Local Delivery Research Articles

Calcipotriol Nanosuspension-Loaded Trilayer Dissolving Microneedle Patches for the Treatment of Psoriasis: In Vitro Delivery and In Vivo Antipsoriatic Activity Studies.

Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.

Chemotherapeutic Agents in Periodontics: A Review

"Selman Waksman" first used the term "antibiotic" in 1942 to refer to any material produced by a bacterium that inhibits the growth of other micro-organisms in high dilution. The pathogenic bacteria, the patient, and the medication are the three main components of the antibiotic periodontal therapy idea. Patients with attachment loss or with aggressive types of periodontitis or those with periodontitis linked with underlying medical conditions are the best candidates for systemic antimicrobial therapy. The three main objectives of Periodontal Therapy are disrupting biofilms, suppressing potential periodontal pathogens throughout the entire oral cavity, and halting the illness. The microbial etiology of inflammatory periodontal disease provides the rationale for the use of antibiotic medication in periodontal therapy. This idea is predicated on the idea that a certain bacterium causes destructive periodontal disease and that antibiotic agents can be present in humans in doses greater than those required to kill or inhibit infections. Keywords: Antibiotics, Systemic drug delivery, Local drug delivery, Periodontal therapy.

Dynamic Hydrogels against Infections: From Design to Applications.

Human defense against infection remains a global topic. In addition to developing novel anti-infection drugs, therapeutic drug delivery strategies are also crucial to achieving a higher efficacy and lower toxicity of these drugs for treatment. The application of hydrogels has been proven to be an effective localized drug delivery approach to treating infections without generating significant systemic adverse effects. The recent emerging dynamic hydrogels further show power as injectable formulations, giving new tools for clinical treatments. In this review, we delve into the potential applications of dynamic hydrogels in antibacterial and antiviral treatments and elaborate on their molecular designs and practical implementations. By outlining the chemical designs underlying these hydrogels, we discuss how the choice of dynamic chemical bonds affects their stimulus responsiveness, self-healing capabilities, and mechanical properties. Afterwards, we focus on how to endow dynamic hydrogels with anti-infection properties. By comparing different drug-loading methods, we highlight the advantages of dynamic chemical bonds in achieving sustained and controlled drug release. Moreover, we also include the design principles and uses of hydrogels that possess inherent anti-infective properties. Furthermore, we explore the design principles and applications of hydrogels with inherent anti-infective properties. Finally, we briefly summarize the current challenges faced by dynamic hydrogels and present a forward-looking vision for their future development. Through this review, we expect to draw more attention to these therapeutic strategies among scientists working with chemistry, materials, as well as pharmaceutics.

Feasibility and Analgesic Efficacy of Thoracolumbar Dorsal Ramus Nerve Block Using Multiorifice Pain Catheters for Scoliosis Surgery: A Prospective Cohort Study.

Approximately 38,000 scoliosis surgery correction operations are performed annually in the United States; these operations are associated with considerable postoperative pain which can be difficult to manage. This is largely attributed to an incision spanning multiple vertebral segments with paraspinal muscle dissection and retraction to facilitate the implantation of segmental hardware and rods. Frequently utilized analgesic modalities include intravenous patient-controlled analgesia and epidural analgesia, often in combination. We sought to ascertain the feasibility and analgesic efficacy of continuous thoracolumbar dorsal ramus nerve (TDRN) block using surgically placed multiorifice catheters. Forty-two patients diagnosed with idiopathic scoliosis who underwent a posterior spinal fusion (PSF) were enrolled after consent was obtained. Patients were managed utilizing a standardized Enhanced Recovery After Surgery) protocol including a perioperative opioid-sparing regimen. Data were collected at specified time intervals during the recovery period. These data points included pain scores using the Numeric Rating Scale. Parenteral or both oral and parenteral opioid consumption doses were also collected every 4 hours. Any significant postoperative adverse events were recorded as well. A total of 42 patients had surgically placed TDRN catheters, and 40 patients were included in this study. The patients all reported low to moderate pain scores with low opioid consumption postoperatively, while the TDRN catheter delivery of local anesthetic analgesics did not result in significant complications. A regional technique utilizing TDRN catheters could be a valuable component of the postoperative pain management protocols for PSF surgery, and additional studies are warranted. This study evaluated the feasibility and analgesic efficacy of TDRN catheters for postoperative pain control following multilevel PSF for idiopathic scoliosis. Continuous local anesthetic delivery through TDRN catheters is a feasible and safe technique for postoperative pain control in these patients. Selective blockade of the dorsal rami might have benefits over epidural analgesia or other regional techniques.

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites.

The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20-25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells.

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies.

Breast cancer poses one of the largest threats to women's health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host's immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.

3D-printed short nanofibers/hydrogel-based vaginal films as a novel system for the delivery of anti-HIV microbicide drugs

Acquired immunodeficiency syndrome (AIDS) is a global epidemic that affects the lives of millions of young women, particularly those who live in poverty-stricken regions and engage in unsafe sexual behaviors, forcing the development of unique pre-exposure anti-HIV prophylaxis tools. Using a combination of antiretroviral medications with various antiviral mechanisms significantly improves the prognosis for HIV patients. The integration of 3D printing technology, short nanofiber technology, and hydrogel into a single system known as “3D-printed nanocomposites” is an emerging approach that is gaining traction in tissue engineering, regenerative medicine, and biomedical applications. Based on these foundations, the current study aims to develop, for the first time, a 3D-printed short nanofiber/film for the vaginal delivery of ritonavir and efavirenz in a fixed-dose combination. To identify an optimal 3D-printable short nanofibers/hydrogel formulation, multiple formulations, and fragmentation methods were investigated. Following that, the generated vaginal films were evaluated using several physicochemical characterizations, mechanical properties measurements, and in vitro release studies. The findings revealed that only cryocutting is effective for polycaprolactone nanofiber fragmentation. The 3D-printed short nanofibers-loaded films had an ultimate tensile strength of 6.75 ± 1.27 MPa and elongation at break of 262.67 ± 44.32 MPa, suggesting their reliability for handling and vaginal application. Furthermore, the in vitro release study demonstrated that rapid EFZ release occurred during the first 45 min, whereas RIT release lasted more than 72 h, indicating that the complex drug release profile was met. In summary, the study emphasizes that 3D printing of short nanofiber-based films is likely to be an effective platform for localized vaginal drug delivery, particularly anti-HIV therapies.

Cascade Nanoreactor Employs Mitochondrial-Directed Chemodynamic and δ-ALA-Mediated Photodynamic Synergy for Deep-Seated Oral Cancer Therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.

Advancements in Nanosystems for Ocular Drug Delivery: A Focus on Pediatric Retinoblastoma.

The eye's complex anatomical structures present formidable barriers to effective drug delivery across a range of ocular diseases, from anterior to posterior segment pathologies. Emerging as a promising solution to these challenges, nanotechnology-based platforms-including but not limited to liposomes, dendrimers, and micelles-have shown the potential to revolutionize ophthalmic therapeutics. These nanocarriers enhance drug bioavailability, increase residence time in targeted ocular tissues, and offer precise, localized delivery, minimizing systemic side effects. Focusing on pediatric ophthalmology, particularly on retinoblastoma, this review delves into the recent advancements in functionalized nanosystems for drug delivery. Covering the literature from 2017 to 2023, it comprehensively examines these nanocarriers' potential impact on transforming the treatment landscape for retinoblastoma. The review highlights the critical role of these platforms in overcoming the unique pediatric eye barriers, thus enhancing treatment efficacy. It underscores the necessity for ongoing research to realize the full clinical potential of these innovative drug delivery systems in pediatric ophthalmology.

Injectable Self-Oxygenating Cardio-Protective and Tissue Adhesive Silk-Based Hydrogel for Alleviating Ischemia After Mi Injury.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by ≈30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by ≈10% and 20%, respectively, with a ≈25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy.

Local Mart

Local Mart is a complete marketplace that provides a wide variety of goods, such as clothing, electronics, groceries, and furnishings. Customers can choose to buy products using the Local Mart app or by going to the store. Customers may quickly place orders and receive their products with a convenience focus; this is especially true for products that are close to the local mart, which ensures faster delivery.Users may easily browse across different categories, place orders, and keep track of their purchases with the platform's smooth shopping experience. Local Mart meets the varied demands of its clients by bridging the gap between online and physical purchasing. The goal of Local Mart's user-friendly interface and effective delivery mechanism is to improve customers' overall purchasing experience. The website is dedicated to guarantee a satisfying purchasing experience by offering top-notch assistance and service.All things considered, Local Mart aims to transform consumer behavior by providing a user-friendly and easily accessible platform for making a broad range of goods purchases.

Metal organic framework-based polymeric hydrogel: A promising drug delivery vehicle for the treatment of breast cancer

The constraints associated with current cancer therapies have inspired scientists to develop advanced, precise, and safe drug delivery methods. These delivery systems boost treatment effectiveness, minimize harm to healthy cells, and combat cancer recurrence. To design advanced drug delivery vehicle with these character, in the present manuscript, we have designed a self-healing and injectable hybrid hydrogel through synergistically interacting metal organic framework, CuBTC with the poly(vinyl alcohol) (PVA). This hybrid hydrogel acts as a localized drug delivery system and was used to encapsulate and release the anticancer drug 5-Fluorouracil selectively at the targeted site in response to the physiological pH. The hydrogel was formed through transforming the gaussian coil like matrix of PVA-CuBTC into a three-dimensional network of hydrogel upon the addition of crosslinker; borax. The biocompatible character of the hydrogel was confirmed through cell viability test. The biocompatible hybrid hydrogel then was used to encapsulate and studied for the pH responsive release behavior of the anti-cancer drug, 5-FU. The in vitro cytotoxicity of the drug-loaded hydrogel was evaluated against MCF-7 and HeLa cells. The study confirms that the hybrid hydrogel is effective for targeted and sustained release of anticancer drugs at cancer sites.

Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

The Effect of Educational Intervention on Inhaler Technique of Patients in Asian Countries: A Systematic Review

Background: Inhalation therapy is the main line of treatment for the management of various respiratory diseases due to localized delivery and rapid onset of action. Incorrect inhaler technique is very common and subsequently leads to poor disease management. Pharmacist can have a positive impact on patient’s education about proper inhaler technique that can lead to a significant improvement of asthma and COPD management. Objective: The objective of this study was to determine the effectiveness of pharmacist education program on inhaler technique of asthmatic and COPD patients in South Asian countries. The outcome regarding inhalation technique was reviewed and summarized. Methodology: The outcome regarding inhalation technique was reviewed and summarized. For this systematic review, basic electronic academic databases (Scopus, Science Direct, ProQuest, Web of Science and PubMed) were used for the search, along with a manual search on Google Scholar. This systematic review was conducted by following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” guidelines. Moreover, utilizing the framework of the PECO-S (Population Exposure Comparison Outcome Study design), various observational studies were recruited for this review. The ZEE tool was utilized to minimize the risk of bias among extracted cross-sectional studies. Inclusion criteria included studies on inhaler using patients of all ages from South Asian countries along with the influence of educational intervention outcomes. Results: Out of 2191 studies, 24 studies meeting the inclusion criteria were included in the current review. All of the included studies were about pharmacist intervention on inhaler technique in South Asian countries. Conclusion: The systematic literature review summarizes the impact of educational intervention provided to inhaler using patients from South Asian countries. It was assessed that patient education and counselling produced improvement in inhalation technique of various devices especially metered dose inhalers. The primary outcome of most the studies was the improvement in inhaler technique assessment and enhanced quality of life. Therefore, inhaler technique education to patients should be made compulsory by the Health-care authorities to enhance compliance and effectiveness of inhalational therapy by avoiding irrational use of inhalers.

An efficient heuristic for very large-scale vehicle routing problems with simultaneous pickup and delivery

The paper discusses two variants of the Capacitated Vehicle Routing Problem (CVRP), in which each customer to be visited can require both pickup and delivery, or only either pickup and delivery but not both. These problems are referred to, respectively, as the Vehicle Routing Problem with Simultaneous Pickup and Delivery (VRPSPD) and as the Vehicle Routing Problem with Mixed Pickup and Delivery (VRPMPD). Both VRPSPD and VRPMPD are particularly relevant in practical logistics distribution scenarios, especially when dealing with a substantial number of pickup and delivery locations. The aim of this work is to provide an algorithm which extends, through a variety of specializations, the FILO framework, originally proposed and specifically designed for the CVRP. This variant, called FSPD, has been developed to accomplish two objectives: first, being competitive with the state-of-the-art algorithms for the VRPSPD and VRPMPD; second, efficiently solving new benchmark instances for these problems with a very large number of customers, while maintaining linear scalability of the computing time with respect to the problem size. The extensive computational study and detailed analysis of the algorithm components conducted in this paper demonstrate the successful achievement of both objectives.

Challenges in Optimizing Nanoplatforms Used for Local and Systemic Delivery in the Oral Cavity.

In this study, we focused on innovative approaches to improve drug administration in oral pathology, especially by transmucosal and transdermal pathways. These improvements refer to the type of microneedles used (proposing needles in the saw), to the use of certain enhancers such as essential oils (which, besides the amplifier action, also have intrinsic actions on oral health), to associations of active substances with synergistic action, as well as the use of copolymeric membranes, cemented directly on the tooth. We also propose a review of the principles of release at the level of the oral mucosa and of the main release systems used in oral pathology. Controlled failure systems applicable in oral pathology include the following: fast dissolving films, mucoadhesive tablets, hydrogels, intraoral mucoadhesive films, composite wafers, and smart drugs. The novelty elements brought by this paper refer to the possibilities of optimizing the localized drug delivery system in osteoarthritis of the temporomandibular joint, neuropathic pain, oral cancer, periodontitis, and pericoronitis, as well as in maintaining oral health. We would like to mention the possibility of incorporating natural products into the controlled failure systems used in oral pathology, paying special attention to essential oils.

The role of curcumin in periodontal therapy: An update

Background: Periodontal diseases, including gingivitis and periodontitis, present a significant global health burden, particularly affecting adults and especially the aging population. The etiology involves complex interactions between microbial colonization and host immune-inflammatory responses, leading to tissue destruction and bone resorption. Current conventional treatments, primarily focused on mechanical debridement and antimicrobial agents, often have limitations and challenges, including antibiotic resistance and limited tissue regenerative potential. Curcumin, a polyphenolic compound derived from the Curcuma longa plant, has emerged as a promising adjunctive therapeutic agent owing to its remarkable pharmacological properties. Extensive preclinical research has revealed the potential anti-inflammatory, antioxidant, antimicrobial, and immunomodulatory effects of curcumin. These attributes make it a compelling candidate for addressing various aspects of periodontal pathogenesis. Furthermore, curcumin's capacity to in vitro inhibit various periodontopathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans demonstrates its potential as a natural antimicrobial agent. Its adjunctive use in local drug delivery systems, such as gels or nanoparticles, holds promise for targeted delivery and sustained release within periodontal pockets, enhancing its therapeutic potential. However, challenges related to its bioavailability, stability, and dosage standardization need to be addressed forsuccessful clinical outcomes. Keywords: periodontal diseases; curcumin; bioactive compounds, inflammatory response, microbial dysbiosis

Redox-Sensitive Poly(lactic-co-glycolic acid) Nanoparticles of Palbociclib: Development, Ultrasound/Photoacoustic Imaging, and Smart Breast Cancer Therapy.

Breast cancer is one of the leading causes of mortality in women globally. The efficacy of breast cancer treatments, notably chemotherapy, is hampered by inadequate localized delivery of anticancer agents to the tumor site, resulting in compromised efficacy and increased systemic toxicity. In this study, we have developed redox-sensitive poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the smart delivery of palbociclib (PLB) to breast cancer. The particle size of formulated PLB@PLGA-NPs (nonredox-sensitive) and RS-PLB@PLGA-NPs (redox-sensitive) NPs were 187.1 ± 1.8 nm and 193.7 ± 1.5 nm, respectively. The zeta potentials of nonredox-sensitive and redox-sensitive NPs were +24.99 ± 2.67 mV and +9.095 ± 1.87 mV, respectively. The developed NPs were characterized for morphological and various physicochemical parameters such as SEM, TEM, XRD, DSC, TGA, XPS, etc. The % entrapment efficiency of PLB@PLGA-NPs and RS-PLB@PLGA-NPs was found to be 85.48 ± 1.29% and 87.72 ± 1.55%, respectively. RS-PLB@PLGA-NPs displayed a rapid drug release at acidic pH and a higher GSH concentration compared to PLB@PLGA-NPs. The cytotoxicity assay in MCF-7 cells suggested that PLB@PLGA-NPs and RS-PLB@PLGA-NPs were 5.24-fold and 14.53-fold higher cytotoxic compared to the free PLB, respectively. Further, the cellular uptake study demonstrated that redox-sensitive NPs had significantly higher cellular uptake compared to nonredox-sensitive NPs and free Coumarin 6 dye. Additionally, AO/EtBr assay and reactive oxygen species analysis confirmed the superior activity of RS-PLB@PLGA-NPs over PLB@PLGA-NPs and free PLB. In vivo anticancer activity in dimethyl-benz(a)anthracene-induced breast cancer rats depicted that RS-PLB@PLGA-NPs was highly effective in reducing the tumor size, hypoxic tumor, and tumor vascularity compared to PLB@PLGA-NPs and free PLB. Further, hemocompatibility study reveals that the developed NPs were nonhemolytic to human blood. Moreover, an in vivo histopathology study confirmed that both nanoparticles were safe and nontoxic to the vital organs.

Exploring in vivo combinatorial chemo-immunotherapy: Addressing p97 suppression and immune reinvigoration in pancreatic cancer with tumor microenvironment-responsive nanoformulation

Pancreatic ductal adenocarcinoma (PDAC) has an extremely devastating nature with poor prognosis and increasing incidence, making it a formidable challenge in the global fight against cancer-related mortality. In this innovative preclinical investigation, the VCP/p97 inhibitor CB-5083 (CB), miR-142, a PD-L1 inhibitor, and immunoadjuvant resiquimod (R848; R) were synergistically encapsulated in solid lipid nanoparticles (SLNs). These SLNs demonstrated features of peptides targeting PD-L1, EGFR, and the endoplasmic reticulum, enclosed in a pH-responsive polyglutamic (PGA)-polyethylene glycol (PEG) shell. The homogeneous size and zeta potential of the nanoparticles were stable for 28 days at 4°C. The study substantiated the concurrent modulation of key pathways by the CB, miR, and R-loaded nanoformulation, prominently affecting VCP/Bip/ATF6, PD-L1/TGF-β/IL-4, −8, −10, and TNF-α/IFN-γ/IL-1, −12/GM-CSF/CCL4 pathways. This adaptable nanoformulation induced durable antitumor immune responses and inhibited Panc-02 tumor growth by enhancing T cell infiltration, dendritic cell maturation, and suppressing Tregs and TAMs in mice bearing Panc-02 tumors. Furthermore, tissue distribution studies, biochemical assays, and histological examinations highlighted enhanced safety with PGA and peptide-modified nanoformulations for CB, miR, and/or R in Panc-02-bearing mice. This versatile nanoformulation allows tailored adjustment of the tumor microenvironment, thereby optimizing the localized delivery of combined therapy. These compelling findings advocate the potential development of a pH-sensitive, three-in-one PGA-PEG nanoformulation that combines a VCP inhibitor, a PD-L1 inhibitor, and an immunoadjuvant for cancer treatment via combinatorial chemo-immunotherapy.

Disparities in Child Protective Services Reporting Among Pregnant Patients With Positive Urine Drug Screening at Delivery Hospitalization [ID 2683555

INTRODUCTION: This study assesses predictors of Child Protective Services (CPS) reporting among patients with a positive urine drug screening (UDS) during delivery hospitalization. METHODS: Patients receiving prenatal care and delivering at any UCHealth location between 2015 and 2022 with a positive UDS at delivery were included. Patient demographics, medical history, UDS, infant toxicology, and CPS reporting were collected from medical records. T-tests or nonparametric equivalents for continuous variables and χ2 or Fisher's exact tests for categorical variables were used to compare patients with and without CPS reporting. RESULTS: We found 523 patients with a positive UDS during their delivery hospitalization, with CPS reporting for 71%. CPS reporting was more common in younger patients (26 versus 28 years; P<.01), patients with prior CPS involvement (15% versus 5%; P<.01), patients with an antenatal UDS positive for any substance (46% versus 29%; P<.01), and any positive neonatal toxicology (87% versus 58%; P<.01). Patients positive for cannabis (78% versus 57%; P<.01) or amphetamines (6% versus 1%; P=.03) were more likely to be reported to CPS, while patients positive for barbiturates (12% versus 1%; P<.01) and benzodiazepines (6% versus 2%; P<.01) were less likely. Hospitals located in large (>400k pop.) or small cities (<100k pop.) were less likely to be reported to CPS than mid-sized cities (>100–399k pop.) (66% and 65% versus 76%; P=.03). CONCLUSION: Differences in CPS reporting depended on the substance that tested positive, infant positivity, and delivery location. Future research should explore reasons for no CPS reporting among patients with a positive UDS during delivery hospitalization.