Showing papers by "Gert Storm published in 2012"
TL;DR: Smart nanocarriers such as pH sensitive nanoccarriers, pre forming liposomes, cell penetrating peptide containing systems and virosomes that can specifically increase the CTL response generating greater antitumor immunity have also been discussed.
190 citations
TL;DR: The potency of a glycoliposome-based vaccine targeting DC-SIGN for CD4(+) and CD8(+) effector T-cell activation is demonstrated and this approach may offer improved options for treatment of cancer patients and opens the way to in situ DC-targeted vaccination.
150 citations
TL;DR: Poly(butyl cyanoacrylate) (PBCA)-based hard-shell MB are shown to be highly suitable systems for image-guided, targeted and triggered drug delivery to tumors and tumor blood vessels.
137 citations
TL;DR: Polymerizable and hydrolytically cleavable dexamethasone derivatives were covalently entrapped in core-cross-linked polymeric micelles that were prepared from a thermosensitive block copolymer.
Abstract: Polymerizable and hydrolytically cleavable dexamethasone (DEX, red dot in picture) derivatives were covalently entrapped in core-cross-linked polymeric micelles that were prepared from a thermosensitive block copolymer (yellow and gray building block). By varying the oxidation degree of the thioether in the drug linker, the release rate of DEX could be controlled. The DEX-loaded micelles were used for efficient treatment of inflammatory arthritis in two animal models.
114 citations
TL;DR: AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobODY-lipOSomes.
84 citations
TL;DR: PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery in vivo with significant gene silencing efficacy found, which was combined with almost no toxicity.
Abstract: Purpose
Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity.
72 citations
Journal Article•
TL;DR: In this paper, a cell-penetrating peptide, which was modified on both termini with an alkyl chain, was anchored to the liposomal surface in a constrained and deactivated form.
Abstract: Herein we report on the development of a novel method of constraining a cell-penetrating peptide, which can be used to trigger transport of liposomes into cells upon in this case radiation with UV-light. A cell-penetrating peptide, which was modified on both termini with an alkyl chain, was anchored to the liposomal surface in a constrained and deactivated form. Since one of the two alkyl chains was connected to the peptide via a UV-cleavable linker, disconnection of this alkyl chain upon irradiation led to the exposure of the cell-penetrating peptide, and mediated the transport of the entire liposome particle into cells.
60 citations
TL;DR: The in vitro model of the inflamed intestinal mucosa demonstrated its ability to differentiate therapeutic efficacy among the formulations while maintaining the convenience of conventional in vitro studies and adequately representing the complex pathophysiological changes observed in vivo.
Abstract: Drug formulation screenings for treatment of inflammatory bowel disease (IBD) are mostly conducted in chemically induced rodent models that represent acute injury-caused inflammation instead of a chronic condition. To accurately screen drug formulations for chronic IBD, a relevant model that mimics the chronic condition in vitro is urgently needed. In an effort to reduce and potentially replace this scientifically and ethically questionable animal testing for IBD drugs, our laboratory has developed an in vitro model for the inflamed intestinal mucosa observed in chronic IBD, which allows high-throughput screening of anti-inflammatory drugs and their formulations. The in vitro model consists of intestinal epithelial cells, human blood-derived macrophages, and dendritic cells that are stimulated by the inflammatory cytokine interleukin-1β. In this study, the model was utilized for evaluation of the efficacy and deposition of budesonide, an anti-inflammatory drug, in three different pharmaceutical formulations: (1) a free drug solution, (2) encapsulated into PLGA nanoparticles, and (3) encapsulated into liposomes. The in vitro model of the inflamed intestinal mucosa demonstrated its ability to differentiate therapeutic efficacy among the formulations while maintaining the convenience of conventional in vitro studies and adequately representing the complex pathophysiological changes observed in vivo.
60 citations
TL;DR: A novel method of constraining a cell-penetrating peptide which can be used to trigger transport of liposomes into cells upon radiation with UV-light, which mediated the transport of the entire liposome particle into cells.
59 citations
TL;DR: It was found that the carrier materials did manage to overcome MDR to some extent, but the overall benefit was quite small; the findings indicate that the ability of classical nanomedicines to overcome cellular MDR should not be overestimated.
55 citations
TL;DR: MRI is a promising method for evaluation of early disease progression and treatment in murine arthritis models and proper siRNA dosing seems to be important for a positive therapeutic outcome in vivo, however, further studies are needed to fully clarify the mechanism(s) underlying the observed anti-inflammatory effects of the siRNA-loaded nanoparticles.
TL;DR: In this paper, quaternized poly[3,5-bis(dimethylaminomethylene)-p-hydroxyl styrene] with two permanently charged cationic sites per monomer unit as well as its block copolymer with PEG were synthesized and compared with the standard transfectant pDMAEMA, in terms of nucleic acid binding strength, gene silencing and transfection activities of the complexes which these polymers form with siRNA and plasmid DNA, respectively.
TL;DR: Dextran nanogels and PAMAM dendrimers mediated high gene silencing with minor toxicity and off-target transcriptional changes and are therefore expected to be suitable siRNA delivery systems in vivo.
Abstract: Purpose
Tumor necrosis factor α (TNF-α) plays a key role in the progression of rheumatoid arthritis and is an important target for anti-rheumatic therapies. TNF-α expression can be silenced with small interfering RNA (siRNA), but efficacy is dependent on efficient and safe siRNA delivery vehicles. We aimed to identify polymeric nanocarriers for anti-TNF-α siRNA with optimal efficacy and minimal off-target effects in vitro.
TL;DR: It is concluded that delivery of dexamethasone phosphate via LCL in combination with rtPA‐induced thrombolysis can significantly improve outcome after stroke and magnetic resonance imaging‐based predictive algorithms provide a sensitive means to measure treatment effects on lesion development.
Abstract: Variable efficacies have been reported for glucocorticoid drugs as anti-inflammatory treatment after stroke. We applied an alternative drug delivery strategy, by injection of dexamethasone phosphate-containing liposomes in combination with recombinant tissue plasminogen activator (rtPA), in an experimental stroke model, and tested the hypothesis that this approach improves behavioral recovery and reduces lesion growth. Rats were subjected to right middle cerebral artery occlusion with a blood clot. After 2 h, animals were intravenously injected with rtPA plus empty long-circulating liposomes (LCL), free dexamethasone phosphate (DXP), or DXP-containing LCL (LCL-DXP). Neurological status was evaluated with different behavioral tests up to 7 days after stroke. Lesion development was assessed by magnetic resonance imaging of tissue and perfusion parameters from 0-2 h until 7 days after stroke. Expression of brain inflammatory markers was measured with RT-PCR at post-stroke day 7. Treatment with rtPA plus LCL-DXP resulted in significantly improved behavioral outcome as compared to treatment with rtPA plus empty LCL or free DXP. Acute and final brain lesion sizes were comparable between treatment groups; however a predictive algorithm revealed a significantly larger salvaged tissue area after treatment with LCL-DXP. We conclude that delivery of dexamethasone phosphate via LCL in combination with rtPA-induced thrombolysis can significantly improve outcome after stroke. Furthermore, magnetic resonance imaging-based predictive algorithms provide a sensitive means to measure treatment effects on lesion development.
TL;DR: The RGD-targeted PEGylated LPD particles containing VEGFR-2 siRNA presented here may be a promising approach for targeting VEGF-mediated angiogenesis in cancer therapy.
TL;DR: It is shown that theranostic systems and strategies hold significant potential for monitoring and improving nanomedicine-mediated drug targeting, and several recent efforts in this regard are summarized.
Abstract: Nanomedicine formulations are considered to be superior to standard low-molecular-weight drugs because of an increased drug accumulation at the pathological site and a decreased localization to healthy non-target tissues, together leading to an improved balance between the efficacy and the toxicity of (chemo-) therapeutic interventions. To better understand and further improve nanomedicine-mediated drug targeting, it is important to design systems and strategies which are able to provide real-time feedback on the localization, the release and the therapeutic efficacy of these formulations. The advances made over the past few years with regard to the development of novel imaging agents and techniques have provided a broad basis for the design of theranostic nanomedicine materials, i.e. multicomponent carrier constructs in which drugs and imaging agents are combined, and which can be used to address issues related to drug localization, drug release and drug efficacy. Here, we summarize several recent efforts in this regard, and we show that theranostic systems and strategies hold significant potential for monitoring and improving nanomedicine-mediated drug targeting.
TL;DR: The in vivo monitoring of the antitumor activity of the nanomedicine revealed that the incorporation of the MRI probe into the liposomal bilayer did not significantly affect the drug efficacy, and indicated a relevant and fast liposome uptake from macrophage-rich organs like spleen and liver, which reduced the tumor accumulation of theliposomes.
TL;DR: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.
Abstract: Background
Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis.
TL;DR: The methods for inducing atherosclerosis in a rabbit model, the production of anti-inflammatory liposomes and monitoring of therapeutic efficacy of experimental therapeutics with the above-mentioned imaging techniques are illustrated.
Abstract: Nanomedicine can provide a potent alternative to current therapeutic strategies for atherosclerosis. For example, the encapsulation of anti-inflammatory drugs into liposomes improves their pharmacokinetics and biodistribution, thereby enhancing bioavailability to atherosclerotic plaques and improving therapeutic efficacy. The evaluation of this type of experimental therapeutics can greatly benefit from in vivo evaluation to assess biological changes, which can be performed by non-invasive imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Here, we will illustrate the methods for inducing atherosclerosis in a rabbit model, the production of anti-inflammatory liposomes and monitoring of therapeutic efficacy of experimental therapeutics with the above-mentioned imaging techniques.
TL;DR: Imatinib-ULS-lysozyme could not be detected in the heart, which is the organ at risk for side-effects of prolonged treatment with imatinib.
TL;DR: The experiments demonstrate that bringing the GLA peptide into the original phage protein environment restores and improves the peptide binding capacity and suggest that the GLa peptide, with some modifications, may be used as a brain-targeting ligand in the future.
TL;DR: This study demonstrates that, in contrast to colchicine, these novel PEGylated colchiine-derived prodrugs are retained within the aqueous interior after encapsulation into liposomes, and that the release of the active parent can be controlled by using different biodegradable linkers.
TL;DR: The specific combination of tumor model, drug delivery system and drug potency are crucial factors that should be considered in the development and evaluation of new nanomedicines for cancer-inflammation therapy, especially when translating from preclinical models.
TL;DR: The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal-specific delivery into proximal tubular cells in vitro and results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.
Abstract: The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal-specific delivery into proximal tubular cells. A novel sunitinib analogue, that is, 17864, is conjugated to a NH(2) -PAMAM-G3 dendrimer via the platinum (II)-based Universal Linkage System (ULS™). The activity of 17864 is retained after coordination to the ULS linker alone or when coupled to NH(2) -PAMAM-G3. 17864-UlS-NH(2) -PAMAM-G3 is non-toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864-UlS-NH(2) -PAMAM-G3 rapidly and efficiently accumulates in the kidneys. These results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.
TL;DR: This paper will provide practical examples of public-private partnerships initiated to expedite the translation of new technology for drug development towards the clinic and MRI guidance for High Intensity Focused Ultrasound mediated drug delivery.
TL;DR: The causes of toxicity are methodically investigated and it is concluded that, even when combining biocompatible materials, the resulting formulation is not guaranteed to be biOCompatible.
TL;DR: Intravenous liposome administration appears to be safe in horses and Radiolabelled liposomes may be useful for detecting infection, inflammation and neoplasia in the horse.
Abstract: REASONS FOR PERFORMING STUDY: Liposomes are phospholipid nanoparticles that extravasate at sites of increased vascular permeability. They have potential in equine medicine for targeted drug delivery and diagnostic imaging of infectious, inflammatory and neoplastic lesions. OBJECTIVES: This study evaluates the safety and biodistribution of i.v. polyethyleneglycol(PEG) liposomes in normal horses. METHODS: PEG-liposomes were prepared by the film hydration method and labelled using (99m) Tc-hexamethyl-propylene-amine-oxime. A single dose of 0.24 micromol/kg bwt (99m) Tc-PEG-liposomes and 2.4 micromol/kg bwt unlabelled PEG-liposomes was administered to 10 conscious horses via i.v. infusion at a rate of 6 micromol/min for the first 15 min and 60 micromol/min thereafter. Clinical parameters, haematology, plasma biochemistry and serum complement activity were monitored serially. Scintigraphic imaging was performed at 1, 12 and 21 h post infusion (PI). Six horses were subjected to euthanasia at 24 h PI. The percentage injected dose per kilogram of tissue was calculated for multiple organs. Results were analysed using repeated measures ANOVA. RESULTS: Horses did not demonstrate adverse reactions during or after liposome infusion. There was a significant elevation in heart rate and respiratory rate at 20 and 25 min PI. No significant complement consumption was detected, although a trend for decreased total haemolytic complement values at 20 min PI was present. Scintigraphic studies revealed a prolonged vascular phase that lasted to 21 h PI, with a reproducible pattern of organ distribution. Biodistribution studies revealed the highest concentrations of radiopharmaceutical within the lung, kidney, liver and spleen. CONCLUSIONS: Intravenous liposome administration appears to be safe in horses. When administered in combination with PEG-liposomes, (99m) Tc-PEG-liposomes have long circulating characteristics and a reproducible pattern of organ distribution in horses. POTENTIAL RELEVANCE: Radiolabelled liposomes may be useful for detecting infection, inflammation and neoplasia in the horse. Liposomes have significant potential for targeted drug delivery in the horse. This study establishes the scintigraphic findings and tissue distribution of 99mTc-PEG-liposomes after i.v. administration in healthy horses.
TL;DR: In this article, female 52 Attack 1: arm 2.00 0.67 1.33 3.1, female 46 Attack 1 : intra-abdominal/ abdominal skin 11.67 24.33 2.5
Abstract: 1, female 52 Attack 1: arm 2.00 0.25 6.50 3 1 Attack 2: upper airway 3.08 0.42 6.08 2 1 Attack 3: upper airway 0.25 1.00 6.75 3 2 Attack 4: intra-abdominal 4.25 3.25 7.75 3 2 2, female 20 Attack 1: intra-abdominal 0.25 1.00 7.00 3 1 3, female 39 Attack 1: intra-abdominal 2.50 0.30 4.30 4 1 Attack 2: upper airway 3.50 0.50 4.00 3 1 4, female 46 Attack 1: intra-abdominal/ abdominal skin 11.67 1.67 24.33 3 3
01 Jan 2012
TL;DR: These findings convincingly demonstrate that combining anatomical μCT with molecular FMT facilitates the noninvasive assessment of nanomedicine biodistribution.
Abstract: Nanomedicines are sub-micrometer-sized carrier ma- terials designed to improve the biodistribution of i.v. administered (chemo-) therapeutic agents. In recent years, ever more efforts in the nanomedicine field have employed optical imaging (OI) techniques to monitor biodistribution and target site accumulation. Thus far, however, the longitudinal assessment of nanomedicine biodistribu- tion using OI has been impossible, due to limited light penetration (in the case of 2D fluorescence reflectance imaging; FRI) and to the inability to accurately allocate fluorescent signals to nonsuperficial organs (in the case of 3D fluorescence molecular tomography; FMT). Using a combination of high-resolution microcomputed tomography (μCT) and FMT, we have here set out to establish a hybrid imaging protocol for noninvasively visualizing and quantifying the accumulation of near-infrared fluorophore-labeled nanomedicines in tissues other than superficial tumors. To this end, HPMA- basedpolymericdrugcarrierswerelabeledwithDy750,theirbiodistributionandtumoraccumulationwereanalyzedusingFMT,andtheresultingdata sets were fused with anatomical μCT data sets in which several different physiologically relevant organs were presegmented. The robustness of 3D organsegmentationwasvalidated,andtheresultsobtainedusing3DCT-FMTwerecomparedtothoseobtaineduponstandard3DFMTand2DFRI.Our findings convincingly demonstrate that combining anatomical μCT with molecular FMT facilitates the noninvasive assessment of nanomedicine biodistribution.