantom underwent MHT heating tests using an alternating magnetic field (AMF) sequence based on current MHT workflow. Successful localization, delivery, and temperature measurement were demonstrated. The purpose of this study was twofold: first, to create and validate the procedural framework for a novel device, providing the groundwork for an upcoming comprehensive animal trial and second, to elucidate a cooperative approach between engineers and clinicians that propels advancements in medical innovation.

Peptide-modified PAMAM-based bone-targeting RNA delivery system

BackgroundOsteoporosis, among other bone diseases, has become a prevalent cause of decreased quality of life in older and postmenopausal women. Traditional anti-osteoporotic therapies, though widely prescribed, are limited by a lack of cell- or tissue-specific targeting ability and effectiveness without side effects. Gene therapy is rapidly replacing traditional therapeutics, primarily because of its specific targeting ability and efficiency. Among viral- and non-viral-based gene therapies, the latter is often preferred over the former due to lower cytotoxicity, immunogenicity, and ease of modification with different molecules to improve efficiency and extend gene expression. We designed and synthesized a multifunctional bone-targeting ribonucleic acid (RNA) delivery system based on polyamidoamine (PAMAM). PAMAM was modified with the serine-aspartate-serine-serine-aspartate (SDSSD) peptide to deliver antagomir 138-5p to osteoblasts (MC3T3-E1 cell line) in vitro and in vivo using the ovariectomized (OVX) mouse model.ResultsThe results showed that this system was less cytotoxic than polyethylenimine (PEI) and could bind to RNA favorably while maintaining gene delivery ability in vitro. In vivo data showed that the distal tibia and femur of the mice in the PAMAM-SDSSD (PS) + RNA group had improved bone mineral density (BMD), bone mineral content (BMC), and bone volume compared to those in the PS + Negative Control (NC) or OVX groups. Moreover, the femurs of the PS + RNA group mice demonstrated a higher breaking point, stress, stiffness, and elasticity than those of the PS + NC or OVX mice, suggesting improved femur strength in the OVX mice treated with RNA delivered through SDSSD-modified PAMAM.ConclusionThis study shows that SDSSD modification of PAMAM not only improves gene delivery capacity but also enhances the cell targeting efficiency of nanoparticles towards osteoblasts. The successful delivery of antagomir 138-5p to osteoblasts demonstrates cell-specificity and gene delivery to alleviate osteoporotic symptoms.