Publications by authors named "Josbert M Metselaar"

74 Publications

Liposomal drug delivery system for anti-inflammatory treatment after cataract surgery: a phase I/II clinical trial.

Drug Deliv Transl Res 2021 Feb 10. Epub 2021 Feb 10.

Singapore National Eye Centre (SNEC), 11 Third Hospital Avenue, Singapore City, 168751, Singapore.

Liposomes as a drug delivery system may overcome the problems associated with non-compliance to eyedrops and inadequate control of inflammation after cataract surgery. We evaluated the safety and efficacy of a single subconjunctival injection of liposomal prednisolone phosphate (LPP) for the treatment of post-cataract surgery inflammation. This is a phase I/II, open-label non-comparative interventional trial of patients undergoing cataract surgery. All patients received a single injection of subconjunctival LPP intraoperatively. The primary outcome measure was the proportion of eyes with an anterior chamber cell count of 0 at postoperative month 1. Ocular and non-ocular adverse events, including elevated intraocular pressure, rebound iritis and pseudophakic macular edema were monitored. Five patients were enrolled in this study. The mean age was 66.6 ± 6.2 and 4 (80%) were male. The proportion of patients with AC cell grading of 0 was 0%, 80%, 80%, and 100% at day 1, week 1, month 1, and month 2 after cataract surgery, respectively. Mean laser flare photometry readings were significantly elevated at week 1 after cataract surgery (48.8 ± 18.9, p = 0.03) compared with baseline, decreasing to 25.8 ± 9.2 (p = 0.04) at month 1 and returned to baseline by month 2 (10.9 ± 5.1, p = 1.0). No ocular or non-ocular adverse events were observed. Liposomal prednisolone phosphate, administered as a single subconjunctival injection intraoperatively, can be a safe and effective treatment for post-cataract surgery inflammation. The delivery of steroids with a liposomal drug delivery system could potentially replace eyedrops as anti-inflammatory therapy following cataract surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13346-021-00912-xDOI Listing
February 2021

A review of the clinical applications of drug delivery systems for the treatment of ocular anterior segment inflammation.

Br J Ophthalmol 2020 Oct 30. Epub 2020 Oct 30.

Singapore National Eye Centre, Singapore

Ocular anterior segment inflammation is a medical problem that is seen in cases of cataract surgery and non-infectious anterior uveitis. Inadequately treated anterior segment inflammation can lead to sight-threatening conditions such as corneal oedema, glaucoma and cystoid macular oedema. The mainstay of treatment for anterior segment inflammation is topical steroid eye-drops. However, several drawbacks limit the critical value of this treatment, including low bioavailability, poor patient compliance, relatively difficult administration manner and risk of blurring of vision and ocular irritation. A drug delivery system (DDS) that can provide increased bioavailability and sustained delivery while being specifically targeted towards inflamed ocular tissue can potentially replace daily eye-drops as the gold standard for management of anterior segment inflammation. The various DDS for anti-inflammatory drugs for the treatment of anterior segment inflammation are listed and summarised in this review, with a focus on commercially available products and those in clinical trials. Dextenza, INVELTYS, Dexycu and Bromsite are examples of DDS that have enjoyed success in clinical trials leading to FDA approval. Nanoparticles and ocular iontophoresis form the next wave of DDS that have the potential to replace topical steroids eye-drops as the treatment of choice for anterior segment inflammation. With the current relentless pace of ophthalmic drug delivery research, the pursuit of a new standard of treatment that eliminates the problems of low bioavailability and patient compliance may soon be realised.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjophthalmol-2020-315911DOI Listing
October 2020

Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer.

Biomaterials 2021 Jan 5;266:120432. Epub 2020 Oct 5.

Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. Electronic address:

Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2020.120432DOI Listing
January 2021

Scale-Up of the Manufacturing Process To Produce Docetaxel-Loaded mPEG--p(HPMA-Bz) Block Copolymer Micelles for Pharmaceutical Applications.

Org Process Res Dev 2019 Dec 29;23(12):2707-2715. Epub 2019 Oct 29.

Department of Bio-Organic chemistry, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.

An efficient, scalable, and good manufacturing practice (GMP) compatible process was developed for the production of docetaxel-loaded poly(ethylene glycol)--poly(-2-benzoyloxypropyl methacrylamide) (mPEG--p(HPMA-Bz)) micelles. First, the synthesis of the mPEG-p(HPMA-Bz) block copolymer was optimized through step-by-step investigation of the batch synthesis procedures. This resulted in the production of 1 kg of mPEG-p(HPMA-Bz) block copolymer with a 5 kDa PEG block and an overall molecular weight of 22.5 kDa. Second, the reproducibility and scalability of micelle formation was investigated for both batch and continuous flow setups by assessing critical process parameters. This resulted in the development of a new and highly efficient continuous flow process, which led to the production of 100 mL of unloaded micelles with a size of 55 nm. Finally, the loading of the micelles with the anticancer drug docetaxel was successfully fine-tuned to obtain precise control on the loaded micelle characteristics. As a result, 100 mL of docetaxel-loaded micelles (20 mg/mL polymer and 5 mg/mL docetaxel in the feed) with a size of 55 nm, an encapsulation efficiency of 65%, a loading capacity of 14%, and stable for at least 2 months in water at room temperature were produced with the newly developed continuous flow process. In conclusion, this study paves the way for efficient and robust large-scale production of docetaxel-loaded micelles with high encapsulation efficiencies and stability, which is crucial for their applicability as a clinically relevant drug delivery platform.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.oprd.9b00387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493301PMC
December 2019

Dexamethasone nanomedicines for COVID-19.

Nat Nanotechnol 2020 08;15(8):622-624

Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41565-020-0752-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116110PMC
August 2020

A Doxorubicin-Glucuronide Prodrug Released from Nanogels Activated by High-Intensity Focused Ultrasound Liberated β-Glucuronidase.

Pharmaceutics 2020 Jun 10;12(6). Epub 2020 Jun 10.

Division of Imaging and Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

The poor pharmacokinetics and selectivity of low-molecular-weight anticancer drugs contribute to the relatively low effectiveness of chemotherapy treatments. To improve the pharmacokinetics and selectivity of these treatments, the combination of a doxorubicin-glucuronide prodrug (DOX-propGA3) nanogel formulation and the liberation of endogenous β-glucuronidase from cells exposed to high-intensity focused ultrasound (HIFU) were investigated in vitro. First, a DOX-propGA3-polymer was synthesized. Subsequently, DOX-propGA3-nanogels were formed from this polymer dissolved in water using inverse mini-emulsion photopolymerization. In the presence of bovine β-glucuronidase, the DOX-propGA3 in the nanogels was quantitatively converted into the chemotherapeutic drug doxorubicin. Exposure of cells to HIFU efficiently induced liberation of endogenous β-glucuronidase, which in turn converted the prodrug released from the DOX-propGA3-nanogels into doxorubicin. β-glucuronidase liberated from cells exposed to HIFU increased the cytotoxicity of DOX-propGA3-nanogels to a similar extend as bovine β-glucuronidase, whereas in the absence of either bovine β-glucuronidase or β-glucuronidase liberated from cells exposed to HIFU, the DOX-propGA3-nanogels hardly showed cytotoxicity. Overall, DOX-propGA3-nanogels systems might help to further improve the outcome of HIFU-related anticancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics12060536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355552PMC
June 2020

Systematic evaluation of design features enables efficient selection of Π electron-stabilized polymeric micelles.

Int J Pharm 2020 Jun 7;584:119409. Epub 2020 May 7.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Uniklinik RWTH Aachen and Helmholtz Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands. Electronic address:

Polymeric micelles (PM) based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) loaded with paclitaxel (PTX-PM) have shown promising results in overcoming the suboptimal efficacy/toxicity profile of paclitaxel. To get insight into the stability of PTX-PM formulations upon storage and to optimize their in vivo tumor-targeted drug delivery properties, we set out to identify a lead PTX-PM formulation with the optimal polymer composition. To this end, PM based on four different mPEG-b-p(HPMA-Bz) block copolymers with varying molecular weight of the hydrophobic block (17-3 kDa) were loaded with different amounts of PTX. The hydrodynamic diameter was 52 ± 1 nm for PM prepared using polymers with longer hydrophobic blocks (mPEG-b-p(HPMA-Bz) and mPEG-b-p(HPMA-Bz)) and 39 ± 1 nm for PM composed of polymers with shorter hydrophobic blocks (mPEG-b-p(HPMA-Bz) and mPEG-b-p(HPMA-Bz)). The best storage stability and the slowest PTX release was observed for PM with larger hydrophobic blocks. On the other hand, smaller sized PM of shorter mPEG-b-p(HPMA-Bz) showed a better tumor penetration in 3D spheroids. Considering better drug retention capacity of the mPEG-b-p(HPMA-Bz) and smaller size of the mPEG-b-p(HPMA-Bz) as two desirable design features, we argue that PM based on these two polymers are the lead candidates for further in vivo studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2020.119409DOI Listing
June 2020

Challenges in nanomedicine clinical translation.

Drug Deliv Transl Res 2020 06;10(3):721-725

Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, 52074, Aachen, Germany.

New nanomedicine formulations and novel applications of nanomedicinal drugs are reported on an almost daily basis. While academic progress and societal promise continue to shoot for the stars, industrial acceptance and clinical translation are being looked at increasingly critically. We here discuss five key challenges that need to be considered when aiming to promote the clinical translation of nanomedicines. We take the perspective of the end-stage users and consequently address the developmental path in a top-down manner. We start off by addressing central and more general issues related to practical and clinical feasibility, followed by more specific preclinical, clinical, and pharmaceutical aspects that nanomedicinal product development entails. We believe that being more aware of the end user's perspective already early on in the nanomedicine development path will help to better oversee the efforts and investments needed, and to take optimally informed decisions with regard to market opportunities, target disease indication, clinical trial design, therapeutic endpoints, preclinical models, and formulation specifications. Critical reflections on and careful route planning in nanomedicine translation will help to promote the success of nanomedicinal drugs. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13346-020-00740-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228980PMC
June 2020

Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection.

Transplantation 2020 04;104(4):744-753

Department of Internal Medicine, Division of Nephology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect.

Methods: Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis.

Results: Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45 cells, and reduced numbers of F4/80 macrophages, and CD3 T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice.

Conclusions: Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147400PMC
April 2020

Development and characterization of liposomal formulation of bortezomib.

Int J Pharm X 2019 Dec 23;1:100011. Epub 2019 Mar 23.

Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.

Bortezomib is a proteasome inhibitor used for the treatment of multiple myeloma. The poor pharmacokinetic profile and off-target adverse effects provide a strong incentive to develop drug delivery systems for bortezomib. In the past, liposomal encapsulation has been proven to improve the therapeutic index of a variety of anti-neoplastic therapeutics. Here, we developed and characterized liposomal bortezomib formulations in order to find the most optimal loading conditions. Polyols were used to entrap bortezomib inside the liposomes as boronate ester via a remote loading strategy. Effect of various polyols, incubation duration, temperature, and total lipid concentration on loading efficiency was examined. Moreover, the effect of drug/lipid ratio on the release kinetics was studied. Loading efficiency was maximal when using meglumine plus mannitol as entrapping agents. Loading at room temperature was better than at 60 °C and loading efficiency was increased with increasing total lipid concentrations. There was a positive correlation between drug/lipid ratio and released amount of bortezomib. release kinetics in HBS and human plasma showed time dependent release. In HBS, at 4 °C, only 20% of the drug was released in three weeks, whereas at 37 °C 85% of the drug was released in 24 h. In human plasma, 5% of the drug retained after 24 h indicating faster release. Taken together, the most favorable liposomal formulation of bortezomib should be further exploited to study and efficacy performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpx.2019.100011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733293PMC
December 2019

ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer.

Sci Adv 2019 09 4;5(9):eaax2770. Epub 2019 Sep 4.

Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, Faculty of Science and Technology, University of Twente, Enschede, Netherlands.

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aax2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726450PMC
September 2019

Liposome-induced hypersensitivity reactions: Risk reduction by design of safe infusion protocols in pigs.

J Control Release 2019 09 8;309:333-338. Epub 2019 Jul 8.

Nanomedicine Research and Education Center, Department of Pathophysiology, Semmelweis University, Budapest, Hungary; SeroScience Ltd, Cambridge, MA, Budapest, Hungary; Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary. Electronic address:

Intravenous administration of liposomal drugs can entail infusion reactions, also known as hypersensitivity reactions (HSRs), that can be severe and sometimes life-threatening in a small portion of patients. One empirical approach to prevent these reactions consists of lowering the infusion speed and extending the infusion time of the drug. However, different liposomal drugs have different levels of reactogenicity, which means that the optimal protocol for each liposomal drug may differ and should be identified and evaluated to make the treatment as safe and convenient as possible. The goal of the present study was to explore the use of pigs for the above purpose, using PEGylated liposomal prednisolone (PLP) as a model drug. We compared the reactogenicities of bolus versus infusion protocols involving 2-, 3- and 4-step dose escalations for a clinically relevant total dose, also varying the duration of infusions. The strength of HSRs was measured via continuous recording of hemodynamic parameters and blood thromboxane B2 levels. We showed that bolus administration or rapid infusion of PLP caused transient changes in systemic and pulmonary blood pressure and heart rate, most notably pulmonary hypertension with paralleling rises in plasma thromboxane B2. These adverse responses could be significantly reduced or eliminated by slow infusion of PLP, with the 3-h 3-step dose escalation protocol being the least reactogenic. These data suggest that the pig model enables the development of safe infusion protocols for reactogenic nanomedicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.07.005DOI Listing
September 2019

Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma.

J Control Release 2019 02 22;296:232-240. Epub 2019 Jan 22.

Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address:

Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.01.028DOI Listing
February 2019

Effect of Formulation and Processing Parameters on the Size of mPEG- b-p(HPMA-Bz) Polymeric Micelles.

Langmuir 2018 12 26;34(50):15495-15506. Epub 2018 Nov 26.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science , Utrecht University , 3508 TB Utrecht , The Netherlands.

Micelles composed of block copolymers of poly(ethylene glycol)- b-poly( N-2-benzoyloxypropyl methacrylamide) (mPEG- b-p(HPMA-Bz)) have shown great promise as drug-delivery carriers due to their excellent stability and high loading capacity. In the present study, parameters influencing micelle size were investigated to tailor sizes in the range of 25-100 nm. Micelles were prepared by a nanoprecipitation method, and their size was modulated by the block copolymer properties such as molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content, as well as formulation and processing parameters. It was shown that the micelles have a core-shell structure using a combination of dynamic light scattering and transmission electron microscopy analysis. By varying the degree of polymerization of the hydrophobic block ( N) between 68 and 10, at a fixed hydrophilic block mPEG ( N = 114), it was shown that the hydrophobic core of the micelle was collapsed following the power law of ( N × N). Further, the calculated brush height was similar for all the micelles examined (10 nm), indicating that crew-cut micelles were made. Both addition of homopolymer and preparation of micelles at lower concentrations or lower rates of addition of the organic solvent to the aqueous phase increased the size of micelles due to partitioning of the hydrophobic homopolymer chains to the core of the micelles and lower nucleation rates, respectively. Furthermore, it was shown that by using different solvents, the size of the micelles substantially changed. The use of acetone, acetonitrile, ethanol, tetrahydrofuran, and dioxane resulted in micelles in the size range of 45-60 nm after removal of the organic solvents. The use of dimethylformamide and dimethylsulfoxide led to markedly larger sizes of 75 and 180 nm, respectively. In conclusion, the results show that by modulating polymer properties and processing conditions, micelles with tailorable sizes can be obtained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.8b03576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333397PMC
December 2018

Comparative analysis of nanosystems' effects on human endothelial and monocytic cell functions.

Nanotoxicology 2018 11 28;12(9):957-974. Epub 2018 Sep 28.

a Section of Experimental Oncology and Nanomedicine (SEON), ENT Department , University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg , Germany.

The objective of our work was to investigate the effects of different types of nanoparticles on endothelial (HUVEC) and monocytic cell functions. We prepared and tested 14 different nanosystems comprising liposomes, lipid nanoparticles, polymer, and iron oxide nanoparticles. Some of the tested nanosystems contained targeting, therapeutic, or contrast agent(s). The effect of particles (0-400 µg/mL) on endothelial-monocytic cell interactions in response to TNF-α was investigated using an arterial bifurcation model and dynamic monocyte adhesion assay. Spontaneous HUVEC migration (0-100 µg/mL nanoparticles) and chemotaxis of monocytic cells towards MCP-1 in presence of particles (0-400 µg/mL) were determined using a barrier assay and a modified Boyden chamber assay, respectively. Lipid nanoparticles dose-dependently reduced monocytic cell chemotaxis and adhesion to activated HUVECs. Liposomal nanoparticles had little effect on cell migration, but one formulation induced monocytic cell recruitment by HUVECs under non-uniform shear stress by about 50%. Fucoidan-coated polymer nanoparticles (25-50 µg/mL) inhibited HUVEC migration and monocytic cell chemotaxis, and had a suppressive effect on monocytic cell recruitment under non-uniform shear stress. No significant effects of iron oxide nanoparticles on monocytic cell recruitment were observed except lauric acid and human albumin-coated particles which increased endothelial-monocytic interactions by 60-70%. Some of the iron oxide nanoparticles inhibited HUVEC migration and monocytic cell chemotaxis. These nanoparticle-induced effects are of importance for vascular cell biology and function and must be considered before the potential clinical use of some of the analyzed nanosystems in cardiovascular applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17435390.2018.1502375DOI Listing
November 2018

From design to the clinic: practical guidelines for translating cardiovascular nanomedicine.

Cardiovasc Res 2018 11;114(13):1714-1727

INSERM U1148, LVTS, Paris Diderot University, Paris 13 University, X. Bichat Hospital, 46 rue H. Huchard, Paris, France.

Cardiovascular diseases (CVD) account for nearly half of all deaths in Europe and almost 30% of global deaths. Despite the improved clinical management, cardiovascular mortality is predicted to rise in the next decades due to the increasing impact of aging, obesity, and diabetes. The goal of emerging cardiovascular nanomedicine is to reduce the burden of CVD using nanoscale medical products and devices. However, the development of novel multicomponent nano-sized products poses multiple technical, ethical, and regulatory challenges, which often obstruct their road to successful approval and use in clinical practice. This review discusses the rational design of nanoparticles, including safety considerations and regulatory issues, and highlights the steps needed to achieve efficient clinical translation of promising nanomedicinal products for cardiovascular applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvy219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198738PMC
November 2018

Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization.

Front Pharmacol 2018 17;9:790. Epub 2018 Jul 17.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.

The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effective dose, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several experimental challenges need to be addressed. This review will discuss the current trends and challenges in the clinical translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clinical development of NNMs will be covered, including biological challenges, large-scale manufacturing, biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056679PMC
July 2018

Evaluation of subconjunctival liposomal steroids for the treatment of experimental uveitis.

Sci Rep 2018 04 26;8(1):6604. Epub 2018 Apr 26.

Singapore National Eye Centre (SNEC), 11 Third Hospital Avenue, Singapore, 168751, Singapore.

Non-infectious anterior uveitis (AU) is a potentially sight threatening inflammatory condition. The current gold standard for treatment is topical steroids, but low ocular bioavailability and compliance issues with the intensive dosing regimen limit the efficacy of this treatment. Liposomes as a drug delivery system may help to overcome these problems. We studied the efficacy of a PEG-liposomal formulation of liposomal steroids, administered as a single subconjunctival dose, in the treatment of experimental uveitis in rabbit eyes. Rabbits that received subconjunctival liposomal triamcinolone acetonide phosphate (LTAP) or liposomal prednisolone phosphate (LPP) had significantly lower mean inflammatory scores than untreated controls on Day 4 after induction of uveitis (LPP vs controls, p = 0.049) and 8 (LPP vs controls, p = 0.007; LTAP vs controls, p = 0.019), and lower scores than rabbits given topical PredForte1% 4 times a day on Day 8 (p = 0.03). After antigen rechallenge, the subconjunctival liposomal steroid groups continued to have greater suppression of inflammation than untreated controls on Day 11 (p = 0.02). Localization of liposomes in inflamed ocular tissue was confirmed by histology and immunostaining, and persisted in the eye for at least one month. Our study demonstrates that a single subconjunctival injection of liposomal steroids induces effective and sustained anti-inflammatory action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24545-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919899PMC
April 2018

Imaging fibroblast activation protein to monitor therapeutic effects of neutralizing interleukin-22 in collagen-induced arthritis.

Rheumatology (Oxford) 2018 04;57(4):737-747

Department of Experimental Rheumatology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.

Objectives: RA is a chronic autoimmune disease leading to progressive destruction of cartilage and bone. RA patients show elevated IL-22 levels and the amount of IL-22-producing Th cells positively correlates with the extent of erosive disease, suggesting a role for this cytokine in RA pathogenesis. The purpose of this study was to determine the feasibility of SPECT/CT imaging with 111In-labelled anti-fibroblast activation protein antibody (28H1) to monitor the therapeutic effect of neutralizing IL-22 in experimental arthritis.

Methods: Mice (six mice/group) with CIA received anti-IL-22 or isotype control antibodies. To monitor therapeutic effects after treatment, SPECT/CT images were acquired 24 h after injection of 111In-28H1. Imaging results were compared with macroscopic, histologic and radiographic arthritis scores.

Results: Neutralizing IL-22 before CIA onset effectively prevented arthritis development, reaching a disease incidence of only 50%, vs 100% in the control group. SPECT imaging showed significantly lower joint tracer uptake in mice treated early with anti-IL-22 antibodies compared with the control-treated group. Reduction of disease activity in those mice was confirmed by macroscopic, histological and radiographic pathology scores. However, when treatment was initiated in a later phase of CIA, progression of joint pathology could not be prevented.

Conclusion: These findings suggest that IL-22 plays an important role in CIA development, and neutralizing this cytokine seems an attractive new strategy in RA treatment. Most importantly, SPECT/CT imaging with 111In-28H1 can be used to specifically monitor therapy responses, and is potentially more sensitive in disease monitoring than the gold standard method of macroscopic arthritis scoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kex456DOI Listing
April 2018

In Vitro Evaluation of Anti-Aggregation and Degradation Behavior of PEGylated Polymeric Nanogels under In Vivo Like Conditions.

Macromol Biosci 2018 01 20;18(1). Epub 2017 Nov 20.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, 52074, Aachen, Germany.

The in vivo stability and biodegradability of nanocarriers crucially determine therapeutic efficacy as well as safety when used for drug delivery. This study aims to evaluate optimized in vitro techniques predictive for in vivo nanocarrier behavior. Polymeric biodegradable nanogels based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) and with various degrees of PEGylation and crosslinking densities are prepared. Three techniques are chosen and refined for specific in vitro evaluation of the nanocarrier performance: (1) fluorescence single particle tracking (fSPT) to study the stability of nanogels in human plasma, (2) tangential flow filtration (TFF) to study the degradation and filtration of nanogel degradation products, and (3) fluorescence fluctuation spectroscopy (FFS) to evaluate and compare the degradation behavior of nanogels in buffer and plasma. fSPT results demonstrate that nanogels with highest PEGylation content show the least aggregation. The TFF results reveal that nanogels with higher crosslink density have slower degradation and removal by filtration. FFS results indicate a similar degradation behavior in human plasma as compared to that in phosphate buffered saline. In conclusion, three methods can be used to compare and select the optimal nanogel composition, and these methods hold potential to predict the in vivo performance of nanocarriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.201700127DOI Listing
January 2018

Local delivery of liposomal prednisolone leads to an anti-inflammatory profile in renal ischaemia-reperfusion injury in the rat.

Nephrol Dial Transplant 2018 Jan;33(1):44-53

Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Treatment of inflammatory kidney diseases with systemic high-dose glucocorticoids (GCs) has severe side effects. Liposomal encapsulation could facilitate local delivery of GCs to the inflamed kidney, as liposomes encapsulate their payload until extravasation at sites of inflammation, potentially resulting in local bioactivity. Our aim was to evaluate the ability of liposomes to accumulate locally after renal ischaemia-reperfusion injury in the rat and to study its effect on macrophages.

Methods: In vitro, human macrophages were incubated with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was studied microscopically and treatment effect was assessed by interkeukin 6 (IL-6) enzyme-linked immunosorbent assay. The mechanism of action was evaluated by analysing GC receptor activation by microscopy and quantitative polymerase chain reaction (qPCR). In vivo, rats were subjected to ischaemia-reperfusion injury and were injected intravenously with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was measured by the FLARE camera and the treatment effect by immunohistochemistry for myeloid cells and qPCR for inflammatory markers.

Results: In vitro, macrophages internalized liposomes after 8 hours. Prednisolone or liposomal prednisolone treatment reduced IL-6 production and both compounds induced translocation of the GC receptor to the nucleus and upregulation of PER1 messenger RNA (mRNA), indicating a similar mechanism of action. In vivo, fluorescent liposomes accumulated in the inflamed kidney. Liposomal prednisolone treatment increased the presence of ED2-positive anti-inflammatory macrophages and both prednisolone and liposomal prednisolone reduced monocyte chemoattractant protein-1 (MCP-1) mRNA production, indicating a reduced pro-inflammatory profile in the kidney.

Conclusions: Liposomal encapsulation is a promising strategy for local delivery of glucocorticoids to the inflamed kidney.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfx204DOI Listing
January 2018

A systematic comparison of clinically viable nanomedicines targeting HMG-CoA reductase in inflammatory atherosclerosis.

J Control Release 2017 Sep 9;262:47-57. Epub 2017 Jul 9.

Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CG, The Netherlands; Imaging Division, University Medical Centre Utrecht, Utrecht 3584 CX, The Netherlands. Electronic address:

Atherosclerosis is a leading cause of worldwide morbidity and mortality whose management could benefit from novel targeted therapeutics. Nanoparticles are emerging as targeted drug delivery systems in chronic inflammatory disorders. To optimally exploit nanomedicines, understanding their biological behavior is crucial for further development of clinically relevant and efficacious nanotherapeutics intended to reduce plaque inflammation. Here, three clinically relevant nanomedicines, i.e., high-density lipoprotein ([S]-HDL), polymeric micelles ([S]-PM), and liposomes ([S]-LIP), that are loaded with the HMG-CoA reductase inhibitor simvastatin [S], were evaluated in the apolipoprotein E-deficient (Apoe) mouse model of atherosclerosis. We systematically employed quantitative techniques, including in vivo positron emission tomography imaging, gamma counting, and flow cytometry to evaluate the biodistribution, nanomedicines' uptake by plaque-associated macrophages/monocytes, and their efficacy to reduce macrophage burden in atherosclerotic plaques. The three formulations demonstrated distinct biological behavior in Apoe mice. While [S]-PM and [S]-LIP possessed longer circulation half-lives, the three platforms accumulated to similar levels in atherosclerotic plaques. Moreover, [S]-HDL and [S]-PM showed higher uptake by plaque macrophages in comparison to [S]-LIP, while [S]-PM demonstrated the highest uptake by Ly6C monocytes. Among the three formulations, [S]-PM displayed the highest efficacy in reducing macrophage burden in advanced atherosclerotic plaques. In conclusion, our data demonstrate that [S]-PM is a promising targeted drug delivery system, which can be advanced for the treatment of atherosclerosis and other inflammatory disorders in the clinical settings. Our results also emphasize the importance of a thorough understanding of nanomedicines' biological performance, ranging from the whole body to the target cells, as well drug retention in the nanoparticles. Such systematic investigations would allow rational applications of nanomaterials', beyond cancer, facilitating the expansion of the nanomedicine horizon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2017.07.013DOI Listing
September 2017

Applying nanomedicine in maladaptive inflammation and angiogenesis.

Adv Drug Deliv Rev 2017 09 12;119:143-158. Epub 2017 May 12.

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

Inflammation and angiogenesis drive the development and progression of multiple devastating diseases such as atherosclerosis, cancer, rheumatoid arthritis, and inflammatory bowel disease. Though these diseases have very different phenotypic consequences, they possess several common pathophysiological features in which monocyte recruitment, macrophage polarization, and enhanced vascular permeability play critical roles. Thus, developing rational targeting strategies tailored to the different stages of the journey of monocytes, from bone marrow to local lesions, and their extravasation from the vasculature in diseased tissues will advance nanomedicine. The integration of in vivo imaging uniquely allows studying nanoparticle kinetics, accumulation, clearance, and biological activity, at levels ranging from subcellular to an entire organism, and will shed light on the fate of intravenously administered nanomedicines. We anticipate that convergence of nanomedicines, biomedical engineering, and life sciences will help to advance clinically relevant therapeutics and diagnostic agents for patients with chronic inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682240PMC
September 2017

Liposome encapsulated berberine treatment attenuates cardiac dysfunction after myocardial infarction.

J Control Release 2017 02 5;247:127-133. Epub 2017 Jan 5.

Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Electronic address:

Inflammation is a known mediator of adverse ventricular remodeling after myocardial infarction (MI) that may lead to reduction of ejection fraction and subsequent heart failure. Berberine is a isoquinoline quarternary alkaloid from plants that has been associated with anti-inflammatory, anti-oxidative, and cardioprotective properties. Its poor solubility in aqueous buffers and its short half-life in the circulation upon injection, however, have been hampering the extensive usage of this natural product. We hypothesized that encapsulation of berberine into long circulating liposomes could improve its therapeutic availability and efficacy by protecting cardiac function against MI in vivo. Berberine-loaded liposomes were prepared by ethanol injection and characterized. They contained 0.3mg/mL of the drug and were 0.11μm in diameter. Subsequently they were tested for IL-6 secretion inhibition in RAW 264.7 macrophages and for cardiac function protection against adverse remodeling after MI in C57BL/6J mice. In vitro, free berberine significantly inhibited IL-6 secretion (IC=10.4μM), whereas encapsulated berberine did not as it was not released from the formulation in the time frame of the in vitro study. In vivo, berberine-loaded liposomes significantly preserved the cardiac ejection fraction at day 28 after MI by 64% as compared to control liposomes and free berberine. In conclusion, liposomal encapsulation enhanced the solubility of berberine in buffer and preserves ejection fraction after MI. This shows that delivery of berberine-loaded liposomes significantly improves its therapeutic availability and identifies berberine-loaded liposomes as potential treatment of adverse remodeling after MI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2016.12.042DOI Listing
February 2017

Docosahexaenoic acid liposomes for targeting chronic inflammatory diseases and cancer: an in vitro assessment.

Int J Nanomedicine 2016;11:5027-5040. Epub 2016 Oct 5.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht.

Inflammation, oxidative stress, and uncontrolled cell proliferation are common key features of chronic inflammatory diseases, such as atherosclerosis and cancer. ω3 polyunsaturated fatty acids (PUFAs; also known as omega3 fatty acids or fish oil) have beneficial effects against inflammation upon dietary consumption. However, these effects cannot be fully exploited unless diets are enriched with high concentrations of fish oil supplements over long periods of time. Here, a nanomedicine-based approach is presented for delivering effective levels of PUFAs to inflammatory cells. Nanoparticles are internalized by immune cells, and hence can adequately deliver bioactive lipids into these target cells. The ω3 FA docosahexaenoic acid was formulated into liposomes (ω-liposomes), and evaluated for anti-inflammatory effects in different types of immune cells. ω-Liposomes strongly inhibited the release of reactive oxygen species and reactive nitrogen species from human neutrophils and murine macrophages, and also inhibited the production of the proinflammatory cytokines TNFα and MCP1. Moreover, ω-liposomes inhibited tumor-cell proliferation when evaluated in FaDu head and neck squamous carcinoma and 4T1 breast cancer cells in in vitro cultures. We propose that ω-liposomes are a promising nanonutraceutical formulation for intravenous delivery of fish oil FAs, which may be beneficial in the treatment of inflammatory disorders and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S115995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063558PMC
January 2017

In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage-Mediated Clearance from the Bone Marrow.

J Nucl Med 2017 02 4;58(2):214-220. Epub 2016 Aug 4.

Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites.

Methods: In vivo localization of In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small-animal SPECT/CT and ex vivo biodistribution studies. Mice were treated with liposomal clodronate to investigate the effect of macrophage depletion on tracer localization and drug clearance in vivo. Moreover, macrophage cell line models RAW264.7 and THP-1, as well as knockout mice, were used to identify the cellular and molecular components controlling asparaginase pharmacokinetics.

Results: In vivo imaging and biodistribution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the liver, spleen, and in particular bone marrow. Clodronate-mediated depletion of phagocytic cells markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these macrophage-rich organs. Immunohistochemistry and in vitro binding assays confirmed the involvement of macrophagelike cells in the uptake of asparaginase. We identified the activity of the lysosomal protease cathepsin B in macrophages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo.

Conclusion: We showed that asparaginase is rapidly cleared from the serum by liver-, spleen-, and bone marrow-resident phagocytic cells. As a consequence of this efficient uptake and protease-mediated degradation, particularly bone marrow-resident macrophages may provide a protective niche to leukemic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.116.177741DOI Listing
February 2017

Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody.

J Nucl Med 2017 Jan 4;58(1):151-155. Epub 2016 Aug 4.

Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis.

Methods: Collagen-induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of Tc-labeled succinimidyl-hydrazinonicotinamide (Tc-S-HYNIC)-conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of Tc-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores.

Results: Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL. Tc-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman ρ, 0.77; P < 0.0001). Moreover, the uptake of Tc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method.

Conclusion: SPECT/CT imaging with Tc-S-HYNIC-28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with Tc-S-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.116.177931DOI Listing
January 2017

Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model.

Sci Rep 2016 07 27;6:30439. Epub 2016 Jul 27.

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep30439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962038PMC
July 2016