An experimental platform for systemic drug delivery to the retina.
Ontology highlight
ABSTRACT:
SUBMITTER: Campbell M
PROVIDER: S-EPMC2760489 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Neuroprotective drug delivery to the posterior segment of the eye represents a major challenge to counteract vision loss. This work focuses on the development of a polymer-based nanocarrier, specifically designed for targeting the posterior eye. Polyacrylamide nanoparticles (ANPs) were synthesised and characterised, and their high binding efficiency was exploited to gain both ocular targeting and neuroprotective capabilities, through conjugation with peanut agglutinin (ANP:PNA) and neurotrophin nerve growth factor (ANP:PNA:NGF). The neuroprotective activity of ANP:PNA:NGF was assessed in an oxidative stress-induced retinal degeneration model using the teleost zebrafish. Upon nanoformulation, NGF improved the visual function of zebrafish larvae after the intravitreal injection of hydrogen peroxide, accompanied by a reduction in the number of apoptotic cells in the retina. Additionally, ANP:PNA:NGF counteracted the impairment of visual behaviour in zebrafish larvae exposed to cigarette smoke extract (CSE). Collectively, these data suggest that our polymeric drug delivery system represents a promising strategy for implementing targeted treatment against retinal degeneration.
| S-EPMC10144786 | biostudies-literature
Project description:Current delivery platforms are typically designed for prolonged circulation that favors superior accumulation of the payload in the targeted tissue. The design of efficient surface modifications determines both a longer circulation time and targeting abilities of particles. The optimization of synthesis protocols to efficiently combine targeting molecules and elements that allow for an increased circulation time can be challenging and almost impossible when several functional elements are needed. On the other hand, in the last decade, the development of bioinspired technologies was proposed as a new approach with which to increase particle safety, biocompatibility and targeting, while maintaining the synthesis protocols simple and reproducible. Recently, we developed a new drug delivery system inspired by the biology of immune cells called leukolike vector (LLV) and formed by a nanoporous silicon core and a shell derived from the leucocyte cell membrane. The goal of this study is to investigate the protein content of the LLV. Here we report the proteomic profiling of the LLV and demonstrate that our approach can be used to modify the surface of synthetic particles with more than 150 leukocyte membrane associated proteins that determine particle safety, circulation time and targeting abilities towards inflamed endothelium.
| S-EPMC4426090 | biostudies-literature
Project description:An endothelial-lined blood vessel model is obtained in a PDMS (Polydimethylsiloxane) microfluidic system, where vascular endothelial cells are grown under physiological shear stress, allowing -like maturation. This experimental model is employed for enhanced drug delivery studies, aimed at characterising the increase in endothelial permeability upon microbubble-enhanced ultrasound-induced (USMB) cavitation. We developed a multi-step protocol to couple the optical and the acoustic set-ups, thanks to a 3D-printed insonation chamber, provided with direct optical access and a support for the US transducer. Cavitation-induced interendothelial gap opening is then analysed using a customised code that quantifies gap area and the relative statistics. We show that exposure to US in presence of microbubbles significantly increases endothelial permeability and that tissue integrity completely recovers within 45 min upon insonation. This protocol, along with the versatility of the microfluidic platform, allows to quantitatively characterise cavitation-induced events for its potential employment in clinics.
| S-EPMC8229805 | biostudies-literature
Project description:Current drug-delivery systems are designed primarily for parenteral applications and are either lipid or polymer drug conjugates. In our quest to inhibit herpes simplex virus infection via the compounds found in commonly used cosmetic products, we found that activated carbon particles inhibit infection and, in addition, substantially improve topical delivery and, hence, the efficacy of a common antiviral drug, acyclovir (ACV). Our in vitro studies demonstrate that highly porous carbon structures trapped virions, blocked infection and substantially improved efficacy when ACV was loaded onto them. Also, using murine models of corneal and genital herpes infections, we show that the topical use of drug-encapsulated carbon (DECON) reduced dosing frequency, shortened treatment duration, and exhibited higher therapeutic efficacy than currently approved topical or systemic antivirals alone. DECON is a nontoxic, cost-effective and nonimmunogenic alternative to current topical drug-delivery systems that is uniquely triggered for drug release by virus trapping.
| S-EPMC6693911 | biostudies-literature
Project description:Treatment options for retinal diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and retinal vascular disorders, have markedly expanded following the development of anti-vascular endothelial growth factor intravitreal injection methods. However, because intravitreal treatment requires monthly or bimonthly repeat injections to achieve optimal efficacy, recent investigations have focused on extended drug delivery systems to lengthen the treatment intervals in the long term. Dose escalation and increasing molecular weight of drugs, intravitreal implants and nanoparticles, hydrogels, combined systems, and port delivery systems are presently under preclinical and clinical investigations. In addition, less invasive techniques rather than intravitreal administration routes, such as topical, subconjunctival, suprachoroidal, subretinal, and trans-scleral, have been evaluated to reduce the treatment burden. Despite the latest advancements in the field of ophthalmic pharmacology, enhancing drug efficacy with high ocular bioavailability while avoiding systemic and local adverse effects is quite challenging. Consequently, despite the performance of numerous in vitro studies, only a few techniques have translated to clinical trials. This review discusses the recent developments in ocular drug delivery to the retina, the pharmacokinetics of intravitreal drugs, efforts to extend drug efficacy in the intraocular space, minimally invasive techniques for drug delivery to the retina, and future perspectives in this field.
| S-EPMC7830424 | biostudies-literature
Project description:Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy.
| S-EPMC4972658 | biostudies-literature
Project description:In the pursuit of effective treatments for cancer, an emerging strategy is "active targeting", where nanoparticles are decorated with targeting ligands able to recognize and bind specific receptors overexpressed by tumor cells or tumor vasculature so that a greater fraction of the administered drugs are selectively trafficked to tumor sites. However, the implementation of this strategy has faced a major obstacle. The interpatient, inter- and intra-tumoral heterogeneity in receptor expression can pose challenges for the design of clinical trials and result in the paucity of targetable receptors within a tumor, which limits the effectiveness of "active targeting" strategy in cancer treatment. Here we report a cooperative drug delivery platform that overcomes the heterogeneity barrier unique to solid tumors. The cooperative platform comprises a coagulation-inducing agent and coagulation-targeted polymeric nanoparticles. As a typical small-molecule vascular disrupting agent (VDA), DMXAA can create a unique artificial coagulation environment with additional binding sites in a solid tumor by locally activating a coagulation cascade. Coagulation-targeted cisplatin-loaded nanoparticles, which are surface-decorated with a substrate of activated blood coagulation factor XIII, can selectively accumulate in the solid tumor by homing to the VDA-induced artificial coagulation environment through transglutamination. In vivo studies show that the cooperative tumor-selective platform recruits up to 7.5-fold increases in therapeutic cargos to the tumors and decreases tumor burden with low systemic toxicity as compared with non-cooperative controls. These indicate that the use of coagulation-targeted nanoparticles, in conjunction with free small-molecule VDAs, may be a valuable strategy for improving standard chemotherapy.
| S-EPMC5530016 | biostudies-literature
Project description:Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life, low targeting ability, and association with serious adverse reactions, such as bleeding complications. Inspired by the natural roles of platelets during thrombus formation, we fabricated a platelet-based delivery system (NO@uPA/PLTs) comprising urokinase (uPA) and arginine (Arg) for targeted thrombolysis and inhibition of re-embolism. The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions. Nitric oxide (NO) generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel, thereby inhibiting re-embolism. NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy. In addition, the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury. The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk, providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.
| S-EPMC9279721 | biostudies-literature
Project description:See https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-the-sonotran-platform-for-bowel-cancer-that-has-spread-to-the-liver-ceedd
Background and study aims
This study will look at a new intervention in patients with bowel cancer that has spread to the liver (called colorectal cancer liver metastases (CRLM)). This is required because bowel cancer is very common, and despite best efforts, once CRLM are present, the chances of cure are small. The planned intervention combines specialist ultrasound treatment delivered to the body through the skin over the liver area (SonoTran System), and the injection of microscopic cup-shaped ‘particles’ (SonoTran Particles) that are given into the vein. The hope is that when these two are delivered together (termed the SonoTran Platform) they will help ‘push’ standard cancer drugs deeper into the tumours and increase the effectiveness of those drugs (both standard chemotherapy drugs, and newer larger cancer antibody drugs). The study is split into three parts. In the first part (cohort 1) patients who have received all standard drugs for their bowel cancer, or who are having a break off standard drugs, will receive one ‘treatment’ with the specialist ultrasound (called SonoTran System-SS) and one injection of the SonoTran Particles(SP), in order to assess the safety of the new intervention. In Cohort 2, patients who are about to have their CRLMs removed by surgery will, on the day before, receive one low dose each of the anticancer drugs irinotecan and cetuximab and, in addition, half of the patients will receive an injection of SonoTran Particles and a single 'treatment' with SonoTran ultrasound. The tumours (CRLMs) that are removed will be examined to see how much and how deep the drugs get into them. In Cohort 3, patients who have not yet received treatment for their CRLMs will receive repeated cycles of standard chemotherapy drugs (5-fluoruracil, irinotecan and cetuximab) and half of them will also receive SonoTran particles and SonoTran Ultrasound. Tumour responses will be measured and compared.
Who can participate?
Patients diagnosed with colorectal (bowel) cancer that has spread to the liver. Patients must be over 18 years of age and meet the trial’s specific eligibility criteria to participate in the study. For more information, please contact your GP or oncologist
What does the study involve?
For Cohort 1 (Safety), the researchers are looking at the safety of the SonoTran Platform intervention alone (ultrasound and particles), and no anticancer drugs will be given. During the SonoTran ‘intervention’ phase, patients will receive a long injection (called an infusion) of SonoTran Particles, and an administration of therapeutic SonoTran ultrasound using the SonoTran System. Additional blood samples will be taken for research tests on Day 1; the first sample will be taken immediately before patients receive the SonoTran Particles, and then at set timepoints after the start of the infusion - 15 minutes, 30 minutes, 45 minutes and 60 minutes. Patients will then be asked to return for a follow-up visit on weekly intervals - Day 8, Day 15 and Day 22 after the intervention and receive a physical examination, be asked about symptoms and any other medications, have weight, heart rate, temperature, pulse and blood pressure checked, and have routine blood tests. About 4 weeks after receiving the SonoTran Platform intervention, patients will have an FDG-PET-CT scan, an MRI scan and a CT scan to assess their tumour(s) and the effect of the SonoTran Platform.
In Cohort 2 (Performance), the researchers will investigate whether the SonoTran Platform (the combination of the SonoTran System and SonoTran Particles) can increase the delivery of a couple of routine anticancer drugs to the tumour. To do this the researchers will recruit 6 patients who, the day before their liver operation, will receive two anticancer drugs alone - cetuximab and irinotecan (at lower than standard doses), and another 6 who will receive the same anticancer drugs plus the SonoTran Platform intervention; and the researchers will compare how much of the drugs get into the tumour and how deep they get into the tumour. The researchers will be taking some of the tumour and normal tissue that is taken from the liver at your operation and they will look at the drug levels in the normal and tumour tissue in the liver. Once patients have received the intervention (drugs alone or drugs plus SonoTran Platform intervention), on Day 1, they will return the following day (Day 2) to have their tumour nodule(s) surgically removed from their liver; patients will undergo this procedure as they normally would in standard of care, and taking part in this study will not affect or delay the surgery. Additional blood samples will be taken for research tests on Day 1 and Day 2. Patients will then be asked to return for a follow-up visit on weekly intervals - Day 8, Day 15, Day 22 and on Day 29 (+/- 3 days) after the intervention and receive a physical examination, be asked about symptoms and any other medications, have weight, heart rate, temperature, pulse and blood pressure checked, and have routine blood tests.
Cohort 3 (Efficacy) will make a comparison of response between the two groups of patients; 12 patients will receive the administration of the SonoTran Particles and SonoTran System in addition to the anticancer drugs, and another 12 patients will receive the chemotherapy without the addition of the SonoTran Platform. All patients in Cohort 3 (Efficacy) will receive anticancer drugs that are used routinely in the treatment of metastatic colorectal cancer (mCRC) i.e. cancer that has spread elsewhere outside the bowel. This treatment involves a drug called cetuximab, which is an antibody treatment that blocks a growth factor receptor on tumour cells to help stop them from growing. Patients will also receive two chemotherapy drugs which are called irinotecan and 5-fluorouracil (5FU). The combination of these drugs is called FOLFIRI. During the ‘intervention’ phase of your study involvement, participants will attend the hospital to receive six cycles of this routine cetuximab and FOLFIRI, which will be given at standard doses, every 2 weeks for a 10-week period (six cycles in all). All patients will have a CT scan, MRI scan and PET-CT scan after three ‘cycles’ of anticancer treatment, to assess their tumour and the effect of the drugs (+/- the SonoTran Platform). These scans will be repeated after six cycles of anticancer agents, or sooner if the patient has to come off trial treatment for any other reason. For patients who are receiving chemotherapy drugs AND the SonoTran intervention, additional blood samples will be taken for research tests on every visit they receive intervention – Day 1, Day 15, Day 29, Day 43, Day 57 and Day 71 – one sample will be taken each treatment day about 30 minutes after patients start receiving the SonoTran Particles. Patients will receive a physical examination, be asked about symptoms and any other medications, have their weight, heart rate, temperature, pulse and blood pressure checked, and have routine blood tests at all visits.
| 2412722 | ecrin-mdr-crc
Project description:Immunotherapy has received increasing attention due to its low potential side effects and high specificity. For instance, cancer immunotherapy has achieved great success. CpG is a well-known and commonly used immunotherapeutic and vaccine adjuvant, but it has the disadvantage of being unstable and low in efficacy and needs to be transported through an effective nanocarrier. With perfect structural programmability, permeability, and biocompatibility, DNA nanostructures are one of the most promising candidates to deliver immune components to realize immunotherapy. However, the instability and low capability of the payload of ordinary DNA assemblies limit the relevant applications. Consequently, DNA nanostructure with a firm structure, high drug payloads is highly desirable. In the paper, the latest progress of biostable, high-payload DNA nanoassemblies of various structures, including cage-like DNA nanostructure, DNA particles, DNA polypods, and DNA hydrogel, are reviewed. Cage-like DNA structures hold drug molecules firmly inside the structure and leave a large space within the cavity. These DNA nanostructures use their unique structure to carry abundant CpG, and their biocompatibility and size advantages to enter immune cells to achieve immunotherapy for various diseases. Part of the DNA nanostructures can also achieve more effective treatment in conjunction with other functional components such as aPD1, RNA, TLR ligands.
| S-EPMC6997790 | biostudies-literature