Local Drug Delivery Research Articles

Bioinspired intratumoral infusion port catheter improves local drug delivery in the liver.

Tumor immune modulation can be achieved using intratumoral injection of different immunomodulators during different phases of the cancer-immunity cycle. Intratumoral infusion catheters have been used in brain tumors, but these are not suitable outside the brain, where breathing motion results in catheter migration. Here, we use microstereolithography to manufacture a barbed sidehole catheter, modeled after the barbs in a bee stinger, where the barbs maintain the catheter position in the tumor, and sideholes within the barbs infuse drug into tumor tissue. In pig liver, we demonstrated 183-fold higher local drug concentration using the barbed sidehole catheter, compared to intravenous injection of water-soluble drug. High resistance sideholes and pulsatile injection both generate higher pressure in the catheter, which overcomes the tissue pressure, resulting in more drug delivery into tumor. A physical model of intratumoral infusion catheters accurately predicts the observed drug delivery results. Our catheter design is retained in the liver (and does not migrate out with breathing motion), and it preferentially infuses the drug into tumor tissue (not intratumoral vessels).

Prospective and challenges of locally applied repurposed pharmaceuticals for periodontal tissue regeneration

Periodontitis is a persistent inflammatory condition that causes periodontal ligament degradation, periodontal pocket development, and alveolar bone destruction, all of which lead to the breakdown of the teeth’s supporting system. Periodontitis is triggered by the accumulation of various microflora (especially anaerobes) in the pockets, which release toxic substances and digestive enzymes and stimulate the immune system. Periodontitis can be efficiently treated using a variety of techniques, both regional and systemic. Effective therapy is dependent on lowering microbial biofilm, minimizing or eradicating pockets. Nowadays, using local drug delivery systems (LDDSs) as an adjuvant therapy to phase I periodontal therapy is an attractive option since it controls drug release, resulting in improved efficacy and lesser adverse reactions. Choosing the right bioactive agent and mode of delivery is the foundation of an efficient periodontal disease management approach. The objective of this paper is to shed light on the issue of successful periodontal regeneration, the drawbacks of currently implemented interventions, and describe the potential of locally delivered repurposed drugs in periodontal tissue regeneration. Because of the multiple etiology of periodontitis, patients must get customized treatment with the primary goal of infection control. Yet, it is not always successful to replace the lost tissues, and it becomes more challenging as the defect gets worse. Pharmaceutical repurposing offers a viable, economical, and safe alternative for non-invasive, and predictable periodontal regeneration. This article clears the way in front of researchers, decision-makers, and pharmaceutical companies to explore the potential, effectiveness, and efficiency of the repurposed pharmaceuticals to generate more economical, effective, and safe topical pharmaceutical preparations for periodontal tissue regeneration.

Abstract 4125106: Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis; A Meta-Analysis.

Background: Internationally, drug-coated balloons have emerged as a new treatment approach in In-Stent Restenosis (ISR) offering localized drug delivery to inhibit neointimal growth without the need for additional stent layers. However, their use has not been assessed or approved in the United States. Paclitaxel-coated balloons (PCBs) are gaining traction as alternatives for in-stent restenosis patients. Yet, their safety and effectiveness compared to uncoated balloons remain uncertain. This meta-analysis seeks to systematically assess PCBs' safety and efficacy for ISR treatment by comparing them to uncoated balloons. Research Question: Are paclitaxel-coated balloons (PCBs) superior to uncoated balloons (UCBs) in terms of safety and efficacy for the treatment of coronary in-stent restenosis (ISR)? Aims: Systematically assess the safety and efficacy of paclitaxel-coated balloons (PCBs) compared to uncoated balloons (UCBs) for the treatment of coronary in-stent restenosis (ISR). Methods: A comprehensive literature review was conducted utilizing multiple databases up to May 2024, focusing on randomized controlled trials comparing PCB vs UCB in patients with coronary in-stent restenosis. Six randomized controlled trials with a total of 1,347 patients who completed 1-year follow-up were included. Dichotomous data were calculated as odds ratios (ORs) and 95% confidence intervals (95% CI). P<0.05 was considered to indicate a statistically significant difference. The primary outcomes included Target Lesion Revascularization (TLR), Myocardial Infarction (MI), Stent Thrombosis (ST) and Total Mortality (TM). Results: Compared with patients who underwent UCB angioplasty, those in the PCB group exhibited a clear superiority in TLR [odds ratio (OR), 0.21; 95% CI [ 0.11,0.41]; P<0.00001], and MI [odds ratio (OR), 0.55; 95% CI [0.33,0.91]; P<0.02]. ST was numerically lower in the PCB arm without statistical significance (OR, 0.21; 95% CI [0.03,1.48]; P=0.11). TM was also numerically lower with PCB without reaching statistical significance (OR, 0.60; 95% CI [0.32,1.11]; P=0.10). Conclusion: This meta analysis supports that PCBs are associated with superior outcomes when compared with UCBs in the management of ISR. Paclitaxel-coated balloons are an effective treatment option for patients with coronary in-stent restenosis as demonstrated by superior outcomes in target lesion revascularization and recurrent myocardial infarction.

Intrinsic PD-L1 Degradation Induced by a Novel Self-Assembling Hexapeptide for Enhanced Cancer Immunotherapy.

Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint protein that facilitates tumor immune evasion. While antibody-based PD-1/PD-L1 inhibitors have shown promise, their limitations necessitate the development of alternative therapeutic strategies. This work addresses these challenges by developing a hexapeptide, KFM (Lys-Phe-Met-Phe-Met-Lys), capable of both directly downregulating PD-L1 and self-assembling into a ROS-responsive supramolecular hydrogel. This dual functionality allows Gel KFM to function as a localized drug delivery system and a PD-L1 inhibitor. Loading the hydrogel with mitoxantrone (MTX) and metformin (MET) further enhances the therapeutic effect by combining chemotherapy with PD-L1 downregulation. In vitro and in vivo studies demonstrate significant tumor growth inhibition, increased CD8+ T cell infiltration, and reduced intratumoral PD-L1 expression following peritumoral administration. Mechanistically, KFM promotes PD-L1 degradation via a ubiquitin-dependent pathway. This "carrier-free" delivery system expands the role of supramolecular hydrogels beyond passive carriers to active immunotherapeutic agents, offering a promising new strategy for cancer therapy.

Treatment of chronic osteomyelitis with gradient release of DGEA and vancomycin hydrogel-microsphere system and its mechanism

In recent years, the treatment of chronic osteomyelitis mediated by biodegradable polymer platforms has received increasing attention. This paper reports an advanced drug delivery system, vancomycin (VA) and DGEA loaded microspheres embedded in injectable thermosensitive polypeptide hydrogels (i.e., hydrogel-microsphere (Gel-MP) construct), for continuous release of drugs with different mechanisms and more comprehensive treatment of chronic osteomyelitis. The Gel-MP construct exhibits continuous biodegradability and excellent biocompatibility. Microspheres (MP) are wrapped inside Gel. With the degradation of Gel, VA and MP are released from them, VA released with faster degradation speed, achieving a potent antibacterial effect and effectively controlling infection. Due to the slower degradation rate of MP compared to Gel, subsequently, DGEA is released from MP to induce bone formation and produce the effect of filling bone defects. Compared with other formulations, the in vivo combinational treatment of Gel/VA-MP/DGEA can simultaneously balance antibacterial and osteogenic effects. More importantly, local sustained-release drug delivery systems can significantly mitigate the systemic toxicity of drugs. Therefore, the injection local sequential drug delivery system has broad prospects in the clinical application of treating chronic osteomyelitis.

Dual action tofacitinib-loaded PLGA nanoparticles alleviate colitis in an IBD mouse model.

Inflammatory bowel disease (IBD) affects over 7 million people worldwide and significant side effects are associated with current therapies such as tofacitinib citrate (TFC), which is linked to increased risks of malignancy and congestive heart issues. To mitigate these systemic adverse effects, localised drug delivery via nano-sized carriers to inflamed gut tissues represents a promising approach. Herein, we aimed to optimise the synthesis of nanoparticles (NPs) using a low molecular weight grade of Poly(lactic-co-glycolic acid) (PLGA) 50:50 loaded with TFC. This approach leverages the dual anti-inflammatory action of TFC and the local production of anti-inflammatory short-chain fatty acids from the degradation of PLGA by colonic gut microbiota. NPs were produced by nanoprecipitation and characterised for their drug release profile in vitro. The efficacy of the enhanced PLGA-TFC NPs was then tested in a C57BL/6 DSS colitis mouse model. The release profile of TFC from the enhanced PLGA NPs showed a 40% burst release within the first hour, followed by up to 80% drug release in the colonic environment. Notably, the degradation of PLGA by colonic gut microbiota did not significantly influence TFC release. In the mouse model, neither PLGA NPs alone nor TFC alone showed significant effects on weight loss compared to the TFC-loaded PLGA NPs, emphasising the enhanced efficacy potential of the combined formulation. Altogether, these results suggest a promising role of NP delivery systems in enhancing TFC efficacy, marking a significant step towards reducing dosage and associated side effects in IBD treatment. This study underscores the potential of PLGA-TFC NPs in providing targeted and effective therapy for IBD.

ADVANCING TOPICAL POSACONAZOLE DELIVERY: BOX BEHNKEN DESIGN MICROSPONGE HYDROGEL OPTIMIZATION AND EXTENSIVE IN VIVO INVESTIGATION

Objective: The primary aim of this study was to develop a novel hydrogel formulation containing Posaconazole (PCZ) encapsulated within microsponges. Furthermore, the study aimed to assess the permeation properties of this formulation in vivo using a mouse model. Methods: To achieve this aim, a series of seventeen trials were conducted using the Box Behnken Design methodology. These trials were designed to optimize the production of PCZ Microsponges (PCZ MS), which were subsequently incorporated into a hydrogel matrix. Skin permeation studies were then performed to evaluate the ability of the PCZ microsponge-based hydrogel to deliver the drug across the skin barrier. These studies involved comparison with a standard hydrogel formulation lacking microsponges. Results: This study assessed the efficacy of microsponge gel formulation PM-3 for drug entrapment, yield, and sustained release compared to a conventional gel. PM-3 displayed the highest entrapment efficiency of 98.5% and a yield of 95.62%, indicating a direct correlation with the 1:1 drug-polymer ratio. Moreover, PM-3 exhibited sustained drug release over 12 h, releasing 83.82% of PCZ compared to 65.31% with the normal gel, suggesting its potential for prolonged therapeutic action. These findings underscore the promise of microsponge-based hydrogels, like PM-3, in enhancing therapeutic outcomes through sustained drug release, warranting further exploration for clinical applications. Conclusion: The findings of this study highlight the promising potential of microsponge-based hydrogels as effective carriers for localized drug delivery, particularly in the context of treating skin fungal infections.

Efficacy of Chlorhexidine Chips as Local Drug Delivery in Nonsurgical Management of Chronic Periodontitis: A Systematic Review

Efficacy of Chlorhexidine Chips as Local Drug Delivery in Nonsurgical Management of Chronic Periodontitis: A Systematic Review

Preparation and Evaluation of Poloxamer/Carbopol In-Situ Gel Loaded with Quercetin: In-Vitro Drug Release and Cell Viability Study.

Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20μmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1: poloxamer 407 and X2: carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798mPas), gelation temperature (36°C), gelation time (213s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives

Drug-coated balloons (DCBs) have emerged as an increasingly valuable option for the treatment of coronary artery disease (CAD). Percutaneous coronary intervention (PCI) with DCBs enables the localized delivery of antiproliferative drugs directly to the target coronary lesion, avoiding the need for permanent scaffold implantation. Historically, paclitaxel-coated balloons (PCBs) have been the most used device in this context. Paclitaxel interferes with intracellular microtubule function, leading to cell cycle arrest. However, its cytotoxicity at a higher dosage and narrow therapeutic range has raised some safety concerns. To address these issues, sirolimus-coated balloons (SCBs) have been introduced as an alternative. Sirolimus acts as a cytostatic agent with potent anti-inflammatory and antiproliferative properties and is characterized by a wider therapeutic range, potentially offering a safer profile. Several experimental and clinical studies comparing the safety and efficacy of PCBs versus SCBs have yielded mixed results. Recently, a novel DCB (SirPlux Duo), which simultaneously releases both paclitaxel and sirolimus, has been tested in a porcine coronary model with promising results. In this review, we will elucidate the mechanisms of action of paclitaxel and sirolimus, examine contemporary preclinical and clinical evidence comparing PCB and SCB angioplasty, and discuss novel devices that may enhance the safety and efficacy of PCI with DCBs.

Intranasal liposomal angiotensin-(1-7) administration reduces inflammation and viral load in the lungs during SARS-CoV-2 infection in K18-hACE2 transgenic mice.

To effectively reduce the health impact of coronavirus disease (COVID-19), it is essential to adopt comprehensive strategies to protect individuals from severe acute respiratory syndrome. In that sense, much effort has been devoted to the discovery and repurposing of effective antiviral and anti-inflammatory molecules. The endogenous peptide angiotensin-(1-7) [Ang-(1-7)] has been recently proposed as a promising anti-inflammatory agent to control respiratory infections. Liposomes also emerged as a safe and effective drug carrier system for local drug delivery to the lungs. In this context, the aim of this study was to develop a liposomal formulation of Ang-(1-7) [LAng (1-7)] and investigate its impact on animal survival as well as its antiviral and anti-inflammatory efficacies after intranasal administration in transgenic K18-hACE2 mice infected with SARS-CoV-2. The liposomal formulation was prepared by the ethanol injection method, exhibiting a mean diameter of 100 nm and a polydispersity index of 0.1. Following treatment of infected mice every 12 hours for 5 days, LAng (1-7) extended animal survival compared to the control groups that received either empty liposomes, free Ang-(1-7), or phosphate-buffered saline. Furthermore, the treatment with LAng (1-7) significantly decreased the viral load, as well as IL-6 and tumor necrosis factor levels in the lungs. Conventional treatment with remdesivir by parenteral route used as a positive control promoted similar effects, leading to improved survival rates and reduced viral load in the lungs without significant effects on IL-6 level. In conclusion, liposomal Ang-(1-7) emerges as a promising formulation to improve the treatment and decrease the severity of respiratory infections, such as COVID-19.

Hyaluronic acid dissolving microneedle patch-assisted acupoint transdermal delivery of triptolide for effective rheumatoid arthritis treatment

Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F, has been shown excellent pharmacological effects on rheumatoid arthritis. However, TP is prone to causing severe organ toxicity, which limits its clinical application. In recent years, microneedle technology has provided a new option for the treatment of arthritis due to its advantages of efficient local transdermal drug delivery. In this study, we constructed a microneedle platform to deliver TP locally to the joints, thereby enhancing TP penetration and reducing systemic toxicity. Additionally, we investigated whether acupoint drug delivery can produce a synergistic effect of needles and drugs. First, TP was loaded into microneedles using polyvinylpyrrolidone and hyaluronic acid as matrix materials. Next, we established a rat adjuvant-induced arthritis (AIA) model to evaluate the therapeutic effect of TP-loaded microneedles. The experiments showed that TP-loaded microneedles alleviated the AIA rats’ inflammatory response, joint swelling, and bone erosion. However, there was no significant difference in the therapeutic effect observed in the acupoint and non-acupoint administration groups. In conclusion, TP-loaded microneedles have the advantages of safety, convenience, and high efficacy over conventional administration routes, laying a foundation for the transdermal drug delivery system-based treatment of rheumatoid arthritis.

Formulation and evaluation of herbal gel containing ethanolic extract of Momordica charantia against socransky’s periodontal pathogens of the oral cavity-an in vitro study

Background: Periodontitis is a multifaceted disease initiated by periodontal pathogens which when left untreated results in inflammation of the supporting tissues of the teeth, resorption of alveolar bone, loss of the periodontal ligament attachment, periodontal pocket formation and/or recession of the gingiva. Hence, the current study aimed at evaluating the efficacy of Momordica charantia leaves extract on Socransky’s periodontal pathogens and formulating a herbal gel for subgingival local drug delivery for the potential treatment of moderate periodontitis. Methods: M. charantia leaves were authenticated from a recognized taxonomist. They were coarsely powdered following which an ethanol-based extract preparation was done. The extract obtained was then assessed for minimum inhibitory concentration, minimum bactericidal concentration followed by gel formulation which was then subjected to time kill assay and zone of inhibition on periodontal pathogens, the efficacy of which was comparatively evaluated against 0.12% chlorhexidine (CHX) gluconate. Kruskal-Wallis Test was employed with the statistical significance set at p≤0.05. Results: The concentration of M. charantia ethanolic extract against periodontal pathogens was determined to be 1 gm/100 ml and a statistically significant difference was found in the effectiveness between the gel so formulated and CHX. Conclusion: The antibacterial activity was evident in the ethanolic extract of M. charantia which when used to formulate a herbal gel against anaerobic periodontal pathogens demonstrated efficacy comparable to that of CHX.

A pH-Responsive Ti-Based Local Drug Delivery System for Osteosarcoma Therapy.

Osteosarcoma is one of the major bone cancers, especially for youngsters. The current treatment usually requires systemic chemotherapy and the removal of bone tumors. Titanium (Ti)-based implants can be modified as local drug delivery (LDD) systems for controllable and localized chemotherapeutic drug release. In this work, a pH-responsive Ti-based LDD prototype was designed by introducing polydopamine (PDA) to release doxorubicin (DOX) around osteosarcoma cells with low pH. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and a contact angle meter were applied for surface characterization. Both direct and indirect cell culture modes were performed for biocompatibility and biofunction assessments. The results indicate that the Ti-based LDD prototype exhibits significant pH-dependent DOX release. The cumulative release can reach up to approximately 40% at pH = 6.0 after 72 h, but only around 20% at pH = 7.4. The Ti-based LDD implant shows good biocompatibility with approximately 93% viability of MC3T3 cells after direct culture in vitro for 24 h. Both direct and indirect culture modes verify the good anti-osteosarcoma function of the LDD implant, which should be attributed to the pH-responsive release of DOX.

Magnetic resonance cavitation imaging for the monitoring of ultrasound therapies

Objective.Focused ultrasound (FUS) is a promising non-invasive therapeutic approach that can be used to generate thermal and non-thermal bioeffects. Several non-thermal FUS therapies rely on FUS-induced oscillations of microbubbles (MBs), a phenomenon referred to as cavitation. Cavitation monitoring in real time is essential to ensure both the efficacy and the safety of FUS therapies. This study aims to introduce a new magnetic resonance (MR) method for cavitation monitoring during FUS therapies.Approach.By finely synchronizing the FUS pulse with an accelerated turbo spin-echo MR sequence, the cavitation effect could be quantitatively estimated on the acquired images at 1-Hz refresh rate. The proposed method was assessed in vitro in a water bath. A series of FUS pulses were generated on a silicone tube filled with MBs at different acoustic pressures (0.07-2.07 MPa) and pulse durations (20-2000μs). MR images and passive cavitation detection (PCD) signals were simultaneously acquired for each FUS pulse.Main results.Inertial cavitation was found to induce a quantitatively interpretable signal loss on the MR image. The transition from stable to inertial cavitation was identified on MR cavitation maps with high repeatability. These results were found to be in good agreement with PCD measurements in terms of pressure thresholds between stable and inertial cavitation. MR cavitation imaging was shown to be sensitive to short and even ultrashort FUS pulses, from 2 ms down to 20μs. The presented theoretical model suggests that the signal loss in MR cavitation imaging relies on susceptibility changes related to the diameter of the oscillating MBs.Significance.The proposed MR cavitation imaging method can both locate and characterize cavitation activity. It has therefore the potential to improve the efficacy and safety of FUS therapies, particularly for localized drug delivery applications.

Optimizing revision arthroplasty: the role of customized articulating spacers

Introduction The advancement of surgery is set against a backdrop of continuous development and surgical innovations have transformed the way clinical care is delivered. Revision surgery might be required to address complications of primary arthroplasty. The first stage of revision arthroplasty would involve removal of an implant and placement of an antibiotic-impregnated cement spacer to maintain the joint space and stability, prevent soft tissue retraction, provide local antibiotic release and preserve bone tissue for revision implantation at the final stage of revision. Custom-made articulating spacers are a promising tool for optimizing the first stage of revision arthroplasty.The objective was to summarize the current data and present comprehensive information about spacers used in two-stage revision arthroplasty including manufacturing techniques, physical and chemical properties, clinical applications, the possibility of customization within the first stage of revision arthroplasty, current and promising directions for research.Material and methods The original literature search was conducted on key resources including Scientific Electronic Library (www.elibrary.ru), the National Library of Medicine (www.pubmed.org), the Cochraine Library (www.cochranelibrary.com) between 2018 and 2023 using search words and phrases: total arthroplasty, complications, revision arthroplasty, articulating spacer, periprosthetic joint infection, additive manufacturing, 3D printing.Results A comparative analysis of factory supplied, home-made, dynamic and static spacer models showed that the choice of articulating spacers for revision arthroplasty of major joints is of great relevance. Advantages of factory-made spacers include standardized range of sizes, the reliability and availability for medical institutions. They are characterized by limited use in repair of severe bone defects.Discussion Custom-made articulating spacers enable specific tailoring to accommodate individual defects. Despite high expectations from custom-made spacers, development of optimal technologies for rapid prototyping is essential. Investments in research and development in this area have the potential to create innovative solutions that can significantly improve the results of revision arthroplasty.Conclusion The paper explores the importance of systemization of knowledge about spacers and the role of new research in improving the design and functionality. Progress in the field of materials science, additive technologies and a personalized approach to spacer manufacturing can expand possibilities of revision arthroplasty and the effectiveness. Personalized approaches and improved methods of local drug delivery that provide controlled release of antibiotics can improve the results of treatment of periprosthetic joint infections.

Nanoetched Stainless Steel Architecture Enhances Cell Uptake of Biomacromolecules and Alters Protein Corona Abundancy.

Nanotexture on biocompatible surfaces promotes cell adhesion and proliferation. High aspect ratio nanoachitecture serves as an ideal interface between implant materials and host cells that is well-suited for localized therapeutic delivery. Despite this potential, nanotextured surfaces have not been widely applied for biomacromolecule delivery. Here, we employed a low-cost, industrially relevant nanoetching process to modify the surface of biocompatible stainless steel 316 (SS316L), creating nanotextured SS316L (NT-SS316L) as a material for intracellular biomacromolecule delivery. As biomacromolecule cargoes are adsorbed to the steel and ultimately would be used in protein-rich environments, we performed serum protein corona analysis on unmodified SS316L and NT-SS316L using tandem mass spectrometry. We observed an increase in proteins associated with cell adhesion on the surface of NT-SS316L compared to that of SS316L, supporting literature reports of enhanced adhesion on nanotextured materials. For delivery to adherent cells, a "hard corona" of model biomacromolecule cargoes including superfolder green fluorescent protein (sfGFP) charge variants, cytochrome c, and siRNA was adsorbed on NT-SS316L to assess delivery. Nanotextured surfaces enhanced cellular biomacromolecule uptake and delivered cytosolic-functional proteins and nucleic acids through energy-dependent endocytosis. Collectively, these findings indicate that NT-SS316L holds potential as a surface modification for implants to achieve localized drug delivery for a variety of biomedical applications.

IN VIVO APPLICATION OF LOCAL DRUG DELIVERY SYSTEMS AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL/TERATOID/RHABOID TUMOURS

Abstract AIMS Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas, but to the best of our knowledge, not for the treatment of paediatric cerebellar tumours. Here we report the applicability of an LDDS against medulloblastoma group 3 (MB3) and atypical teratoid/rhaboid tumours (AT/RT), both of which are associated with poor prognoses. METHOD We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)- poly(ethyleneglycol) (PECE) hydrogel, which has been investigated with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and AT/RT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and AT/RT intracranial xenograft surgical resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement, including long-term survivors. Against AT/RT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSION The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For AT/RT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.

Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.

Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.

Guava leaf extract - Phytochemical therapy for periodontitis patients

Introduction: Periodontitis is one of the most prevailing diseases associated with the oral cavity. It is important to treat the disease effectively as it results in tooth loss and also affects the host extensively. Treatment of periodontitis includes various surgical and non-surgical modalities. Non-Surgical modalities include Scaling and Root Planing (SRP), Local Drug Delivery (LDD), laser and HMT therapy. In the present study, the effect of guava leaf extract gel as a local drug delivery agent for the treatment of chronic periodontitis is evaluated. Aim: The aim of this study is to analyze the efficacy of guava gel extract as a local drug delivery agent in patients with periodontitis following scaling and root planing (SRP). Materials and method: A randomized, controlled study was conducted in 21 systemically healthy patients suffering from moderate periodontitis with isolated pockets (pocket depths 45mm). Clinical parameters GI, PI and PPD were recorded at baseline and subsequently after 7th, 14th and 21st day. The study design consisted of three groups, each group having 7 subjects, allocated in these groups randomly. Group A - Guava leaf extract gel (7), Group B – Chlorhexidine group (7), Group C - Control group (7). Results: Both the groups, Group A and Group B showed similar reduction in Gingival Index, Plaque Index and Probing Pocket Depth values when compared at baseline and on 21st day but the differences failed to reach the level of significance. Conclusions: The results suggest that Guava leaf extract gel as a local drug delivery is highly effective and comparable to gold standard.