Browsing by Author "Larsson, Mikael"

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A new type of gadodiamide-conjugated amphiphilic chitosan nanoparticle and its use for MR imaging with significantly enhanced contrastability
(2019-01-01)
Huang, Wei-Ting
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Ko, Yi-Ping
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Kuo, Ting-Yu
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Larsson, Mikael
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Chang, Min-Chih
Magnetic resonance imaging (MRI) has been one of the most frequently-used diagnostic tools with high dimensional precision and positioning accuracy in clinical practices. To achieve contrast enhancement, utilization of high-efficient MR imaging contrast agents becomes a prime consideration and is indispensably reinforced the diagnosis precision, especially for the emerging precision medicine. Gadolinium (Gd)-based complexes has been widely used in current clinical MRI operations, however, numerous side effects were reported and highlighted in clinic. Those drawbacks render specific unmet needs to be clinically and technically improved with a new version of Gd-based compound. Here we report a newly-synthesized amphiphilic Gadodiamide-conjugated carboxymethyl-hexanoyl chitosan (termed as CHC-Gd) hybrid. The gadodiamide was selected is due to its smallest molecular size among other Gd-based complexes reported in literature, which assumed to give least influence on the resulting physicochemical properties such as colloidal stability, nanostructural evolution, and cytocompability, particularly self-assembly capability, of the resulting hybrid upon practical uses. Experimental outcomes showed a successful synthesis of the CHC-Gd hybrid using a one-pot synthesis protocol, where the gadodiamide complexes were covalently attached to the carboxyl groups along the CHC backbone. Self-assembly behavior can be observed to form a sphere-like nanoparticle of 100-200 nm in size as of amphiphilic native CHC macromolecule. Experimental outcomes indicated a largely improved cytocompatibility of the hybrid, compared with free Gd, suggesting the Gd+3 ions were well stabilized in the CHC nanostructure. Excellent contrastability in-vitro and in particular in vivo were measured, where for in-vivo test, a 10-40-folded reduction in dosage, compared with clinical Gd dose, was used and demonstrated a comparative-to-better imaging resolution and brightness. Therefore, from this preliminary investigation, a potential translation to clinical practice through the use of newly-synthesized amphiphilic CHC-Gd hybrid appears to be relatively promising.
A novel dual-structure, self-healable, polysaccharide based hybrid nanogel for biomedical uses
(2011)
Lin, Li-Jih
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Larsson, Mikael
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Liu, Dean-Mo
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材料科學與工程學系
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Department of Materials Science and Engineering
A new unique dual-structure hydrogel composed of nanostructures of amphiphilic chitosan (CHC) dispersed in a sodium alginate matrix (SAL) is presented. The successful creation of the composite is based on combining chitosan and sodium alginate without precipitation or agglomeration, which has not been previously reported. The CHC/SAL composite gels present a number of properties making them attractive for biomedical applications, in particular as implantable depot gels or in dermal applications. The gels are shown to form rapidly upon exposure of the combination solution to Ca(2+) containing gelation medium. The formed gels have storage moduli similar to soft tissue and display shear reversible gelation with fast recovery of mechanical properties, in addition to self-healing capability at certain compositions. The gels exhibit moderate swelling in deionized water and low swelling in simulated body fluid and cell culture media. The drug release from the composite gels is demonstrated using the hydrophobic drug all-trans retinoic acid, which is used in cancer and skin disorder therapies. The drug release initially occurs through a Fickian mechanism for a fraction of the loaded drug, where the fraction released during this process depends on release media and gel composition. A large fraction of the loaded drug can be retained for long term depot drug delivery. Furthermore, the CHC/SAL gels are determined to have low toxicity and skin irritation.
A temperature-induced and shear-reversible assembly of latanoprost-loaded amphiphilic chitosan colloids: Characterization and in vivo glaucoma treatment
(2014-07-01)
Hsiao, Meng-Hsuan
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Chiou, Shih-Hwa
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Larsson, Mikael
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Hung, Kuo-Hsuan
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Wang, Yi-Ling
Hydrogels composed of assembled colloids is a material class that is currently receiving much interest and shows great promise for use in biomedical applications. This emerging material class presents unique properties derived from the combination of nanosized domains in the form of colloidal particles with a continuous gel network and an interspersed liquid phase. Here we developed an amphiphilic chitosan based, thermogelling, shear-reversible colloidal gel system for improved glaucoma treatment and addressed how preparation procedures and loading with the anti-glaucoma drug latanoprost and commonly used preservative benzalkonium chloride influenced the mechanical properties of and drug release from the colloidal gels. The results highlight that incorporated substances and preparation procedures have effects both on mechanical properties and drug release, but that the release of drug loaded in the colloidal carriers is mainly limited by transport out of the carriers, rather than by diffusion within the gel. The developed colloidal chitosan based gels hold outstanding biomedical potential, as confirmed by the ease of preparation and administration, low cytotoxicity in MTT assay, excellent biocompatibility and lowering of intraocular pressure for 40 days in a rabbit glaucoma model. The findings clearly justify further investigations towards clinical use in the treatment of glaucoma. Furthermore, the use of this shear-reversible colloidal gel could easily be extended to localized treatment of a number of critical conditions, from chronic disorders to cancer, potentially resulting in a number of new therapeutics with improved clinical performance. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
A unique tetrameric structure of deer plasma haptoglobin - an evolutionary advantage in the Hp 2-2 phenotype with homogeneous structure
(2008-03-01)
Lai, I. H.
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Lin, Kung-Yu
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Larsson, Mikael
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Yang, Ming Chi
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Shiau, Chuen-Huei
Similar to blood types, human plasma haptoglobin (Hp) is classified into three phenotypes: Hp 1-1, 2-1 and 2-2. They are genetically inherited from two alleles Hp 1 and Hp 2 (represented in bold), but only the Hp 1-1 phenotype is found in almost all animal species. The Hp 2-2 protein consists of complicated large polymers cross-linked by alpha 2-beta subunits or (alpha 2-beta)(n) (where n >= 3, up to 12 or more), and is associated with the risk of the development of diabetic, cardiovascular and inflammatory diseases. In the present study, we found that deer plasma Hp mimics human Hp 2, containing a tandem repeat over the alpha-chain based on our cloned cDNA sequence. Interestingly, the isolated deer Hp is homogeneous and tetrameric, i.e. (alpha-beta)(4), although the locations of -SH groups (responsible for the formation of polymers) are exactly identical to that of human. Denaturation of deer Hp using 6 M urea under reducing conditions (143 mM beta-mercaptoethanol), followed by renaturation, sustained the formation of (alpha-beta)(4), suggesting that the Hp tetramers are not randomly assembled. Interestingly, an alpha-chain monoclonal antibody (W1), known to recognize both human and deer alpha-chains, only binds to intact human Hp polymers, but not to deer Hp tetramers. This implies that the epitope of the deer alpha-chain is no longer exposed on the surface when Hp tetramers are formed. We propose that steric hindrance plays a major role in determining the polymeric formation in human and deer polymers. Phylogenetic and immunochemical analyses revealed that the Hp 2 allele of deer might have arisen at least 25 million years ago. A mechanism involved in forming Hp tetramers is proposed and discussed, and the possibility is raised that the evolved tetrameric structure of deer Hp might confer a physiological advantage.
Biomedical applications and colloidal properties of amphiphilically modified chitosan hybrids
(2013-09-01)
Larsson, Mikael
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Huang, Wei-Chen
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Hsiao, Meng-Hsuan
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Wang, Yen-Jen
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Nyden, Magnus
Chitosan is among the most abundant biopolymers on earth and has been either used or exhibited potential in a wide variety of industrial and biomedical applications. With the advancement of materials technologies, chitosan has been chemically modified to self-assemble into nanoarchitectures that are usable in advanced biomedical applications, such as drug nanocarriers, macroscopic injectables, tissue-engineering scaffolds, and nanoimaging agents. Colloidal amphiphilically modified chitosan (AMC) is a relatively recent material receiving increased attention with numerous publications addressing the medical advantages of specific systems. To date, many reviews have focused on the synthesis and biomedical properties of chitosan-based biomaterials, but a comprehensive study focusing on the colloidal properties of AMC in relation to biomedical performance appears to be lacking. This review provides a survey of the field, critically reviewing the colloidal properties and biomedical performance of AMC systems, such as nanoparticle drug delivery systems and macroscopic medical devices. Finally, the future development, market potential, and clinical implications of these promising colloidal-structured biomaterials are summarised. (C) 2013 Elsevier Ltd. All rights reserved.
Demethoxycurcumin-Carrying Chitosan Antibody Core Shell Nanoparticles with Multitherapeutic Efficacy toward Malignant A549 Lung Tumor: From in Vitro Characterization to in Vivo Evaluation
(2015-04-01)
Huang, Wei-Ting
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Larsson, Mikael
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Wang, Yen-Jen
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Chiou, Shih-Hwa
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Lin, Hui-Yi
Targeting controlled release core-shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core-shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core-shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core-shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.
Design and characterization of a novel amphiphilic chitosan nanocapsule-based thermo-gelling biogel with sustained in vivo release of the hydrophilic anti-epilepsy drug ethosuximide
(2012-08-10)
Hsiao, Meng-Hsuan
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Larsson, Mikael
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Larsson, Anette
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Evenbratt, Hanne
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Chen, Ying-Yu
Thermo-gelling injectable nanogels, with no burst release of loaded drug, were prepared by a simple route by combining self assembled nanocapsules of amphiphilically modified chitosan with glycerophosphate di-sodium salt and glycerol. The potential as a depot drug delivery system was demonstrated in vivo through the therapeutic effect of ethosuximide (ESM) loaded nanogels, suppressing spike wave discharges (SWDs) in Long Evan rat model. Simultaneously clearance of gels from the site of administration was monitored non-invasively using MRI. The gel structure was characterized using TEM and SEM, confirming the gels to be an assembly of nanocapsules and using two-photon microscopy to visualize the network structure. In vitro drug release studies using ESM revealed that the nanogels exhibited extended, mostly Fickian release. Finally, all investigated formulations displayed excellent cytotoxicity data determined by MTT assay using human retinal pigmented epithelium cells. All presented properties are highly desirable for injectable depot gels for drug delivery. (c) 2012 Elsevier B.V. All rights reserved.
Design and optimization of a nanoprobe comprising amphiphilic chitosan colloids and Au-nanorods: Sensitive detection of human serum albumin in simulated urine
(2016-12-30)
Jean, Ren-Der
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Larsson, Mikael
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Cheng, Wei-Da
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Hsu, Yu-Yuan
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Bow, Jong-Shing
Metallic nanoparticles have been utilized as analytical tools to detect a wide range of organic analytes. In most reports, gold (Au)-based nanosensors have been modified with ligands to introduce selectivity towards a specific target molecule. However, in a recent study a new concept was presented where bare Au-nanorods on self-assembled carboxymethyl-hexanoyl chitosan (CHC) nanocarriers achieved sensitive and selective detection of human serum albumin (HSA) after manipulation of the solution pH. Here this concept was further advanced through optimization of the ratio between Au-nanorods and CHC nanocarriers to create a nanotechnology-based sensor (termed CHC-AuNR nanoprobe) with an outstanding lower detection limit (LDL) for HSA. The CHC-AuNR nanoprobe was evaluated in simulated urine solution and a LDL as low as 1.5 pM was achieved at an estimated AUNR/CHC ratio of 2. Elemental mapping and protein adsorption kinetics over three orders of magnitude in HSA concentration confirmed accumulation of HSA on the nanorods and revealed the adsorption to be completed within 15 min for all investigated concentrations. The results suggest that the CHC-AuNR nanoprobe has potential to be utilized for cost-effective detection of analytes in complex liquids. (C) 2016 Elsevier B.V. All rights reserved.
Dual drug-loaded biofunctionalized amphiphilic chitosan nanoparticles: Enhanced synergy between cisplatin and demethoxycurcumin against multidrug-resistant stem-like lung cancer cells
(2016-12)
Huang, Wei-Ting
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Larsson, Mikael
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Lee, Yi-Chi
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Liu, Dean-Mo
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Chiou, Guang-Yuh
Lung cancer kills more humans than any other cancer and multidrug resistance (MDR) in cancer stem like cells (CSC) is emerging as a reason for failed treatments. One concept that addresses this root cause of treatment failure is the utilization of nanoparticles to simultaneously deliver dual drugs to cancer cells with synergistic performance, easy to envision - hard to achieve. (1) It is challenging to simultaneously load drugs of highly different physicochemical properties into one nanoparticle, (2) release kinetics may differ between drugs and (3) general requirements for biomedical nanoparticles apply. Here self-assembled nanoparticles of amphiphilic carboxymethyl-hexanoyl chitosan (CHC) were shown to present nano-microenvironments enabling simultaneous loading of hydrophilic and hydrophobic drugs. This was expanded into a dual-drug nano-delivery system to treat lung CSC. CHC nanoparticles were loaded/chemically modified with the anticancer drug cisplatin and the MDR-suppressing Chinese herbal extract demethoxycurcumin, followed by biofunctionalization with CD133 antibody for enhanced uptake by lung CSC, all in a feasible one-pot preparation. The nanoparticles were characterized with regard to chemistry, size, zeta potential and drug loading/release. Biofunctionalized and non-functionalized nanoparticles were investigated for uptake by lung CSC. Subsequently the cytotoxicity of single and dual drugs, free in solution or in nanoparticles, was evaluated against lung CSC at different doses. From the dose response at different concentrations the degree of synergy was determined through Chou-Talalay\'s Plot. The bio-functionalized nanoparticles promoted synergistic effects between the drugs and were highly effective against MDR lung CSC. The efficacy and feasible one-pot preparation suggests preclinical studies using relevant disease models to be justified. (C) 2016 Elsevier B.V. All rights reserved.
Evaluation of Carboxymethyl-Hexanoyl Chitosan as a Protein Nanocarrier
(2013-06-18)
Larsson, Mikael
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Borde, Annika
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Mattisson, Emma
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Liu, Dean-Mo
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Larsson, Anette
Carboxymethyl-hexanoyl chitosan (CHC) has the ability to self-assemble into nanocapsules in an aqueous solution and it has recently shown potential in numerous biomedical applications. Here we investigate the protein loading efficiency and release, as well as the structural properties of CHC protein nanocarriers. Bovine serum albumin (BSA) or its chromophore labelled version, fluorescein-BSA, was used as a model protein and the loading was performed with a simple mixing of pre-formed nanocapsules and protein. Dynamic light scattering and zeta potential analysis revealed that protein loaded nanocarriers with high positive zeta potential were formed. The protein loaded nanocarriers displayed a loading efficiency of 75% and a very slow protein release. In summary, our results highlight the potential of CHC as a protein nanocarrier, but also indicate that protein-CHC interactions need to be considered in protein containing CHC formulations where protein release is not the main function.
Injectable insulin-lysozyme-loaded nanogels with enzymatically-controlled degradation and release for basal insulin treatment: In vitro characterization and in vivo observation
(2016-02-28)
Chou, Hao-Syun
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Larsson, Mikael
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Hsiao, Meng-Hsuan
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Chen, Yi-Chieh
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Roeding, Magnus
Diabetes is a common global disease that causes immense suffering for individuals and huge costs for the health care system. To minimize complications such as organ degeneration, diabetic patients are required to undergo treatments to maintain the blood glucose level in the normal range, ideally mimicking normal insulin secretion. The normal physiological insulin secretion pattern in healthy individuals consists of a base (basal) level through the day and increased secretion after meals (bolus insulin). Thus effective treatments may combine long acting, low-level insulin therapy with boosts of short acting insulin and/or oral agents. To achieve long term management of basal insulin level, an injectable insulin-loaded gel composed of self-assembled nanoparticles from carboxymethyl-hexanoyl chitosan (CHC) and integrated lysozyme for controlled biodegradation and insulin release was developed. In vitro characterizations and evaluations confirmed that lysozyme was active on CHC and that the amount of lysozyme in a CHC hydrogel determined the degradation and insulin release rate. The degradation products were found to be highly cytocompatible using a cell assay. In vivo evaluation of the system in a diabetic mouse model revealed that the fasted blood glucose level could be maintained in the normal range for 10 days with a single injection of insulin-loaded CHC-lysozyme gel. The insulin-loaded CHC-lysozyme gels clearly show promise for use as a novel injectable long-acting insulin delivery system, with potential to manage the basal insulin level for many days with a single injection. (C) 2015 Elsevier B.V. All rights reserved.
Local co-administration of gene-silencing RNA and drugs in cancer therapy: State-of-the art and therapeutic potential
(2017-04-01)
Larsson, Mikael
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Huang, Wei-Ting
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Liu, Dean-Mo
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Losic, Dusan
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材料科學與工程學系
Gene-silencing miRNA and siRNA are emerging as attractive therapeutics with potential to suppress any genes, which could be especially useful in combination cancer therapy to overcome multidrug resistant (MDR) cancer. Nanomedicine aims to advance cancer treatment through functional nanocarriers that delivers one or more therapeutics to cancer tissue and cells with minimal off-target effects and suitable release kinetics and dosages. Although much effort has gone into developing circulating nanocarriers with targeting functionality for systemic administration, another alternative and straightforward approach is to utilize formulations to be administered directly to the site of action, such as pulmonary and intratumoral delivery. The combination of gene-silencing RNA with drugs in nanocarriers for localized delivery is emerging with promising results. In this review, the current progress and strategies for local co-administration of RNA and drug for synergistic effects and future potential in cancer treatment are presented and discussed. Key advances in RNA-drug anticancer synergy and localized delivery systems were combined with a review of the available literature on local co-administration of RNA and drug for cancer treatment. It is concluded that advanced delivery systems for local administration of gene-silencing RNA and drug hold potential in treatment of cancer, depending on indication. In particular, there are promising developments using pulmonary delivery and intratumoral delivery in murine models, but further research should be conducted on other local administration strategies, designs that achieve effective intracellular delivery and maximize synergy and feasibility for clinical use. (C) 2017 Elsevier Ltd. All rights reserved.
The use of polymer-based nanoparticles and nanostructured materials in treatment and diagnosis of cardiovascular diseases: Recent advances and emerging designs
(2016-06)
Wang, Yen-Jen
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Larsson, Mikael
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Huang, Wei-Ting
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Chiou, Shih-Hwa
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Nicholls, Stephen J.
This review summarizes important advances in polymer-based nanotechnologies for the treatment and diagnosis of cardiovascular diseases, focusing on nanoparticles and nanostructured materials/devices. The current state of the art and design parameters are discussed with the aim of providing a source of information that can aid in the development of new treatments by bridging between materials development, preclinical, and clinical trials. This is highly relevant as cardiovascular diseases remain a leading cause of death worldwide and as current treatments burden the healthcare systems with great costs. Different strategies, from targeting theranostic nanocarriers, to dual-drug depot systems, injectable cell scaffolds, and LDL acceptors are treated. The review ends with a concluding outlook on the ossibilities and challenges presented to polymer-based nanotechnologies in cardiovascular disease therapy. (c) 2016 Elsevier Ltd. All rights reserved.
Unique Assembly Structure Of Human Haptoglobin Phenotypes 1-1, 2-1, And 2-2 And A Predominant Hp1 Allele Hypothesis
(2009-02-01)
Cheng, Tsai-Mu
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Larsson, Mikael
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Chiang, Fang-Hsing
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Chou, Fu-Hsaun
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Mao, Simon J. T.