Controlled Release Devices Research Articles

Hydrogels in Biomedicine: Granular Controlled Release Systems Based on 2-Hydroxyethyl Methacrylate Copolymers. A Review

The article analyzes and summarizes the latest achievements in the field of polymer systems for controlled release devices based on hydrogel materials. Possible directions of drug delivery are presented, including the use of granular hydrogels, which work on the principle of drug sorption − release in the body. The research on the synthesis regularities, structure, properties, and prospects for the use of granular hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and its copolymers, in particular with polyvinylpyrrolidone (PVP), as systems for the controlled release of substances, in particular, drugs, is analyzed.

A Comprehensive Review on Transformative Role of Polymer in Advancing Pharmaceutical Drug Delivery System

: The present analysis study emphasizes the polymers that are used to deliver therapeutic agents through pharmaceutical drugs. Among such dosage forms are tablets, patches, cassettes, films, semi-solids, and powders. The use of biodegradable polymers is becoming more and more common. They can degrade into non-toxic monomers, and, more significantly, they can be used to make controlled-release devices that release medications at a steady rate. Natural polymers may facilitate the distribution of medications at predetermined rates. Their readily available nature and advantageous physico-chemical characteristics make them a good candidate for use in drug delivery systems. Due to their well-established biocompatibility and biodegradability, biodegradable polymers possess extensive application within the biomedical field. In the biomedical sector, polymers are typically utilized as implants because of their ability to provide long-term capabilities. These advancements help to lessen adverse effects and other side effects while simultaneously increasing the effectiveness of healthcare. The suffering that the sick endure. Polymers are mainly used to extend the release period of pharmaceuticals and shield them against physiological circumstances. The polymer releases medication to promote swelling, breakdown, and diffusion. The review also presents mucoadhesive functions and characteristics. Systems for delivering medications already make use of plant-based polymers.

K+ Ions Crosslinked Kappa-Carrageenan/Methylene Blue Composite Film. Part-1: Synthesis, Characterization and Application as Controlled Release Device for Photodynamic Therapy Application

K+ ions crosslinked (KC/MB) Methylene blue photosensitizer loaded composite film is prepared for photodynamic therapy (PDT) application as Photosensitizer released by composite film can conveniently be controlled by using different quantities of K+ ions and this application is based on dynamic interaction between light with suitable wavelength, photosensitizer and molecular oxygen, promoting the death of the target tissue or bacterial cells. In this work, the Methylene Blue (MB) loaded Carrageenan polymeric film was prepared by the method of direct addition of MB into pre-polymerization solution of Carrageenan (KC). This composite film and plain KC film were characterized by FTIR, XRD and SEM analysis. The characteristic peaks of MB photosensitizer were obtained in FTIR spectrum of composite film. The composite film KC/MB shows prominence of amorphous nature may be due to MB is present in very small quantity. The SEM analysis reveals that the composite film (KC/MB) having much more smooth surface texture throughout the film. Finally, the result of effect of variation in degree of crosslinking on amount of MB release is, as the amount of K+ ions used to crosslink the film increases, MB release decreases.

Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

Differing planes of nutrition alter serum and histotroph amino acid composition in nonpregnant, multiparous beef cows on day 3 of the estrous cycle.

Endometrial-derived uterine histotroph is a critical component of nutrient supply to a growing conceptus throughout gestation; however, the effect of nutritional plane on histotroph nutrient composition remains unknown in multiparous cows. We hypothesized that differing planes of nutrition would alter histotroph and serum nutrient composition in beef cattle. Thus, we evaluated serum and histotroph amino acid and glucose composition, and serum non-esterified fatty acids (NEFA) and blood urea nitrogen (BUN) in cows individually fed to maintain body weight (BW; 0 kd/d, n = 9; CON) compared with those losing moderate BW (-0.7 kg/d, n = 9; NEG). After 49 d of differing nutritional planes, cows were subjected to the 7-d CoSynch + controlled internal drug release device estrus synchronization protocol and then slaughtered on day 62. Blood serum (days 0 and 62) and uterine histotroph [day 62; from uterine horns ipsilateral and contralateral to the corpus luteum (CL)] were collected and analyzed for concentrations of amino acids, glucose, and NEFA. Performance characteristics, body composition via ultrasound (days 0 and 62), and carcass characteristics were collected. Body condition score, change in BW, average daily gain, dry matter intake, and gain:feed were decreased (P ≤ 0.05) in NEG vs. CON cows. There were no differences in body composition or carcass characteristics, except an increase (P ≤ 0.05) in dressing percentage in NEG cows due to differences in gut fill, consistent with study design. Serum NEFA increased (P ≤ 0.05) in the NEG group, but there were no differences between NEG vs. CON in glucose or BUN. Serum histidine increased (P ≤ 0.05) and alanine, isoleucine, and tryptophan decreased (P ≤ 0.05) in NEG vs. CON cows. Compared with that of the uterine horn ipsilateral to the CL, histotroph from the uterine horn contralateral to the CL had increased (P ≤ 0.05) isoleucine, asparagine, and proline concentrations in NEG cows, and decreased (P ≤ 0.05) tryptophan as a proportion of essential and total amino acids. There were no differences in glucose concentrations of histotroph contralateral or ipsilateral to the CL. Cow nutritional plane does alter serum and histotroph amino acid composition, although the presence of an embryo may be necessary to fully elucidate these changes. Differences in serum and histotroph tryptophan should be given consideration in future studies due to its importance as an essential amino acid in protein synthesis and bioactive affects.

Multiloaded drug delivery devices for the treatment of glaucoma

(rociohv@ucm.es)Glaucoma is a leading cause of blindness worldwide. In this neurodegenerative disease, a progressive death of retinal ganglion cells (RGC) and a glaucomatous optic disc neuropathy occurs which lead to visual impairment. Increase of Intraocular pressure (IOP) is a major risk factor strongly associated with retinal degeneration although a non IOP‐dependent neurodegeneration also occurs. Neurodegeneration process observed in glaucoma and other chronic retinal diseases occurs through different pathways: glutamate‐induced RGC cytotoxicity, apoptosis, neurotrophic factors deprivation, oxidative stress, calcium channel alteration and inflammation, among others. Due to the multifactorial character of the disease there is special interest in designing treatments able to include a combination of active agents in the same formulation. Unlike treatment to control IOP, which acts on the anterior segment of the eye and it can be administered topically, the applicability of neuroprotective therapies requires the administration of the active substances near to the retinal tissues using intraocular injections. Furthermore, due to the chronicity of the disease frequents administrations are required to reach and maintain therapeutic concentrations in the target site.Intraocular drug delivery systems are able to provide effective concentrations inside the eye for long term, thus reducing the number of interventions. Among the controlled release devices, implants (>1 mm) and microparticles (1–1000 μm), are capable of releasing the active substance in the vicinity of the retina for extended periods of time. Furthermore, if they are prepared with biodegradable polymers as the case of poly‐(lactic‐co‐glycolic) (PLGA), they have the advantage of disappearing from the site of administration after releasing the drug. Moreover, the final products of these biodegradable biomaterials result well tolerated and are finally eliminated from the body. Among the intraocular drug delivery devices, microspheres present a lot of advantages as they can be administered as a suspension in the vitreous using small gauge needles (30‐32G) without the need to surgery or stitches, which is more comfortable for ophthalmologists and patients, also reducing the risk of infection. Microspheres can be loaded with different agents that can be delivered simultaneously during long term. Another interesting advantage of microspheres is that, by being able to easily modify the amount of microparticles to be administered, they become very useful tools for personalized therapies. Thus, with these microsystems the number of administrations could be considerably reduced, spacing them even several months.Bravo‐Osuna I., Andrés‐Guerrero V., Arranz‐Romera A., Esteban‐Pérez S., Molina‐Martínez I.T., Herrero‐Vanrell R. Microspheres as intraocular therapeutic tools in chronic diseases of the optic nerve and retina. (2018) Advanced drug delivery reviews 126, 127–144.Acknowledgments: Grants PID2020‐113281RB‐C21 and PID2020‐113281RB‐C22 funded by MCIN/AEI/ 10.13039/501100011033; N° 813440 (ORBITAL– Ocular Research by Integrated Training and Learning).

An Ultrasoft and Flexible PDMS-Based Balloon-Type Implantable Device for Controlled Drug Delivery.

Non-biodegradable implants have undergone extensive investigation as drug delivery devices to enable advanced healthcare toward personalized medicine. However, fibroblast encapsulation is one of the major challenges in all non-biodegradable implants, besides other challenges such as high initial burst, risk of membrane rupture, high onset time, non-conformal contact with tissues, and tissue damage. To tackle such challenges, we propose a novel ultrasoft and flexible balloon-type drug delivery device for unidirectional and long-term controlled release. The ultrasoft balloon-type device (USBD) was fabricated by using selective bonding between 2 polydimethylsiloxane (PDMS) membranes and injecting a fluid into the non-bonded area between them. The balloon acted as a reservoir containing a liquid drug, and at the same time, the membrane of the balloon itself acted as the pathway for release based on diffusion. The release was modulated by tuning the thickness and composition of the PDMS membrane. Regardless of the thickness and composition, all devices exhibited zero-order release behavior. The longest zero-order release and nearly zero-order release were achieved for 30 days and 58 days at a release rate of 1.16 μg/day and 1.68 μg/day, respectively. Invivo evaluation was performed for 35 days in living rats, where the USBD maintained zero-order and nearly zero-order release for 28 days and 35 days, respectively. Thanks to the employment of ultrasoft and flexible membranes and device design, the USBD could achieve minimal tissue damage and foreign body responses. It is expected that the proposed device may provide a novel approach for long-term drug delivery with new therapeutic modalities.

A Review on the Role of Polymers in Pharmaceutical Drug Delivery System

Abstract : This review article focuses on polymers of therapeutic agents used in pharmaceuticals. These dosage forms include e.g tablets, patches, tapes, films, semi-solids and powders. As such, polymers are the backbone of pharmaceutical drug delivery systems check the release of the drug from the device. Biodegradable polymers draw attention to its use because they can degrade Based on a biodegradable polymer, non-toxic monomers and, most importantly, a constant drug release rate can be achieved. controlled release device. Natural polymers can be used as a tool to achieve predetermined drug release rates and these Physicochemical properties and easy availability create a platform for its use as a polymer in drug delivery systems. Biodegradable polymers have been widely used in biomedical applications due to their known biocompatibility and biodegradability In the biomedical field, polymers are often used as implants and are expected to function for a long time. These improvements improve the effectiveness of treatment and minimize side effects and other types harm to patients. The main function of the polymer is to protect the drug from the physiological environment and prolong the release of the drug improve its stability. The drug is released from the polymer by diffusion, degradation and swelling. In addition to this review presents Properties and behavior of plant-based and mucoadhesive polymers currently used for drug delivery.

Advancements in red propolis: a technological prospection for antimicrobial applications

The red propolis is a bee product with great biotechnological potential due to its antimicrobial and therapeutic properties. The present study used technological mapping to investigate the antimicrobial activities of red propolis in patents deposited in Brazil (INPI) and in international databases such as the European Patent Office (Espacenet) and World Intellectual Property Organization (WIPO). The results indicated that Brazil holds the highest number of patents related to red propolis, and propolis produced in Alagoas was the most cited. Class A61K was the most frequent, suggesting strong therapeutic potential, especially in dental applications. Public universities were the main patent depositors, with institutions in Alagoas standing out. The data also revealed potential for patent deposits in areas such as agriculture and new pharmaceutical applications, including the production of controlled-release devices and the synthesis of nanomaterials. Red propolis is a promising raw material for the development of products with antimicrobial activity, and the deposited patents indicate a growing interest in exploring its properties in various areas, including the pharmaceutical industry and agriculture.

Injectable On-Demand Pulsatile Drug Delivery Hydrogels Using Alternating Magnetic Field-Triggered Polymer Glass Transitions.

Remote-controlled pulsatile or staged release has significant potential in a wide range of therapeutic treatments. However, most current approaches are hindered by the low resolution between the on- and off-states of drug release and the need for surgical implantation of larger controlled-release devices. Herein, we describe a method that addresses these limitations by combining injectable hydrogels, superparamagnetic iron oxide nanoparticles (SPIONs) that heat when exposed to an alternating magnetic field (AMF), and polymeric nanoparticles with a glass transition temperature (Tg) just above physiological temperature. Miniemulsion polymerization was used to fabricate poly(methyl methacrylate-co-butyl methacrylate) (p(MMA-co-BMA)) nanoparticles loaded with a model hydrophobic drug and tuned to have a Tg value just above physiological temperature (∼43 °C). Co-encapsulation of these drug-loaded nanoparticles with SPIONs inside a carbohydrate-based injectable hydrogel matrix (formed by rapid hydrazone cross-linking chemistry) enables injection and immobilization of the nanoparticles at the target site. Temperature cycling facilitated a 2.5:1 to 6:1 on/off rhodamine release ratio when the nanocomposites were switched between 37 and 45 °C; release was similarly enhanced by exposing the nanocomposite hydrogel to an AMF to drive heating, with enhanced release upon pulsing observed even 1 week after injection. Coupled with the apparent cytocompatibility of all of the nanocomposite components, these injectable nanocomposite hydrogels are promising as minimally invasive but remotely actuated release delivery vehicles capable of complex release kinetics with high on-off resolution.

Polymers Used In Novel Drug Delivery System

This review focus on the role of polymers used in novel drug delivery system of therapeutic agents. The polymers are used as carriers for delivery of drug at target site. These dosage forms include tablets, patches, tapes, films, semisolids and powders. Polymers are the backbone of a pharmaceutical drug delivery system as they control the release of the drug from the device. Biodegradable polymers attracts the attention of its use as they can be degraded to non‐toxic monomers and most important, a constant rate of drug release can be achieved from a biodegradable polymer based controlled release device.

Synergistic Approaches in the Design and Applications of UCST Polymers.

This review summarizes recent progress in the synergistic design strategy for thermoresponsive polymers possessing an upper critical solution temperature (UCST) in aqueous systems. To achieve precise control of the responsive behavior of the UCST polymers, their molecular design can benefit from a synergistic effect of hydrogen bonding with other interactions or modification of the chemical structures. The combination of UCST behavior with other stimuli-responsive properties of the polymers may yield new functional materials with potential applications such as sensors, actuators, and controlled release devices. The advances in this area provide insight or inspiration into the understanding and design of functional UCST polymers for a wide range of applications.

Novel Approach for a Controlled Delivery of Essential Oils during Long-Term Maize Storage: Clove Bud and Pennyroyal Oils Efficacy to Control Sitophilus zeamais, Reducing Grain Damage and Post-Harvest Losses

Maize grains represent a significant contribution for assuring food safety all over the globe. Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae), also known as the maize weevil, is one of the most destructive pests in stored maize, causing qualitative and quantitative losses. To control S. zeamais populations in maize storage sites, synthetical chemical insecticides are applied. However, these are often used wastefully, have environmental implications, and can induce the development of resistant populations. In this work, the insecticidal and grain protecting efficacy of an innovative macro-capsule delivery device, loaded with essential oils from Clove bud and Pennyroyal, as well as their combined solutions, was tested against naturally S. zeamais-infested maize grains. The blend of both compounds incorporated in a controlled release device reduced losses by more than 45% over a long storage period of twenty weeks, diminishing the survivability of maize weevils by over 90%. The usage of the blend at a concentration of 370 μL⋅Lair-1 with an antioxidant showed the best results, however, by halving the concentration (185 μL⋅Lair-1), a significant control of S. zeamais populations was still achieved.

Controlled release devices as adjuvants in nonsurgical periodontal therapy: A systematic review.

Controlled release devices (CRD) have been widely studied regarding their application in periodontal therapy. Therefore, the present study aims to evaluate the use and effectiveness of controlled-release devices in nonsurgical periodontal therapy through a systematic review. The research was carried out in six different databases, namely: Online Medical Literature Search and Analysis System (Medline-PubMed), Web of Science, Science Direct, Scopus, Scielo, and Google Scholar. The descriptors "Delayed-Action Preparation," "Therapeutics," and "Periodontitis," were used with their EntryTerms and connected through the Boolean operators AND and OR. A total of 2847 studies were found, and after applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist flowchart, 34 were selected using the eligibility criteria. After that, the qualitative results were tabulated and the risk of bias in each of them was evaluated. It can be observed that the use of CRD presents itself as a successful alternative for adjuvant treatment to periodontal therapy, a fact due to its availability and local concentration in the crevicular fluid. However, further clinical research is still needed to develop devices that are effective, with an easy and quick application, as well as available at a good cost-benefit ratio.

Semi-field evaluation of a novel controlled release device using transfluthrin as spatial repellent to prevent entry of mosquitoes into military tents

Mosquitoes can impact military operational readiness by transmission of disease-causing pathogens or through secondary effects, e.g., annoyance and bites. The focus of this research was to determine if an array of novel controlled release passive devices (CRPD) utilizing the spatial repellent, transfluthrin (TF), as the active ingredient could prevent entry of mosquitoes into military tents for up to 4 weeks. The TF-charged CRPDs were spaced along six strands of monofilament and hung across the tent entrance. Efficacy was evaluated with caged Aedes aegypti to indicate knockdown/mortality effects, and four species of free-flying mosquitoes, Ae. aegypti, Aedes taeniorhynchus, Anopheles quadrimaculatus and Culex quinquefasciatus, to indicate repellent effects. Bioassay cages containing Ae. aegypti were hung vertically at 0.5, 1.0 and 1.5 ​m above ground level at designated locations inside of the tents. Knockdown/mortality counts were made every 15 min for the first hour, then at 2, 4 and 24 h post-exposure. Free fliers were recaptured in BG traps operated from 4 to 24 h post-exposure. Knockdown/mortality was gradual until 4 h post-exposure. This increased to near 100% by 24 h in the treated tent but was < 2% in the control tent. There was a significant reduction in the recapture rates of all free-flying species in the treated tent compared with the control tent. Results indicate that TF-charged CRPDs can significantly reduce the numbers of mosquitoes entering military tents and that the four species were affected similarly by the TF. The needs for additional research are discussed.

Release of ranibizumab using a porous poly(dimethylsiloxane) capsule suppressed laser-induced choroidal neovascularization via the transscleral route

The administration of anti-vascular endothelial growth factor drugs in the posterior eye segment with sustained release through less invasive methods is a challenge in the treatment of age-related macular disease. We developed a flexible capsule device using porous poly(dimethylsiloxane) (PDMS) that was able to release ranibizumab. The porous PDMS sheet was fabricated by salt-leaching of a micro-sectioned PDMS sheet containing salt microparticles. Observation with scanning electron microscopy revealed that the pore densities could be adjusted by the concentration of salt. The in vitro release study showed that the release rate of fluorescein isothiocyanate-tagged albumin could be adjusted based on the pore density of the porous PDMS sheet. Ranibizumab could be released in a sustained-release manner for 16 weeks. The device was implanted on the sclera; its efficacy in terms of the suppression of laser-induced choroidal neovascularization (CNV) in rats was compared with that of monthly intravitreal injections of ranibizumab. At 8 and 18 weeks after implantation, the CNV area was significantly reduced in rats that received the ranibizumab-releasing device compared with those that received the placebo device. However, although monthly intravitreal injections of ranibizumab reduced CNV for 8 weeks, this reduction was not sustained for 18 weeks. In conclusion, we demonstrated a novel controlled-release device using a porous PDMS sheet that could suppress CNV via a less invasive transscleral route versus intravitreal injections. This device may also reduce the occurrence of side effects associated with frequent intravitreal injections.Graphical

Novel formulations in the treatment of glaucoma

AbstractNeuroprotective therapy in glaucoma is gaining a lot of interest to be used alone or simultaneously with the control of intraocular pressure (IOP). Neuronal degeneration process occurs through different pathways. For this reason, effective neuroprotection of retinal ganglion cells (RGC) and other retinal cells in glaucoma must be performed according to different targets. Recently, there is special interest in designing treatments able to include a combination of active agents in the same formulation.Treatments destined to lower IOP, in which the target is the anterior segment of the eye are administered topically. By the contrary, neuroprotective therapies require the administration of the active substances close to the retinal tissues as well as their maintenance during long term. Since the last decades the development of intraocular drug delivery systems (IDDS) has emerged as therapeutic tools to provide therapeutic concentrations inside the eye during long term, thus reducing the number of injections. Among the controlled release devices, implants (&gt;1 mm) and microparticles (1–1000 μm), are capable of releasing the active substance during long time. Furthermore, if they are prepared with biodegradable polymers, they have the advantage of disappearing from the site of administration after releasing the drug. There are currently two biodegradable implants in the clinical practice to avoid frequent administrations. One of them is loaded with dexamethasone (Ozurdex®) for intravitreal injection and Durysta™ administered in the anterior chamber. Both devices are prepared from the biopolymers derived from the lactic and glycolic acid poly‐(lactic‐co‐glycolic) acid, named as PLGA. The final products of this biodegradable biomaterial result well tolerated and they are finally eliminated from the body.Despite the advantages of the commercialized biodegradable implants, they did not allow personalized therapy and microparticles (mainly PLGA microspheres) are under investigation as therapeutic platforms for intraocular purposes(1). One of their main advantages is that they can be administered as a suspension in the vitreous using small gauge needles (30‐32G). Another interesting advantage of microspheres is that, by being able to easily modify the amount of microparticles to be administered, they become very useful tools for personalized therapies.Microspheres allow to incorporate several drugs in the same device providing a simultaneous delivery of the active substances, resulting of special interest in multifactorial diseases(2). Furthermore, the amount of injected polymer in the co‐loaded device resulted lower compared to single‐loaded systems.Acknowledgements‐Grant: PID2020‐113281RB‐C21 funded by MCIN/AEI/ 10.13039/501100011033, Research Group UCM 920415 “Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal)” and the ISCII‐FEDER RETICS (OFTARED) (RD16/0008/0004 and RD16/0008/0009).

Field Evaluation of Novel Spatial Repellent Controlled Release Devices (CRDs) against Mosquitoes in an Outdoor Setting in the Northern Peruvian Amazon.

U.S. military troops are exposed to mosquito-borne pathogens when deployed to endemic regions. Personal protective measures such as permethrin-treated uniforms and dermal repellents are the cornerstones of mosquito-borne disease prevention for the U.S. military. These measures have limitations and additional personal protection tools, such as spatial repellent devices to decrease the risk of vector-borne pathogen transmission, are required. Novel spatial repellent controlled-release devices formulated with metofluthrin were evaluated in an outdoor setting in the northern Amazon of Peru to evaluate performance under field conditions. The metofluthrin emitting devices lowered the number of mosquitoes captured in protected human landing collections (HLC) compared to blank devices, although there were effect differences between Anopheles spp. and species in other mosquito genera. A computational-experimental model was developed to correlate HLC and active ingredient (AI) concentrations as a function of time and space. Results show a strong correlation between the released AI and the decrease in HLC. This model represents the first effort to obtain a predictive analytical tool on device performance using HLC as the entomological endpoint.

Nanopore Generation in Biodegradable Silk/Magnetic Nanoparticle Membranes by an External Magnetic Field for Implantable Drug Delivery.

Implantable devices for localized and controlled drug release are important, e.g., for therapies of cancer and chronic pain. However, most of the existing active implants are limited by the usage of nonbiodegradable materials; thus, surgery is needed to extract them after the treatment, which leads to secondary damage. Here, we show a fully biodegradable composite membrane made from silk fibroin and magnetic nanoparticles (MNPs). The membrane porosity can be remotely modified by an alternating magnetic field, which opens nanopores by local heating of MNPs in the composite allowing a liquid to diffuse through them. The stability of the silk membrane in water can be prolonged up to several months by increasing its β-sheet content through ethanol annealing. We present the following original findings. (a) Nanopores can be generated inside the silk/MNP composite membrane by exposing it to an external alternating magnetic field. (b) A longer exposure time results in more nanopore sites. (c) The controllable release of rhodamine B dye is achieved by tuning the period of exposure to the magnetic field. The obtained results demonstrate the suitability of the investigated silk/MNP composite membrane as a potential functional material for implantable drug delivery.

Abstract 4196: A controlled drug release device facilitates the identification of favorable combinations of immune-oncology drugs with targeted or cytotoxic drugs in a patient-derived humanized mouse model of renal cancer

Abstract Identifying how to optimally combine immunotherapies with other available anti-cancer therapies is a major challenge in oncology. We have utilized an implantable microdevice performing cassette microdosing that measures intratumor drug responses and anti-tumor immunity for eleven agents in parallel. Local tumor response is measured by cyclical immunofluorescence for deep cellular response phenotyping. This approach is combined with the systemic administration of checkpoint inhibitors to examine whether local immunogenic cell death (ICD) induced by a given drug microdose potentiates the immunotherapy’s anti-tumor effect. The measurements were performed in a humanized mouse model of clear cell renal cancer, patient derived xenograft (PDX) RXF488. RXF488 was implanted subcutaneously in 30 NSG mice. Animals were stratified into 6 groups with n= 4-6. Humanization was performed by the intravenous injection of 5x10e6 human peripheral blood mononuclear cells prior to the first treatment. Systemic anti-PD1 treatment was applied in the presence and absence of the microdevice loaded with eleven different drugs. Control groups received the empty microdevice in the presence or absence of PBMC. Beside the histological examination of the tumor tissue, flow cytometry (FC) was performed on bone marrow, spleen and tumor tissue to determine infiltration of human immune cells. FC analyses revealed no influence of the treatment on the human immune cells in bone marrow and spleen. The anti-PD1 treatment induced an increase in huCD45+ cells specifically in the tumor tissue only 48h after treatment. Several agents showed a significant increase in apoptosis induction when nivolumab was added: The largest increase was observed for the panRAF inhibitor LXH254, Sorafenib, Oxaliplatin and Doxorubicin. The increased efficacy from immunotherapy administration has a strong positive correlation with increased induction of ICD in the tumor microenvironment determined by CD11b, ICAM-1 and MHC-II expression: drugs that showed the highest increase in apoptosis when combined with aPD-1 showed an increased likelihood for markers associated with ICD, namely Oxaliplatin and LXH254. We were able to verify the results of the screening experiment in a conventional setting with systemic combination treatment arms in the same PDX model. Our results demonstrate that local tumor response signatures of ICD can be used to systemically identify synergistic combinations of a range of drugs with immunotherapy on a tumor specific basis. The approach may represent a new paradigm for efficient in vivo screening of novel combinations, particularly with combinations involving immunotherapies. Citation Format: Oliver Jonas, Eva Oswald, Kanstantsin Lashuk, Sebastian Ahn, Julia Schüler. A controlled drug release device facilitates the identification of favorable combinations of immune-oncology drugs with targeted or cytotoxic drugs in a patient-derived humanized mouse model of renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4196.