Publications by authors named "Gert Storm"

356 Publications

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system.

Drug Discov Today 2021 Feb 19. Epub 2021 Feb 19.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands; Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands. Electronic address:

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders.
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http://dx.doi.org/10.1016/j.drudis.2021.02.017DOI Listing
February 2021

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

Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges.

Biotechnol J 2021 Jan 23:e2000212. Epub 2021 Jan 23.

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

Background: CriPec technology enables the generation of drug-entrapped biodegradable core-crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)-entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below -60°C, in order to prevent premature release of DTX and hydrolysis of the core-crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue.

Methods And Results: Freeze-drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze-dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze-drying methodology was validated in an industrial setting, yielding a CPC634 freeze-dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose-cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose-cryoprotected freeze-dried CPC634 upon reconstitution were identical to those of non-freeze-dried CPC634.

Conclusion: Our findings provide proof-of-concept for the lyophilization of drug-containing CCPM and our methodology is readily translatable to large-scale manufacturing for future commercialization.
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http://dx.doi.org/10.1002/biot.202000212DOI Listing
January 2021

Liposomal Nanovaccine Containing α-Galactosylceramide and Ganglioside GM3 Stimulates Robust CD8 T Cell Responses via CD169 Macrophages and cDC1.

Vaccines (Basel) 2021 Jan 16;9(1). Epub 2021 Jan 16.

Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.

Successful anti-cancer vaccines aim to prime and reinvigorate cytotoxic T cells and should therefore comprise a potent antigen and adjuvant. Antigen targeting to splenic CD169 macrophages was shown to induce robust CD8 T cell responses via antigen transfer to cDC1. Interestingly, CD169 macrophages can also activate type I natural killer T-cells (NKT). NKT activation via ligands such as α-galactosylceramide (αGC) serve as natural adjuvants through dendritic cell activation. Here, we incorporated ganglioside GM3 and αGC in ovalbumin (OVA) protein-containing liposomes to achieve both CD169 targeting and superior DC activation. The systemic delivery of GM3-αGC-OVA liposomes resulted in specific uptake by splenic CD169 macrophages, stimulated strong IFNγ production by NKT and NK cells and coincided with the maturation of cDC1 and significant IL-12 production. Strikingly, superior induction of OVA-specific CD8 T cells was detected after immunization with GM3-αGC-OVA liposomes. CD8 T cell activation, but not B cell activation, was dependent on CD169 macrophages and cDC1, while activation of NKT and NK cells were partially mediated by cDC1. In summary, GM3-αGC antigen-containing liposomes are a potent vaccination platform that promotes the interaction between different immune cell populations, resulting in strong adaptive immunity and therefore emerge as a promising anti-cancer vaccination strategy.
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http://dx.doi.org/10.3390/vaccines9010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830461PMC
January 2021

Synthesis, characterization, and imaging of radiopaque bismuth beads for image-guided transarterial embolization.

Sci Rep 2021 Jan 12;11(1):533. Epub 2021 Jan 12.

Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, USA.

Current therapy for hypervascular cancers, e.g., hepatocellular carcinoma, includes occlusion of the tumor blood supply by arterial infusion of embolic microspheres (beads) suspended in iodine-based contrast under fluoroscopic guidance. Available radiopaque, imageable beads use iodine as the radiopacifier and cannot be differentiated from contrast. This study aimed to synthesize and characterize imageable beads using bismuth as the radiopacifier that could be distinguished from iodine contrast based upon the difference in the binding energy of k-shell electrons (k-edge). Radiodense bismuth beads were successfully synthesized some with uniform bismuth distribution across the beads. The beads were spherical and could be infused through clinical microcatheters. The bismuth beads could be imaged with clinical dual-energy computed tomography (CT), where iodine-based contrast could be distinguished from the microspheres. The ability to separate iodine from bismuth may enhance the diagnostic information acquired on follow-up CT, identifying the distribution of the embolic beads separately from the contrast. Furthermore, with sequential use of iodine- and bismuth-based beads, the two radiopaque beads could be spatially distinguished on imaging, which may enable the development of dual drug delivery and dual tracking.
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http://dx.doi.org/10.1038/s41598-020-79900-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804415PMC
January 2021

Treatment Outcome Measurement Instruments for Port Wine Stains: A Systematic Review of Their Measurement Properties.

Dermatology 2020 Dec 3:1-17. Epub 2020 Dec 3.

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

Background: A plethora of outcome measurement instruments (OMIs) are being used in port wine stain (PWS) studies. It is currently unclear how valid, responsive, and reliable these are.

Objectives: The aim of this systematic review was to appraise the content validity and other measurement properties of OMIs for PWS treatment to identify the most appropriate instruments and future research priorities.

Methods: This study was performed using the updated Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) methodology and adhered to PRISMA guidelines. Comprehensive searches in Medline and Embase were performed. Studies in which an OMI for PWS patients was developed or its measurement properties were evaluated were included. Two investigators independently extracted data and assessed the quality of included studies and instruments to perform qualitative synthesis of the evidence.

Results: In total, 1,034 articles were screened, and 77 full-text articles were reviewed. A total of 8 studies were included that reported on 6 physician-reported OMIs of clinical improvement and 6 parent- or patient-reported OMIs of life impact, of which 3 for health-related quality of life and 1 for perceived stigmatization. Overall, the quality of OMI development was inadequate (63%) or doubtful (37%). Each instrument has undergone a very limited evaluation in PWS patients. No content validity studies were performed. The quality of evidence for content validity was very low (78%), low (15%), or moderate (7%), with sufficient comprehensibility, mostly sufficient comprehensiveness, and mixed relevance. No studies on responsiveness, minimal important change, and cross-cultural validity were retrieved. There was moderate- to very low-quality evidence for sufficient inter-rater reliability for some clinical PWS OMIs. Internal consistency and measurement error were indeterminate in all studies.

Conclusions: There was insufficient evidence to properly guide outcome selection. Additional assessment of the measurement properties of OMIs is needed, preferentially guided by a core domain set tailored to PWS.
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http://dx.doi.org/10.1159/000511438DOI Listing
December 2020

Optimization of Liposomes for Antigen Targeting to Splenic CD169 Macrophages.

Pharmaceutics 2020 Nov 25;12(12). Epub 2020 Nov 25.

Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam Infection and Immunity Institute, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.

Despite promising progress in cancer vaccination, therapeutic effectiveness is often insufficient. Cancer vaccine effectiveness could be enhanced by targeting vaccine antigens to antigen-presenting cells, thereby increasing T-cell activation. CD169-expressing splenic macrophages efficiently capture particulate antigens from the blood and transfer these antigens to dendritic cells for the activation of CD8 T cells. In this study, we incorporated a physiological ligand for CD169, the ganglioside GM3, into liposomes to enhance liposome uptake by CD169 macrophages. We assessed how variation in the amount of GM3, surface-attached PEG and liposomal size affected the binding to, and uptake by, CD169 macrophages in vitro and in vivo. As a proof of concept, we prepared GM3-targeted liposomes containing a long synthetic ovalbumin peptide and tested the capacity of these liposomes to induce CD8 and CD4 T-cell responses compared to control liposomes or soluble peptide. The data indicate that the delivery of liposomes to splenic CD169 macrophages can be optimized by the selection of liposomal constituents and liposomal size. Moreover, optimized GM3-mediated liposomal targeting to CD169 macrophages induces potent immune responses and therefore presents as an interesting delivery strategy for cancer vaccination.
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http://dx.doi.org/10.3390/pharmaceutics12121138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760819PMC
November 2020

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

Selective tumor antigen vaccine delivery to human CD169 antigen-presenting cells using ganglioside-liposomes.

Proc Natl Acad Sci U S A 2020 11 16;117(44):27528-27539. Epub 2020 Oct 16.

Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands;

Priming of CD8 T cells by dendritic cells (DCs) is crucial for the generation of effective antitumor immune responses. Here, we describe a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1 antigen-presenting cells using gangliosides as targeting ligands. Ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro-generated monocyte-derived DCs (moDCs) and macrophages and by ex vivo-isolated splenic macrophages in a CD169-dependent manner. In blood, high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14 CD169 monocytes and Axl CD169 DCs. Liposomal codelivery of tumor antigen and Toll-like receptor ligand to CD169 moDCs and Axl CD169 DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8 T cells. Finally, Axl CD169 DCs were present in cancer patients and efficiently captured ganglioside-liposomes. Our findings demonstrate a nanovaccine platform targeting CD169 DCs to drive antitumor T cell responses.
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http://dx.doi.org/10.1073/pnas.2006186117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959579PMC
November 2020

Optical imaging of the whole-body to cellular biodistribution of clinical-stage PEG-b-pHPMA-based core-crosslinked polymeric micelles.

J Control Release 2020 12 30;328:805-816. Epub 2020 Sep 30.

Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. Electronic address:

Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro-computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 %ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 %ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80 phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the formulation mainly results from sustained release of the chemotherapeutic payload in the tumor microenvironment. In addition, their high uptake by phagocytic immune cells encourages potential use for immunomodulatory anticancer therapy. Altogether, the beneficial biodistribution, efficient tumor targeting and prominent engagement of PEG-b-pHPMA-lactate-based CCPM with key cell populations underline the clinical versatility of this clinical-stage nanocarrier formulation.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.046DOI Listing
December 2020

Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo.

J Control Release 2020 12 24;328:640-652. Epub 2020 Sep 24.

Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands. Electronic address:

Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.041DOI Listing
December 2020

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

Endogenous or Exogenous Retinal Pigment Epithelial Cells: A Comparison of Two Experimental Animal Models of Proliferative Vitreoretinopathy.

Transl Vis Sci Technol 2020 08 31;9(9):46. Epub 2020 Aug 31.

Singapore National Eye Centre, Singapore.

Purpose: Proliferative vitreoretinopathy (PVR) is a blinding condition that can occur following ocular penetrating injury and retinal detachment. To develop effective therapeutics for PVR, it is imperative to establish an animal model that is reproducible, closest in anatomy to the human eye, and most representative of the human disease. We compared two in vivo models of PVR in minipig eyes to assess reproducibility and consistency.

Methods: Six minipigs underwent PVR induction with procedure A and six underwent procedure B. In both procedures, PVR was induced with vitrectomy, bleb retinal detachment, retinotomy, and injection of platelet-rich plasma. In procedure A, retinal pigment epithelial (RPE) cells were harvested from cadaveric pig eyes and injected at the end of surgery. In procedure B, native RPE cells were released into the vitreous cavity by creating a RPE detachment and scraping the RPE layer. PVR severity was graded on fundoscopic examination with a modified Silicone Study Classification System for PVR. Severe PVR was defined as stages 2 to 5.

Results: Three eyes (50%) and five eyes (83.3%) developed re-detachment of the retina from severe PVR in procedures A and B, respectively ( = 0.55). Median PVR stage was higher in eyes that underwent procedure B compared to eyes that underwent procedure A, although the difference was not statistically significant (2.5 vs. 1.5, = 0.26).

Conclusions: This new model utilizing native RPE cells achieved a high consistency in inducing severe PVR in the minipig.

Translational Relevance: Our model closely follows pathogenic events in human PVR, making it ideal for preclinical testing of novel therapeutics for PVR.
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http://dx.doi.org/10.1167/tvst.9.9.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463202PMC
August 2020

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.

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

In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy.

Pharmaceutics 2020 Jun 25;12(6). Epub 2020 Jun 25.

Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China.

Antifibrinolytic site-specific pharmaco-laser therapy (SSPLT) is an experimental treatment modality for refractory port wine stains (PWS). Conceptually, antifibrinolytic drugs encapsulated in thermosensitive liposomes are delivered to thrombi that form in semi-photocoagulated PWS blood vessels after conventional laser treatment. Local release of antifibrinolytics is induced by mild hyperthermia, resulting in hyperthrombosis and complete occlusion of the target blood vessel (clinical endpoint). In this study, 20 thermosensitive liposomal formulations containing tranexamic acid (TA) were assayed for physicochemical properties, TA:lipid ratio, encapsulation efficiency, and endovesicular TA concentration. Two candidate formulations (DPPC:DSPE-PEG, DPPC:MPPC:DSPE-PEG) were selected based on optimal properties and analyzed for heat-induced TA release at body temperature (T), phase transition temperature (T), and at T > T. The effect of plasma on liposomal stability at 37 °C was determined, and the association of liposomes with platelets was examined by flow cytometry. The accumulation of PEGylated phosphocholine liposomes in laser-induced thrombi was investigated in a hamster dorsal skinfold model and intravital fluorescence microscopy. Both formulations did not release TA at 37 °C. Near-complete TA release was achieved at T within 2.0-2.5 min of heating, which was accelerated at T > T. Plasma exerted a stabilizing effect on both formulations. Liposomes showed mild association with platelets. Despite positive in vitro results, fluorescently labeled liposomes did not sufficiently accumulate in laser-induced thrombi in hamsters to warrant their use in antifibrinolytic SSPLT, which can be solved by coupling thrombus-targeting ligands to the liposomes.
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http://dx.doi.org/10.3390/pharmaceutics12060591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356038PMC
June 2020

The hepatic lipidome: From basic science to clinical translation.

Adv Drug Deliv Rev 2020 30;159:180-197. Epub 2020 Jun 30.

Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede 7500 AE, the Netherlands. Electronic address:

The liver is the key organ involved in lipid metabolism and transport. Excessive lipid accumulation due to dysregulated lipid metabolism predisposes the liver to steatosis, cirrhosis, and hepatocellular carcinoma. Lipids are generally compartmentalized in specialized organelles called lipid droplets that enable cells to store and release lipids in a regulated manner. However, during flux-in and flux-out of droplets, lipids are converted into toxic species leading to lipid-mediated liver damage. Lipids are categorized into 'toxic' or 'healthy' lipids that are involved in liver disease pathogenesis or resolution, respectively. Lipidomic analysis have revealed unique lipid signature that correlates with the disease progression therefore being used for disease diagnosis. In this comprehensive review, we provide an overview on hepatic lipid homeostasis, lipid compartmentalization mechanisms and lipidomic profiles in different liver diseases. We further discuss promising therapeutics targeting the hepatic lipidome including pro-resolving lipids, liposomes, and small-molecule inhibitors for the treatment of liver diseases.
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http://dx.doi.org/10.1016/j.addr.2020.06.027DOI Listing
June 2020

Clinical outcome measures and scoring systems used in prospective studies of port wine stains: A systematic review.

PLoS One 2020 2;15(7):e0235657. Epub 2020 Jul 2.

Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China.

Background: Valid and reliable outcome measures are needed to determine and compare treatment results of port wine stain (PWS) studies. Besides, uniformity in outcome measures is crucial to enable inter-study comparisons and meta-analyses. This study aimed to assess the heterogeneity in reported PWS outcome measures by mapping the (clinical) outcome measures currently used in prospective PWS studies.

Methods: OVID MEDLINE, OVID Embase, and CENTRAL were searched for prospective PWS studies published from 2005 to May 2020. Interventional studies with a clinical efficacy assessment were included. Two reviewers independently evaluated methodological quality using a modified Downs and Black checklist.

Results: In total, 85 studies comprising 3,310 patients were included in which 94 clinician/observer-reported clinical efficacy assessments had been performed using 46 different scoring systems. Eighty-one- studies employed a global assessment of PWS appearance/improvement, of which -82% was expressed as percentage improvement and categorized in 26 different scoring systems. A wide variety of other global and multi-item scoring systems was identified. As a result of outcome heterogeneity and insufficient data reporting, only 44% of studies could be directly compared. A minority of studies included patient-reported or objective outcomes. Thirteen studies of good quality were found.

Conclusion: Clinical PWS outcomes are highly heterogeneous, which hampers study comparisons and meta-analyses. Consensus-based development of a core outcome-set would benefit future research and clinical practice, especially considering the lack of high-quality trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235657PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332045PMC
September 2020

Cancer nanomedicine meets immunotherapy: opportunities and challenges.

Acta Pharmacol Sin 2020 Jul 17;41(7):954-958. Epub 2020 Jun 17.

Institute for Experimental Molecular Imaging, Uniklinik RWTH Aachen and Helmholtz Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

Cancer nanomedicines have shown promise in combination immunotherapy, thus far mostly preclinically but also already in clinical trials. Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. Combination nano-immunotherapy can be realized via three targeting strategies, i.e., by targeting cancer cells, targeting the tumor immune microenvironment, and targeting the peripheral immune system. The clinical potential of nano-immunotherapy has recently been demonstrated in a phase III trial in which nano-albumin paclitaxel (Abraxane®) was combined with atezolizumab (Tecentriq®) for the treatment of patients suffering from advanced triple-negative breast cancer. In the present paper, besides strategies and initial (pre)clinical success stories, we also discuss several key challenges in nano-immunotherapy. Taken together, nanomedicines combined with immunotherapy are gaining significant attention, and it is anticipated that they will play an increasingly important role in clinical cancer therapy.
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http://dx.doi.org/10.1038/s41401-020-0448-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470866PMC
July 2020

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam (Erasmus MC), Rotterdam, The Netherlands.

Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNPs) or lipid-core micelles (MCLs). The antimicrobial activity of AA139-PNP and AA139-MCL was determined The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by extended-spectrum β-lactamase-producing In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent antimicrobial activities (similar to free AA139). In uninfected rats, they exhibited longer residence times in the lungs than free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity, enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanomedicines. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.
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http://dx.doi.org/10.1128/AAC.00517-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449162PMC
August 2020

Apoptosis-inducing peptide loaded in PLGA nanoparticles induces anti-tumor effects in vivo.

Int J Pharm 2020 Jul 10;585:119535. Epub 2020 Jun 10.

Targeted Therapeutics and Nanomedicine, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands. Electronic address:

Induction of apoptosis in tumor cells specifically within the complex tumor microenvironment is highly desirable to kill them efficiently and to enhance the effects of chemotherapy. Second mitochondria-derived activator of caspase (Smac) is a key pro-apoptotic pathway which can be activated with a Smac mimetic peptide. However, in vivo application of peptides is hampered by several limitations such as poor pharmacokinetics, rapid elimination, enzymatic degradation, and insufficient intracellular delivery. In this study, we developed a nanosystem to deliver a Smac peptide to tumor by passive targeting. We first synthesized a chimeric peptide that consists of the 8-mer Smac peptide and a 14-mer cell penetrating peptide (CPP) and then encapsulated the Smac-CPP into polymeric nanoparticles (Smac-CPP-NPs). In vitro, Smac-CPP-NPs were rapidly internalized by 4T1 mammary tumor cells and subsequently released Smac-CPP into the cells, as shown with fluorescence microscopy. Furthermore, Smac-CPP-NPs induced apoptosis in tumor cells, as confirmed with cell viability and caspase 3/7 assays. Interestingly, combination of Smac-CPP-NPs with doxorubicin (dox), a clinically used cytostatic drug, showed combined effects in vitro in 4T1 cells. The effect was significantly better than that of SMAC-CPP-NPs alone as well as empty nanoparticles and dox. In vivo, co-treatment with Smac-CPP-NPs and free dox reduced the tumor growth to 85%. Furthermore, the combination of Smac-CPP-NPs and free dox showed reduced proliferating tumor cells (Ki-67 staining) and increased apoptotic cells (cleaved caspase-3 staining) in tumors. In conclusion, the present study demonstrates that the intracellular delivery of Smac-mimetic peptide using nanoparticle system can be an interesting strategy to attenuate the tumor growth and to potentiate the therapeutic efficacy of chemotherapy in vivo.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119535DOI Listing
July 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.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119409DOI Listing
June 2020

Role of spleen tyrosine kinase in liver diseases.

World J Gastroenterol 2020 Mar;26(10):1005-1019

Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses. SYK mediate diverse cellular responses an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways, ITAMs-independent and ITAMs-semi-dependent signalling pathways. In liver, SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells), and found to be positively correlated with the disease severity. The implication of SYK pathway has been reported in different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target. This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.
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http://dx.doi.org/10.3748/wjg.v26.i10.1005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081001PMC
March 2020

Multimodal and multiscale optical imaging of nanomedicine delivery across the blood-brain barrier upon sonopermeation.

Theranostics 2020 12;10(4):1948-1959. Epub 2020 Jan 12.

Institute for Experimental Molecular Imaging (ExMI), University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.

: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation. : Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB. : Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes. : BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders.
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http://dx.doi.org/10.7150/thno.41161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993230PMC
February 2021

Transferrin-binding peptide functionalized polymersomes mediate targeted doxorubicin delivery to colorectal cancer in vivo.

J Control Release 2020 03 7;319:407-415. Epub 2020 Jan 7.

Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China. Electronic address:

Transferrin receptor (TfR) is a promising target validated in the clinical trials for managing various malignancies. Transferrin (Tf) and single chain antibody fragment can target TfR and are typically conjugated to nanomedicines via post-modification, which poses significant production challenges. Here, we report that the polymersomes functionalized with a Tf-binding peptide CGGGHKYLRW (TBP-Ps) can selectively and stably bind Tf and subsequently mediate targeted doxorubicin (Dox) delivery to TfR over-expressing HCT-116 colorectal cancer cells in vitro and in vivo. The Tf surface density of the polymersomes could be controlled by the surface content of TBP. Interestingly, modifying Dox-loaded TBP-Ps with Tf led to greatly increased cellular uptake and inhibitory effect of HCT-116 cells. Tf-bound TBP-Ps demonstrated rapid accumulation in the tumor xenografts in nude mice following i.v. injection. More importantly, Dox-loaded Ps with Tf binding significantly enhanced the antitumor efficacy in mice bearing HCT-116 tumors compared to polymersomes without Tf binding. Surface functionalization of the nanoparticles with Tf-binding peptide provides an appealing strategy in formulating Tf-targeted nanomedicines.
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http://dx.doi.org/10.1016/j.jconrel.2020.01.012DOI Listing
March 2020

FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor.

Nanotheranostics 2020 1;4(1):26-39. Epub 2020 Jan 1.

Targeted Therapeutics, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and technology, University of Twente, Enschede, The Netherlands.

Pancreatic ductal adenocarcinoma (PDAC), characterized with abundant tumor stroma, is a highly malignant tumor with poor prognosis. The tumor stroma largely consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and is known to promote tumor growth and progression as well as acts as a barrier to chemotherapy. Inhibition of tumor stroma is highly crucial to induce the effect of chemotherapy. In this study, we delivered fibroblast growth factor 2 (FGF2) to human pancreatic stellate cells (hPSCs), the precursors of CAFs, using superparamagnetic iron oxide nanoparticles (SPIONs). FGF2 was covalently conjugated to functionalized PEGylated dextran-coated SPIONs. FGF2-SPIONs significantly reduced TGF-β induced hPSCs differentiation (α-SMA and collagen-1 expression) by inhibiting pSmad2/3 signaling and inducing ERK1/2 activity, as shown with western blot analysis. Then, we established a stroma-rich self-assembling 3D heterospheroid model by co-culturing PANC-1 and hPSCs in 3D environment. We found that FGF2-SPIONs treatment alone inhibited the tumor stroma-induced spheroid growth. In addition, they also potentiated the effect of gemcitabine, as shown by measuring the spheroid size and ATP content. These effects were attributed to the reduced expression of the hPSC activation and differentiation marker, α-SMA. Furthermore, to demonstrate an application of SPIONs, we applied an external magnetic field to spheroids while incubated with FGF2-SPIONs. This resulted in an enhanced effect of gemcitabine in our 3D model. In conclusion, this study presents a novel approach to target FGF2 to tumor stroma using SPIONs and thereby enhancing the effect of gemcitabine as demonstrated in the complex 3D tumor spheroid model.
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http://dx.doi.org/10.7150/ntno.38092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940204PMC
April 2021

High-resolution 3D visualization of nanomedicine distribution in tumors.

Theranostics 2020 1;10(2):880-897. Epub 2020 Jan 1.

Bioscience, Discovery, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.

To improve the clinical translation of anti-cancer nanomedicines, it is necessary to begin building specific insights into the broad concept of the Enhanced Permeability and Retention (EPR) effect, using detailed investigations of the accumulation, distribution and retention of nanomedicines in solid tumors. Nanomedicine accumulation in preclinical tumors has been extensively studied; however, treatment efficacy will be heavily influenced by both the quantity of drug-loaded nanomedicines reaching the tumor as well as their spatial distribution throughout the tumor. It remains a challenge to image the heterogeneity of nanomedicine distribution in 3 dimensions within solid tumors with a high degree of spatial resolution using standard imaging approaches. To achieve this, an ex vivo micro computed tomography (µCT) imaging approach was developed to visualize the intratumoral distribution of contrast agent-loaded PEGylated liposomes. Using this semi-quantitative method, whole 3-dimensional (3D) tumor liposome distribution was determined with 17 µm resolution in a phenotypically diverse panel of four preclinical xenograft and patient-derived explant (PDX) tumor models. High-resolution ex vivo μCT imaging revealed striking differences in liposome distribution within tumors in four models with different vascular patterns and densities, stromal contents, and microenvironment morphologies. Following intravenous dosing, the model with the highest density of pericyte-supported vessels showed the greatest liposome accumulation, while the model with vessels present in regions of high α-smooth muscle actin (αSMA) content presented with a large proportion of the liposomes at depths beyond the tumor periphery. The two models with an unsupported vascular network demonstrated a more restricted pattern of liposome distribution. Taken together, vessel distribution and support (the latter indicative of functionality) appear to be key factors determining the accumulation and distribution pattern of liposomes in tumors. Our findings demonstrate that high-resolution 3D visualization of nanomedicine distribution is a useful tool for preclinical nanomedicine research, providing valuable insights into the influence of the tumor vasculature and microenvironment on nanomedicine localization.
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http://dx.doi.org/10.7150/thno.37178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929971PMC
April 2021

The role of liposomes in clinical nanomedicine development. What now? Now what?

J Control Release 2020 02 14;318:256-263. Epub 2019 Dec 14.

Dept. Pharmaceutics, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands. Electronic address:

The rapid rise in interest in 'nanomedicines' in the academic world over the last twenty years and the claims of success led to calls for reflection. The main body of text of this Commentary will be on answering the question: 'where to go with nanomedicines'? Research priorities for the future will be outlined based on experience with the most successful nanomedicines family within the broad field of nanomedicine so far: liposomes. An analysis of currently clinically tested, approved and marketed liposome-drug combinations provides these insights.
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http://dx.doi.org/10.1016/j.jconrel.2019.12.023DOI Listing
February 2020

Cyclic RGD-Functionalized and Disulfide-Crosslinked Iodine-Rich Polymersomes as a Robust and Smart Theranostic Agent for Targeted CT Imaging and Chemotherapy of Tumor.

Theranostics 2019 17;9(26):8061-8072. Epub 2019 Oct 17.

Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China.

There is tremendous interest in integrating CT imaging with chemotherapy; however, reported iodine-based nanosystems such as nanogels and nano-emulsions display typically reduced contrast coefficient, low drug loading and stability, and poor targetability. Here, cRGD-functionalized disulfide-crosslinked iodine-rich polymersomes (cRGD-XIPs) were designed as a novel, robust and smart theranostic agent and investigated for targeted CT imaging and chemotherapy of malignant tumors. cRGD-XIPs were prepared from co-self-assembly of poly(ethylene glycol)--poly(dithiolane trimethylene carbonate--iodinated trimethylene carbonate) (PEG-P(DTC-IC)) and cRGD-PEG-P(DTC-IC) block copolymers. and CT contrast effect of cRGD-XIPs was studied using αβ-overexpressing B16 melanoma as a tumor model in comparison with clinical agent iohexol. The therapeutic efficacy of doxorubicin-loaded cRGD-XIPs (cRGD-XIPs-Dox) to B16 melanoma was investigated and compared with XIPs-Dox (non-targeted), cRGD-IPs-Dox (non-crosslinked) and free Dox. cRGD-XIPs were formed with 55.5 wt.% iodine and ca. 90 nm in diameter. cRGD-XIPs-Dox with a Dox loading of 15.3 % bared superior colloidal stability and reduction-responsive drug release. Notably, blank cRGD-XIPs showed a maximum-tolerated dose (MTD) > 400 mg iodine equiv./kg while cRGD-XIPs-Dox had an MTD > 150 mg Dox equiv./kg, ca. 15-fold improvement over free Dox. cRGD-XIPs revealed superior CT contrast effect and achieved 46.5- and 24.0-fold better enhancement of CT imaging of B16 melanoma than iohexol at 4 h following intratumoral and intravenous injection, respectively. cRGD-XIPs-Dox displayed an elimination half-life of 6.5 h and an elevated accumulation of 6.68% ID/g in the tumors. Furthermore, cRGD-XIPs-Dox was significantly more effective than XIPs-Dox and cRGD-XPs-Dox in inhibiting growth of B16 melanoma model. This proof-of-concept study demonstrates that cRGD-XIPs are a robust, non-toxic and smart polymeric theranostic agent that can not only significantly enhance CT imaging of tumors but also mediate efficient tumor-targeted chemotherapy. XIPs offer a unique and safe platform for theranostic polymersomes that pre-select patients using CT imaging prior to targeted chemotherapy with the same system.
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http://dx.doi.org/10.7150/thno.37184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857068PMC
September 2020