Delivery Approaches Research Articles

Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.

Perceived barriers and opportunities for the introduction of post-discharge malaria chemoprevention (PDMC) in five sub-Saharan countries: a qualitative survey amongst malaria key stakeholders

BackgroundPost-discharge malaria chemoprevention (PDMC) is an intervention aimed at reducing morbidity and mortality in patients hospitalized with severe anaemia, with its effectiveness established in several clinical trials. The aim of this study was to better understand factors that would influence the scale up of this intervention, and to identify preferences for two delivery mechanisms, facility-based or community-based.MethodsForty-six qualitative individual interviews were conducted in five sub-Saharan countries amongst malaria key opinion leaders and national decision makers. Findings were analysed following a thematic inductive approach.ResultsHalf of participants were familiar with PDMC, with a satisfactory understanding of the intervention. Although PDMC was perceived as beneficial by most respondents, there was some unclarity on the target population. Both delivery approaches were perceived as valuable and potentially complementary. From an adoption perspective, relevant evidence generation, favorable policy environment, and committed funding were identified as key elements for the scale up of PDMC.ConclusionsThe findings suggest that although PDMC was perceived as a relevant tool to prevent malaria, further clarification was needed in terms of the relevant patient population, delivery mechanisms, and more evidence should be generated from implementation research to ensure policy adoption and funding.

The impact of protein delivery on short-term and long-term clinical outcomes in critically ill patients: Protocol for a multicenter, prospective, observational study (The ACTION study)

Background and aimsNutrition therapy is a vital part of the management of critically ill patients. Efforts have been made to optimize nutrition therapy in the ICU setting, and it is argued that protein might be the most important substrate to deliver during critical illness. However, the impact of protein delivery on patient-centered outcomes, including short-term and long-term outcomes, is controversial. Moreover, previous studies showed that compliance with the guidelines is poor in practice, and the amounts of protein intake vary significantly among different hospitals. The objective of this study is to describe the current practice of protein delivery for critically ill patients and to investigate the association between different protein delivery amounts and approaches during ICU admission and multiple patient-centered outcomes (short-term and long-term). MethodsThis is a multicenter, prospective, observational study conducted in 70 hospitals, aiming to recruit more than 1800 newly admitted critically ill patients who are expected to stay in ICU for at least 48 hours. Data, including the baseline characteristics, illness severity scores, requirements of organ support therapy, and daily nutritional therapy, will be recorded until day 28 after enrollment unless discharge from the ICU or death occurs first. The key long-term clinical outcomes, like readmission post the index discharge and health-related quality of life, will be collected via telephone contact on Day 90 and Day 180 after recruitment. Quality of life will be assessed by the EuroQol five dimensions five-level questionnaire (EQ5D5L) visual analogue scale score. Apart from descriptive data, multivariate analyses adjusted for potential confounders will be applied to assess the association between protein intake during ICU stay and short-term and long-term clinical outcomes. Ethics and trial registrationThis study was reviewed and approved by the ethics committee of Jinling Hospital (2021NZKY-027-01) and the participating sites. The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200067016) before enrollment.

Nanoparticle LDH enhances RNAi efficiency of dsRNA in piercing-sucking pests by promoting dsRNA stability and transport in plants

Piercing-sucking pests are the most notorious group of pests for global agriculture. RNAi-mediated crop protection by foliar application is a promising approach in field trials. However, the effect of this approach on piercing-sucking pests is far from satisfactory due to the limited uptake and transport of double strand RNA (dsRNA) in plants. Therefore, there is an urgent need for more feasible and biocompatible dsRNA delivery approaches to better control piercing-sucking pests. Here, we report that foliar application of layered double hydroxide (LDH)-loaded dsRNA can effectively disrupt Panonychus citri at multiple developmental stages. MgAl-LDH-dsRNA targeting Chitinase (Chit) gene significantly promoted the RNAi efficiency and then increased the mortality of P. citri nymphs by enhancing dsRNA stability in gut, promoting the adhesion of dsRNA onto leaf surface, facilitating dsRNA internalization into leaf cells, and delivering dsRNA from the stem to the leaf via the vascular system of pomelo plants. Finally, this delivery pathway based on other metal elements such as iron (MgFe-LDH) was also found to significantly improve the protection against P. citri and the nymphs or larvae of Diaphorina citri and Aphis gossypii, two other important piercing-sucking hemipeteran pests, indicating the universality of nanoparticles LDH in promoting the RNAi efficiency and mortality of piercing-sucking pests. Collectively, this study provides insights into the synergistic mechanism for nano-dsRNA systemic translocation in plants, and proposes a potential eco-friendly control strategy for piercing-sucking pests.Graphical

Lipopolymer/siRNA complexes engineered for optimal molecular and functional response with chemotherapy in FLT3-mutated acute myeloid leukemia

Approximately 25% of newly diagnosed AML patients display an internal tandem duplication (ITD) in the fms-like tyrosine kinase 3 (FLT3) gene. Although both multi-targeted and FLT3 specific tyrosine kinase inhibitors (TKIs) are being utilized for clinical therapy, drug resistance, short remission periods, and high relapse rates are challenges that still need to be tackled. RNA interference (RNAi), mediated by short interfering RNA (siRNA), presents a mechanistically distinct therapeutic platform with the potential of personalization due to its gene sequence-driven mechanism of action. This study explored the use of a non-viral approach for delivery of FLT3 siRNA (siFLT3) in FLT3-ITD positive AML cell lines and primary cells as well as the feasibility of combining this treatment with drugs currently used in the clinic. Treatment of AML cell lines with FLT3 siRNA nanocomplexes resulted in prominent reduction in cell proliferation rates and induction of apoptosis. Quantitative analysis of relative mRNA transcript levels revealed downregulation of the FLT3 gene, which was accompanied by a similar decline in FLT3 protein levels. Moreover, an impact on leukemic stem cells was observed in a small pool of primary AML samples through significantly reduced colony numbers. An absence of a molecular response post-treatment with lipopolymer/siFLT3 complexes in peripheral blood mononuclear cells, obtained from healthy individuals, denoted a passive selectivity of the complexes towards malignant cells. The effect of combining lipopolymer/siFLT3 complexes with daunorubucin and FLT3 targeting TKI gilteritinib led to a significant augmentation of anti-leukemic activity. These findings demonstrate the promising potential of RNAi implemented with lipopolymer complexes for AML molecular therapy. The study prospectively supports the addition of RNAi therapy to current treatment modalities available to target the heterogeneity prevalent in AML. Statement of significanceWe show that a clinically validated target, the FLT3 gene, can be eradicated in leukemia cells using non-viral RNAi. We validated these lipopolymers as effective vehicles to deliver nucleic acids to leukemic cells. The potency of the lipopolymers was superior to that of the ‘gold-standard’ delivery agent, lipid nanoparticles (LNPs), which are not effective in leukemia cells at clinically relevant doses. Mechanistic studies were undertaken to probe structure-function relationships for effective biomaterial formulations. Cellular and molecular responses to siRNA treatment have been characterized in cell models, including leukemia patient-derived cells. The use of the siRNA therapy with clinically used chemotherapy was demonstrated.

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model.

Prevention of Violence Against Children: A Qualitative Exploration of Colombian Policymakers', Programme Facilitators' and Caregivers' Perceptions.

Violence against children (VAC) is a global public health and human rights issue that can lead to long-lasting negative consequences for individual and societal outcomes. While extensive evidence indicates that parenting programmes might be effective in preventing VAC, there are several unsolved questions on how to ensure interventions are acceptable, feasible, effective and sustainable, particularly in low- and- middle-income countries (LMICs). In this study, we report findings from a qualitative examination of policymakers' (N = 10), early childhood and parenting programme facilitators' (N = 20) and parents' and other caregivers' (N = 38) perspectives on VAC prevention to examine the implementation ecosystem of parenting programmes in Colombia, including contextual risk and protection factors, features of existing programmes, and stakeholders' needs. We conducted interviews and focus groups using a semistructured format, along with a thematic approach, to analyse the data from each group of participants (i.e., policymakers, facilitators and caregivers) independently. Overall, the data revealed the critical role of intersecting and interacting factors at the micro (e.g., caregivers' capabilities and beliefs), meso (e.g., programme content and delivery approaches) and macro (e.g., policymakers' vision and existing infrastructure) levels in exacerbating risks/imposing barriers versus protecting/promoting VAC prevention. These findings provide evidence on the implementation ecosystem of prevention programmes to inform the design of novel strategies and programmes aimed at preventing violence and promoting families' well-being and young children's development.

Microsponge: A Novel Approach for Topical Drug Delivery of Anti Rheumatoid Drugs

Microsponge: A Novel Approach for Topical Drug Delivery of Anti Rheumatoid Drugs

From Conventional to Cutting-edge: A Comprehensive Review on Drug Delivery Systems

: The essential need for efficacious conveyance of therapeutics to specific tissues or cells, refinement of drug formulations, and the scalability of industrial production drives the pre-sent-day demand for enhanced drug delivery systems (DDS). Newly devised drugs often exhibit suboptimal biopharmaceutical properties, resulting in diminished patient adherence and adverse side effects. The paramount importance of site-specific drug delivery lies in its capacity to facili-tate the targeted administration of diverse therapeutic agents, catering to both localized ailments and systemic treatments. Alongside targeted drug delivery strategies encompassing ligand-based targeting and stimuli-responsive systems, the advent of cutting-edge nanotechnologies such as nanoparticles, liposomes, and micelles has marked a paradigm shift. Additionally, personalized medicines have emerged as a consequential facet of drug delivery, emphasizing the customization of treatment approaches. Researchers have explored an excess of methodologies in the advance-ment of these formulation technologies, including stimuli-responsive drug delivery, 3D printing, gene delivery, and various other innovative approaches. This comprehensive review aims to pro-vide a holistic understanding of the past, present, and future of drug delivery systems, offering in-sights into the transformative potential of emerging technologies.

A Review on Nanosponges: An Idiosyncratic Approach for Delivery of Proactive Molecules

Background: A lot of work has been done by many researchers to develop a system that is targeted at a specific site. Nanosponges are one of the systems that serve this purpose and have several advantages over other methods. Objective: The article’s strategy is to provide access to data regarding the nanosponges system, including its preparation, evaluation, and advantages in various fields, such as the transportation of proteins, vaccines, biocatalysts, and drugs with enhanced bioavailability. Nanosponges also contribute significantly to the treatment of breast cancer, lung cancer, fungal infection, water treatment, and topical application than other approaches. Method: Nanosponges contain a solid, porous system in which hydrophilic or lipophilic drugs are loaded at their core in the nanocavity. All the information provided in this article was collected after analysing various reports on nanosponges available on Google Scholar, PubMed, Scopus, Web of Science, and Science Direct. It is concluded that the nanosponges have excellent aqueous solubility properties. Therefore, they can be used as carriers for drugs with poor water solubility. Moreover, greater bioavailability can be achieved by using the nanosponge approach. Conclusion: Nanosponges possess various outstanding properties that form the unique system of this approach. Nanosponges provide an effective carrier system for enzymes, proteins, vaccines, and therapeutic fields. This review provides a broad overview of the development of nanosponges, their evaluation, and the uses of nanosponges based on cyclodextrin for drug delivery.

Nanotechnology: Current Developments, Applications and Patents for Non-invasive Topical Cosmetics and Dermatological Therapeutic Delivery

: Nanotechnology exhibits the advancement in the field of invention, by improving the potency of the formulation through the delivery of inventive solutions. To resolve several limita-tions related to conventional formulations, nanotechnology applications are increasing in the cosmetics and dermatological area. Cosmetic and dermatological preparations are considered a thriving branch of the body care arena and their usage has increased dramatically through the past years. Scientists are designing innovative delivery mechanisms and emerging innovations that are presently being utilized in the development of cosmetics. Inventive nanocarriers such as nio-somes, liposomes, microemulsions, nanoemulsions, solid-lipid nanoparticles, nanospheres, and nanostructured (lipid) carriers have substituted the use of traditional drug delivery. These innova-tive nanocarriers have the convenience of better skin permeation, sustained and controlled drug delivery, precise location, higher stability, and greater incorporated capability. Since the usage of cosmetics has increased, the usual delivery system has been substituted by modern delivery ap-proaches. The introduction of newer advancements and novel drug delivery systems make cos-metics and cosmeceuticals more popular with increased market share. This review article on nan-otechnology employed in cosmetics and dermatology emphasizes the numerous innovative nanocarriers designed for cosmetic and dermatologic drug delivery, their negative and positive aspects, and their toxicity.

HazARdSnap: Gazed-Based Augmentation Delivery for Safe Information Access While Cycling.

During cycling activities, cyclists often monitor a variety of information such as heart rate, distance, and navigation using a bike-mounted phone or cyclocomputer. In many cases, cyclists also ride on sidewalks or paths that contain pedestrians and other obstructions such as potholes, so monitoring information on a bike-mounted interface can slow the cyclist down or cause accidents and injury. In this article, we present HazARdSnap, an augmented reality-based information delivery approach that improves the ease of access to cycling information and at the same time preserves the user's awareness of hazards. To do so, we implemented real-time outdoor hazard detection using a combination of computer vision and motion and position data from a head mounted display (HMD). We then developed an algorithm that snaps information to detected hazards when they are also viewed so that users can simultaneously view both rendered virtual cycling information and the real-world cues such as depth, position, time to hazard, and speed that are needed to assess and avoid hazards. Results from a study with 24 participants that made use of real-world cycling and virtual hazards showed that both HazARdSnap and forward-fixed augmented reality (AR) user interfaces (UIs) can effectively help cyclists access virtual information without having to look down, which resulted in fewer collisions (51% and 43% reduction compared to baseline, respectively) with virtual hazards.

Impact of the COVID-19 pandemic on psychotropic prescribing: a systematic review

ObjectivesThe global prevalence of mental health disorders has risen significantly since the beginning of the COVID-19 pandemic. The pandemic has additionally caused disruption to mental health services, leading to a...

A Versatile Platform of Novel Approaches in Transdermal Delivery

A Versatile Platform of Novel Approaches in Transdermal Delivery

Development of formulation and evaluation of topical micro emulsion gel loaded with terbinafine HCL micro emulsion

Fungal infections, particularly in immunocompromised patients, present significant health challenges and are often difficult to treat with conventional topical therapies due to bioavailability issues. This study explores the development of a topical gel formulation using solid lipid nanoparticles (SLNs) loaded with Terbinafine, an antifungal agent, to improve drug delivery and efficacy. SLNs were prepared by a solvent diffusion method and optimized with stearic acid and poloxamer 188. The formulation with the highest entrapment efficiency (SLN F6) exhibited 92.13% ± 0.975. The optimized SLN formulation was incorporated into a gel base containing carbopol 934, resulting in SLN gel G3 with 1.5% carbopol showing the highest drug entrapment (91.39% ± 0.187). The gel was evaluated for physicochemical properties, including viscosity (369 cP), pH (6.12 ± 0.255), and spreadability (4.5). In vitro release studies indicated controlled drug release, fitting best with the Higuchi and Korsmeyer-Peppas models. FTIR analysis confirmed no significant interactions between the drug and excipients, supporting the formulation's purity and effectiveness. Scanning electron microscopy (SEM) confirmed the spherical shape and smooth surface of the nanoparticles. This study demonstrates that Terbinafine-loaded SLNs in a topical gel formulation provide a promising approach for sustained drug delivery in treating fungal infections.

Bioactive Glial-Derived Neurotrophic Factor from a Safe Injectable Collagen-Alginate Composite Gel Rescues Retinal Photoreceptors from Retinal Degeneration in Rabbits.

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen-alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.

Mapping the immunopeptidome of seven SARS-CoV-2 antigens across common HLA haplotypes

Most COVID-19 vaccines elicit immunity against the SARS-CoV-2 Spike protein. However, Spike protein mutations in emerging strains and immune evasion by the SARS-CoV-2 virus demonstrates the need to develop more broadly targeting vaccines. To facilitate this, we use mass spectrometry to identify immunopeptides derived from seven relatively conserved structural and non-structural SARS-CoV-2 proteins (N, E, Nsp1/4/5/8/9). We use two different B-lymphoblastoid cell lines to map Human Leukocyte Antigen (HLA) class I and class II immunopeptidomes covering some of the prevalent HLA types across the global human population. We employ DNA plasmid transfection and direct antigen delivery approaches to sample different antigens and find 248 unique HLA class I and HLA class II bound peptides with 71 derived from N, 12 from E, 28 from Nsp1, 19 from Nsp4, 73 from Nsp8 and 45 peptides derived from Nsp9. Over half of the viral peptides are unpublished. T cell reactivity tested against 56 of the detected peptides shows CD8+ and CD4+ T cell responses against several peptides from the N, E, and Nsp9 proteins. Results from this study will aid the development of next-generation COVID vaccines targeting epitopes from across a number of SARS-CoV-2 proteins.

GUANIDINE DELIVERY BY Si-DOPED C60 AND SWCNT: A DFT APPROACH

The interactions between guanidine and silicon decorated fullerene or single walled carbon nanotube were examined for insight into the drug delivery approach. The calculations show that the chemical reactivity and interaction energies are strongly dependent on the interaction site of the guanidine molecule. Depending on the purpose, by determining the interaction sites, it is possible to use Si decorated fullerenes and single walled carbon nanotubes as selective drug delivery vehicles. The results will contribute to further searches on improving drug delivery platforms.

Localized delivery of Roxadustat via cubosomes-based thermosensitive in-situ hydrogel enhances diabetic wound healing by stabilizing HIF-1α in rats

Chronic non-healing wounds are a major complication among diabetic patients, significantly affecting their quality of life. The dysfunction of HIF-1, a crucial regulator of wound healing, contributes to impaired wound repair in diabetes. Roxadustat (ROX), an HIF-1α stabilizer, has emerged as a promising therapeutic candidate for addressing chronic wounds. Accordingly, a few studies have investigated the systemic administration of ROX for wound healing. However, concerns have arisen about potential side effects. Our study aimed to address these limitations by developing a localized delivery approach using ROX-loaded cubosomes (ROX-CUs) incorporated into a thermosensitive hydrogel. ROX-CUs were prepared and evaluated for particle size (125.6 ± 3.11 nm), zeta potential (−26.60 ± 2.08 mV), and entrapment efficiency (94.23 ± 2.93 %). ROX-CUs were then integrated into a poloxamer-based thermosensitive hydrogel with varying ratios of poloxamers 188 and 407. The selected formulation (F13) showed a phase transition temperature of 36.5 ± 0.4 °C and a drug content of 97.80 ± 1.60 %. In vitro drug release studies demonstrated a biphasic release for F13: an initial burst after 3 h (15.25 %) followed by sustained release up to 48 h (52.13 %), offering sustained release advantages. In vivo studies on diabetic rats revealed that F13 significantly accelerated wound closure (93 % reduction), with enhanced tissue characteristics, including neovascularization and increased collagen deposition. Additionally, F13 upregulated the HIF-1α and other tissue remodeling factors, creating an optimal environment for tissue repair. Consequently, ROX-CUs incorporated into a thermosensitive hydrogel hold significant promise as a novel therapeutic strategy for promoting wound healing in clinical settings.

Molecular Imprinting Technology for Advanced Delivery of Essential Oils.

Essential oils (EOs) hold therapeutic potential, but their conventional delivery systems have some limitations. This review focuses on the critical review and discussion of research related to EO delivery systems. The review also explores how molecular imprinting technologies (MIT) can advance EO delivery. MIT offer several techniques, namely covalent, non-covalent, and semi-covalent imprinting, creating targeted cavities that selectively bind and release EOs. These approaches promise significant advantages including increased selectivity, controlled release, and protection from environmental degradation. However, some challenges related to the stability and biocompatibility of MIPs remain unsolved. Integrating nanotechnology through methods like nanoparticle imprinting and some lithographic techniques seems promising to overcome these limitations. Some recently established models and systems used for EO-related research are paving the way for a more efficient and targeted EO delivery approach to harnessing the therapeutic power of EOs. Therefore, some recent and future research seems promising, and eventually it will increase the effectiveness of MIP-based EO delivery systems.