Publications by authors named "Eiji Yuba"

83 Publications

pH-Sensitive branched β-glucan-modified liposomes for activation of antigen presenting cells and induction of antitumor immunity.

J Mater Chem B 2021 Sep 21. Epub 2021 Sep 21.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

Induction of cellular immunity is important for effective cancer immunotherapy. Although various antigen carriers for cancer immunotherapy have been developed to date, balancing efficient antigen delivery to antigen presenting cells (APCs) and their activation innate immune receptors, both of which are crucially important for the induction of strong cellular immunity, remains challenging. For this study, branched β-glucan was selected as an intrinsically immunity-stimulating and biocompatible material. It was engineered to develop multifunctional liposomal cancer vaccines capable of efficient interactions with APCs and subsequent activation of the cells. Hydroxy groups of branched β-glucan (Aquaβ) were modified with 3-methylglutaric acid ester and decyl groups, respectively, to provide pH-sensitivity and anchoring capability to the liposomal membrane. The modification efficiency of Aquaβ derivatives to the liposomes was significantly high compared with linear β-glucan (curdlan) derivatives. Aquaβ derivative-modified liposomes released their contents in response to weakly acidic pH. As a model antigenic protein, ovalbumin (OVA)-loaded liposomes modified with Aquaβ derivatives interacted efficiently with dendritic cells, and induced inflammatory cytokine secretion from the cells. Subcutaneous administration of Aquaβ derivative-modified liposomes suppressed the growth of the E.G7-OVA tumor significantly compared with curdlan derivative-modified liposomes. Aquaβ derivative-modified liposomes induced the increase of CD8 T cells, and polarized macrophages to the antitumor M1-phenotype within the tumor microenvironment. Therefore, pH-sensitive Aquaβ derivatives can be promising materials for liposomal antigen delivery systems to induce antitumor immune responses efficiently.
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http://dx.doi.org/10.1039/d1tb00786fDOI Listing
September 2021

Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery.

Mol Pharm 2021 Sep 8;18(9):3290-3301. Epub 2021 Aug 8.

Graduate School of Science, Osaka Prefecture University, 1-1, Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

The antimicrobial protein CAP18 (approximate molecular weight: 18 000), which was first isolated from rabbit granulocytes, comprises a C-terminal fragment that has negatively charged lipopolysaccharide binding activity. In this study, we found that CAP18 (106-121)-derived (sC18) peptides have macropinocytosis-inducible biological functions. In addition, we found that these peptides are highly applicable for use as extracellular vesicle (exosomes, EV)-based intracellular delivery, which is expected to be a next-generation drug delivery carrier. Here, we demonstrate that dimerized (sC18) peptides can be easily introduced on EV membranes when modified with a hydrophobic moiety, and that they show high potential for enhanced cellular uptake of EVs. By glycosaminoglycan-dependent induction of macropinocytosis, cellular EV uptake in targeted cells was strongly increased by the peptide modification made to EVs, and intriguingly, our herein presented technique is efficiently applicable for the cytosolic delivery of the biologically cell-killing functional toxin protein, saporin, which was artificially encapsulated in the EVs by electroporation, suggesting a useful technique for EV-based intracellular delivery of biofunctional molecules.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00244DOI Listing
September 2021

Multifunctional Traceable Liposomes with Temperature-Triggered Drug Release and Neovasculature-Targeting Properties for Improved Cancer Chemotherapy.

Mol Pharm 2021 Sep 29;18(9):3342-3351. Epub 2021 Jul 29.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Poor distribution of nanocarriers at the tumor site and insufficient drug penetration into the tissue are major challenges in the development of effective and safe cancer therapy. Here, we aim to enhance the therapeutic effect of liposomes by accumulating doxorubicin-loaded liposomes at high concentrations in and around the tumor, followed by heat-triggered drug release to facilitate low-molecular-weight drug penetration throughout the tumor. A cyclic RGD peptide (cRGD) was incorporated into liposomes decorated with a thermosensitive polymer that allowed precise tuning of drug release temperature (i.e., Polymer-lip) to develop a targeted thermosensitive liposome (cRGD-Polymer-lip). Compared with conventional thermosensitive liposomes, cRGD-Polymer-lip enhanced the binding of liposomes to endothelial cells, leading to their accumulation at the tumor site upon intravenous administration in tumor-bearing mice. Drug release triggered by local heating strongly inhibited tumor growth. Notably, tumor remission was achieved via multiple administrations of cRGD-Polymer-lip and heat treatments. Thus, combining the advantages of tumor neovascular targeting and heat-triggered drug release, these liposomes offer high potential for minimally invasive and effective cancer chemotherapy.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00263DOI Listing
September 2021

Carboxylated polyamidoamine dendron-bearing lipid-based assemblies for precise control of intracellular fate of cargo and induction of antigen-specific immune responses.

Biomater Sci 2021 Apr 8;9(8):3076-3089. Epub 2021 Mar 8.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

For the establishment of advanced medicines such as cancer immunotherapy, high performance carriers that precisely deliver biologically active molecules must be developed to target organelles of the cells and to release their contents there. From the viewpoint of antigen delivery, endosomes are important target organelles because they contain immune-response-related receptors and proteins of various types. To obtain carriers for precision endosome delivery, a novel type of polyamidoamine dendron-based lipid having pH-sensitive terminal groups was synthesized for this study. Liposomes were prepared using these pH-sensitive dendron-based lipids and egg yolk phosphatidylcholine. Their pH-responsive properties and performance as an endosome delivery carrier were investigated. pH-Sensitive dendron lipid-based liposomes retained water-soluble molecules at neutral pH but released them under weakly acidic conditions. Particularly, liposomes containing CHexDL-G1U exhibited highly sensitive properties responding to very weakly acidic pH. These dendron lipid-based liposomes released the contents specifically in the endosome. The timing of content release can be controlled by selecting pH-sensitive dendron lipids for liposome preparation. Significant tumor regression was induced in tumor-bearing mice by the administration of CHexDL-G1U-modified liposomes containing the model antigenic protein. Furthermore, CHexDL-G1U-modified liposomes induced WT1 tumor antigenic peptide-specific helper T cell proliferation. The results demonstrate that dendron lipid-based liposomes are useful as a potent vaccine for cancer immunotherapy.
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http://dx.doi.org/10.1039/d0bm01813aDOI Listing
April 2021

Hydrophilic Hyperbranched Polymer-Coated siRNA/Polyamidoamine Dendron-Bearing Lipid Complexes Preparation for High Colloidal Stability and Efficient RNAi.

Bioconjug Chem 2021 03 4;32(3):563-571. Epub 2021 Mar 4.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

RNA interference (RNAi) using siRNA has gained much attention for use in therapies for cancer and genetic disorders. To establish RNAi-based therapeutics, the development of efficient siRNA nanocarriers is desired. Earlier, we developed polyamidoamine dendron-bearing lipids able to form complexes with nucleic acids as gene vectors. Especially, dendron lipids with unsaturated alkyl chains (DL-G1-U2) induced efficient endosomal escape by membrane fusion, leading to efficient transfection . For this study, dendron lipids having oleyl/linoleyl groups (DL-G1-U3) were designed to increase membrane fusogenic activity further. Indeed, DL-G1-U3/siRNA complexes achieved higher membrane fusogenic activity and knockdown of the target gene more efficiently than conventional DL-G1-U2/siRNA complexes did. A hydrophilic polymer, hyperbranched polyglycidol lauryl ester (HPG-Lau), was modified further on the surface of DL-G1-U3/siRNA complexes to provide colloidal stability. Surface modification of HPG-Lau increased the colloidal stability in a physiological condition more than complexes without HPG-Lau. Importantly, HPG-Lau-coated DL/siRNA complexes showed identical RNAi effects to those of parental DL/siRNA complexes, whereas the RNAi activity of poly(ethylene glycol)-bearing lipid (PEG-PE)-modified DL/siRNA complexes was hindered completely. Introduction of unsaturated bonds into dendron lipids and selection of suitable hydrophilic polymers for nanocarrier modification are important for obtaining efficient siRNA vectors toward siRNA delivery.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00035DOI Listing
March 2021

Environmental pH stress influences cellular secretion and uptake of extracellular vesicles.

FEBS Open Bio 2021 03 18;11(3):753-767. Epub 2021 Feb 18.

Keio University School of Medicine, Tsukuba, Japan.

Exosomes (extracellular vesicles/EVs) participate in cell-cell communication and contain bioactive molecules, such as microRNAs. However, the detailed characteristics of secreted EVs produced by cells grown under low pH conditions are still unknown. Here, we report that low pH in the cell culture medium significantly affected the secretion of EVs with increased protein content and zeta potential. The intracellular expression level and location of stably expressed GFP-fused CD63 (an EV tetraspanin) in HeLa cells were also significantly affected by environmental pH. In addition, increased cellular uptake of EVs was observed. Moreover, the uptake rate was influenced by the presence of serum in the cell culture medium. Our findings contribute to our understanding of the effect of environmental conditions on EV-based cell-cell communication.
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http://dx.doi.org/10.1002/2211-5463.13107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931216PMC
March 2021

Suppression of Rheumatoid Arthritis by Enhanced Lymph Node Trafficking of Engineered Interleukin-10 in Murine Models.

Arthritis Rheumatol 2021 05 8;73(5):769-778. Epub 2021 Mar 8.

University of Chicago, Chicago, Illinois, USA.

Objective: Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials have been performed using interleukin-10 (IL-10), an antiinflammatory cytokine, as a potential treatment of RA, the therapeutic effects of IL-10 have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. This study was undertaken to engineer an IL-10-serum albumin (SA) fusion protein and evaluate its effects in 2 murine models of RA.

Methods: SA-fused IL-10 (SA-IL-10) was recombinantly expressed. Mice with collagen antibody-induced arthritis (n = 4-7 per group) or collagen-induced arthritis (n = 9-15 per group) were injected intravenously with wild-type IL-10 or SA-IL-10, and the retention of SA-IL-10 in the lymph nodes (LNs), immune cell composition in the paws, and therapeutic effect of SA-IL-10 on mice with arthritis were assessed.

Results: SA fusion to IL-10 led to enhanced accumulation in the mouse LNs compared with unmodified IL-10. Intravenous SA-IL-10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive alternatively activated macrophages, reduced IL-17A levels in the paw-draining LN, and protected joint morphology. Intravenous SA-IL-10 treatment showed similar efficacy as treatment with an anti-tumor necrosis factor antibody. SA-IL-10 was equally effective when administered intravenously, locally, or subcutaneously, which is a benefit for clinical translation of this molecule.

Conclusion: SA fusion to IL-10 is a simple but effective engineering strategy for RA therapy and has potential for clinical translation.
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http://dx.doi.org/10.1002/art.41585DOI Listing
May 2021

Prolonged residence of an albumin-IL-4 fusion protein in secondary lymphoid organs ameliorates experimental autoimmune encephalomyelitis.

Nat Biomed Eng 2021 05 12;5(5):387-398. Epub 2020 Oct 12.

Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.

Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show that, in mice with EAE, the accumulation and persistence in the lymph nodes and spleen of a systemically administered serum albumin (SA)-IL-4 fusion protein leads to higher efficacy in preventing disease development than the administration of wild-type IL-4 or of the clinically approved drug fingolimod. We also show that the SA-IL-4 fusion protein prevents immune-cell infiltration in the spinal cord, decreases integrin expression in antigen-specific CD4 T cells, increases the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal cord-draining lymph nodes and decreases the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA-IL-4 inhibits immune-cell infiltration into the spinal cord and completely abrogates immune responses to myelin antigen in the spleen. The SA-IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis.
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http://dx.doi.org/10.1038/s41551-020-00627-3DOI Listing
May 2021

Development of Mannose-Modified Carboxylated Curdlan-Coated Liposomes for Antigen Presenting Cell Targeted Antigen Delivery.

Pharmaceutics 2020 Aug 11;12(8). Epub 2020 Aug 11.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

Specific delivery to antigen presenting cells (APC) and precise control of the intracellular fate of antigens are crucial to induce cellular immunity that directly and specifically attacks cancer cells. We previously achieved cytoplasmic delivery of antigen and activation of APC using carboxylated curdlan-modified liposomes, which led to the induction of cellular immunity in vivo. APCs express mannose receptors on their surface to recognize pathogen specifically and promote cross-presentation of antigen. In this study, mannose-residue was additionally introduced to carboxylated curdlan as a targeting moiety to APC for further improvement of polysaccharide-based antigen carriers. Mannose-modified curdlan derivatives were synthesized by the condensation between amino group-introduced mannose and carboxy group in pH-sensitive curdlan. Mannose residue-introduced carboxylated curdlan-modified liposomes showed higher pH-sensitivity than that of liposomes modified with conventional carboxylated curdlan. The introduction of mannose-residue to the liposomes induced aggregation in the presence of Concanavalin A, indicating that mannose residues were presented onto liposome surface. Mannose residue-introduced carboxylated curdlan-modified liposomes exhibited high and selective cellular association to APC. Furthermore, mannose residue-introduced carboxylated curdlan-modified liposomes promoted cross-presentation of antigen and induced strong antitumor effects on tumor-bearing mice. Therefore, these liposomes are promising as APC-specific antigen delivery systems for the induction of antigen-specific cellular immunity.
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http://dx.doi.org/10.3390/pharmaceutics12080754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465930PMC
August 2020

Temperature-Responsive Molecular Assemblies Using Oligo(Ethylene Glycol)-Attached Polyamidoamine Dendron Lipids and their Functions as Drug Carriers.

J Funct Biomater 2020 Mar 13;11(1). Epub 2020 Mar 13.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Temperature-responsive nanocarrier systems using external stimuli are one of the most widely investigated stimuli-responsive strategies because heat is easy and safe to use for hyperthermia and controlled drug delivery. Polyamidoamine dendron lipids (PAMAM-DLs) composed of PAMAM dendron as head group and two alkyl chains can exhibit temperature-responsive morphological change through the attachment of suitable moieties to terminal of PAMAM dendron. In this study, oligo(ethylene glycol)s including ethoxy- or methoxy-diethylene glycols were attached to the terminals of PAMAM-DL, and temperature-responsive properties of their self-assemblies were evaluated by calorimetric and turbidity measurements. In the evaluation of temperature-responsive properties, ethoxy diethylene glycol (EDEG)-attached PAMAM-DL composed of two saturated alkyl chains and PAMAM dendron with 1st generation had lipid bilayer structure and suitable cloud point for the application as drug carrier. performances of the assemblies combining EDEG-attached PAMAM-DLs with cholesteryl-oxy-poly(ethylene glycol) (PEG-Chol) was evaluated using doxorubicin (DOX) as an anticancer drug. Cellular uptake of DOX-loaded EDEG-attached PAMAM-DL/PEG-Chol assemblies was promoted at 42 °C rather than 37 °C, resulting in an effective decrease in cell viability.
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http://dx.doi.org/10.3390/jfb11010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151555PMC
March 2020

Preparation of photothermal-chemotherapy nanohybrids by complexation of gold nanorods with polyamidoamine dendrimers having poly(ethylene glycol) and hydrophobic chains.

J Mater Chem B 2020 04 13;8(14):2826-2833. Epub 2020 Mar 13.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

The combination of anticancer drugs and laser hyperthermia could lead to efficient cancer treatment with less-adverse effects. This study combined anticancer drug-loaded functional dendrimers and light-responsive gold nanorods to fabricate nanohybrids that can provide anticancer-drug delivery and subsequent heat generation under near-infrared laser irradiation. A condensation reaction was used to conjugate poly(ethylene glycol)-modified polyamidoamine dendrimers to carboxylated gold nanorod surfaces. Oleoyl groups were incorporated into dendrimers to improve the drug loading capacity. Doxorubicin loading capacity was improved by incorporation of oleoyl chains into dendrimers in the nanohybrid, indicating increased hydrophobic interaction between anticancer drugs and nanohybrids. The nanohybrids exhibited heat generation properties under near infrared laser irradiation. They released anticancer drugs over time. The combination of doxorubicin-loaded nanohybrids and laser irradiation showed markedly better cytotoxicity than that of the nanohybrids used with lasers and drug-loaded nanohybrids without the use of lasers. After intravenous or intratumoral injection of nanohybrids to tumor-bearing mice, a sharp temperature increase was observed at the tumor site under laser irradiation. Especially, intratumorally injected doxorubicin-loaded nanohybrids showed almost complete tumor growth suppression under laser irradiation. The results demonstrate that functional dendrimer-gold nanorod nanohybrids are promising as multi-functional nanomaterials to achieve synergistic effects of anticancer drugs and heat ablation to support effective cancer treatments.
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http://dx.doi.org/10.1039/c9tb02163aDOI Listing
April 2020

Light-Activatable Transfection System Using Hybrid Vectors Composed of Thermosensitive Dendron Lipids and Gold Nanorods.

Pharmaceutics 2020 Mar 7;12(3). Epub 2020 Mar 7.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 5998531, Japan.

Background: Gene delivery to target cells is crucially important to establish gene therapy and regenerative medicine. Although various virus-based and synthetic molecule-based gene vectors have been developed to date, selective transfection in a site or a cell level is still challenging. For this study, both light-responsive and temperature-responsive synthetic gene vectors were designed for spatiotemporal control of a transfection system.

Methods: 11-Mercaptoundecanoic acid-coated gold nanorods were mixed with polyamidoamine dendron-bearing lipids of two types having amino-terminus or ethoxydiethylene glycol-terminus to obtain hybrid vectors. Hybrid vectors were mixed further with pDNA. Then we investigated their physicochemical properties and transfection efficacy with or without near infrared laser irradiation.

Results: Hybrid vectors formed complexes with pDNA and exhibited enhanced photothermal property under near infrared laser irradiation compared with parent gold nanorods. Transfection efficacy of complexes was promoted considerably by brief laser irradiation soon after complex application to the cells. Analysis of intracellular distribution revealed that laser irradiation promoted the adsorption of complexes to the cells and cytosolic release of pDNA, which is derived from the change in surface hydrophobicity of complexes through dehydration of temperature-responsive groups.

Conclusions: Hybrid vector is promising as a light-activatable transfection system.
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http://dx.doi.org/10.3390/pharmaceutics12030239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150951PMC
March 2020

Manipulation of the tumor microenvironment by cytokine gene transfection enhances dendritic cell-based immunotherapy.

FASEB Bioadv 2020 Jan 26;2(1):5-17. Epub 2019 Nov 26.

Department of Advanced Pathobiology Graduate School of Life and Environmental Sciences Osaka Prefecture University Izumisano Japan.

The tumor microenvironment strongly influences clinical outcomes of immunotherapy. By transfecting genes of relevant cytokines into tumor cells, we sought to manipulate the microenvironment so as to elicit activation of T helper type 1 (Th1) responses and the maturation of dendritic cells (DCs). Using a synthetic vehicle, the efficiency of in vivo transfection of GFP-cDNA into tumor cells was about 7.5% by intratumoral injection and about 11.5% by intravenous injection. Survival was significantly improved by both intratumoral and intravenous injection of the plasmid containing cDNA of interferon-gamma, followed by intratumoral injection of DCs presenting the tumor antigens. Also, tumor growth was inhibited by these treatments. A more significant effect on survival and tumor growth inhibition was observed following injection of the plasmid containing cDNA of CD40 ligand, which is a potent inducer of DC-maturation. Furthermore, the co-injection of both IFNγ- and CD40 ligand-encoding cDNA-plasmids, followed by DC treatment, gave rise to further marked and enhancement, including 100% survival and more than 50% complete remission. This treatment regimen elicited significant increases in mature DCs and types of cells contributing to Th1 responses, and significant decreases in immune suppressor cells in the tumor. In the spleen, the treatment significantly increased activities of tumor-specific killer and natural killer cells, but no alteration was observed in mature DCs or suppressor cells. These results indicate that transfection of these cytokine genes into tumor cells significantly alter the tumor microenvironment and improve the therapeutic results of DC-based immunotherapy.
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http://dx.doi.org/10.1096/fba.2019-00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996313PMC
January 2020

Plant lectins and their usage in preparing targeted nanovaccines for cancer immunotherapy.

Semin Cancer Biol 2020 Feb 14. Epub 2020 Feb 14.

Protein Biochemistry Research Laboratory, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Tathawade, Pune, 411033, Maharashtra, India. Electronic address:

Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, ManGlcNAcAsn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8 T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.
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http://dx.doi.org/10.1016/j.semcancer.2020.02.005DOI Listing
February 2020

Development of functional liposomes by modification of stimuli-responsive materials and their biomedical applications.

Authors:
Eiji Yuba

J Mater Chem B 2020 02 21;8(6):1093-1107. Epub 2020 Jan 21.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Liposomes are a promising nanocarrier for drug delivery because of their biocompatibility and the encapsulation capacity of drugs. Liposomes can be functionalized easily by introduction of functional materials such as stimulus-responsive materials. Temperature-responsive liposomes and pH-responsive liposomes are representative stimulus-responsive liposomes that can deliver drugs to locally heated target tissues and intracellular organelles. Here, temperature-responsive liposomes for the selective release of cargo and pH-responsive liposomes for the induction of antigen-specific immunity are overviewed. Temperature-responsive polymer-modified liposomes immediately released drugs in response to heating, which achieved selective drug release at a tumour after topical heating of tumour-bearing mice. Introduction of MR-detectable molecules enabled the tracing of liposome accumulation into target sites to optimize the heating timing. These liposomes can also be combined with magnetic nanoparticles or carbon nanomaterials to attain magnetic field-responsive, electric field-responsive and light-responsive properties to support on-demand drug release or control of biological reactions using these external stimuli. pH-Responsive liposomes were produced by modification of poly(carboxylic acid) derivatives or by pH-responsive amphiphiles. These liposomes delivered antigenic proteins into the cytosol of antigen presenting cells, which induced cross-presentation and antigen-specific cellular immunity. Adjuvant molecules or bioactive polysaccharide-based pH-responsive polymers improved their immunity-inducing effect further, leading to tumour regression in tumour-bearing mice. Precise design and control of the structures of stimulus-responsive materials and combination with functional materials are expected to create novel methodologies to control biological functions and to produce highly potent liposomal drugs that can achieve selective release of bioactive molecules.
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http://dx.doi.org/10.1039/c9tb02470kDOI Listing
February 2020

Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-α antibody in a murine model of rheumatoid arthritis.

Arthritis Res Ther 2019 12 23;21(1):298. Epub 2019 Dec 23.

Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA.

Background: Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model.

Methods: α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2). The binding activity of PlGF-2-conjugated α-TNF (PlGF-2-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse.

Results: PlGF-2 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose.

Conclusion: These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.
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http://dx.doi.org/10.1186/s13075-019-2075-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929495PMC
December 2019

Effects of Lyophilization of Arginine-rich Cell-penetrating Peptide-modified Extracellular Vesicles on Intracellular Delivery.

Anticancer Res 2019 Dec;39(12):6701-6709

Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Osaka, Japan

Background/aim: Extracellular vesicles (exosomes, EVs) (30-200 nm in diameter) are secreted by various cells in the body. Owing to the pharmaceutical advantages of EVs, an EV-based drug delivery system (DDS) for cancer therapy is expected to be the next-generation therapeutic system. However, preservation methods for functional and therapeutic EVs should be developed. Here, we developed the method of lyophilization of arginine-rich cell penetrating peptide (CPP)-modified EVs and investigated the effects of lyophilization on the characteristics of EVs.

Materials And Methods: Particle size, structure, zeta-potential, and cellular uptake efficacy of the arginine-rich CPP-modified EVs were analyzed. The model protein saporin (SAP), having anti-cancer effects, was encapsulated inside the EVs to assess the cytosolic release of EV content after cellular uptake.

Results: Lyophilization of the EVs did not affect their particle size, structure, zeta-potential, and cellular uptake efficacy; however, the biological activity of the encapsulated SAP was inhibited by lyophilization.

Conclusion: Lyophilization of EVs may affect SAP structures and/or reduce the cytosolic release efficacy of EV's content after cellular uptake and needs attention in EV-based DDSs.
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http://dx.doi.org/10.21873/anticanres.13885DOI Listing
December 2019

Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

Sci Adv 2019 11 6;5(11):eaay1971. Epub 2019 Nov 6.

Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-β (α-TGF-β) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.
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http://dx.doi.org/10.1126/sciadv.aay1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834392PMC
November 2019

Gene Expression of Aspect Ratio-Controlled Polyplexes Based on the Effect of Multi-Arm Poly(ethylene glycol).

ACS Biomater Sci Eng 2019 Nov 29;5(11):5681-5687. Epub 2019 Mar 29.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Controlling the aspect ratio of polyplexes prepared by mixing pDNA with a polycation mixture of a poly(l-lysine) (PLL) homopolymer and PLL terminally bearing a multiarm poly(ethylene glycol) (PEG) part (maPEG-PLL) was examined. By varying the maPEG-PLL content in the polycation mixture, the condensation of pDNA accompanied by polyplex formation and the morphology of the polyplexes were evaluated by a dye exclusion assay and AFM observations, respectively. Increasing the maPEG-PLL content caused elongation of the polyplex, and polyplexes with aspect ratios from 2 to 10 were prepared successfully by controlling the maPEG-PLL content. The reactivity of pDNA in the polyplexes with varying aspect ratios against DNase I and polymerase were examined by agarose gel electrophoresis and real-time PCR measurements, respectively. Moreover, cellular uptake and transfection efficiency of the polyplexes by HeLa cells was evaluated. The results revealed that an increase in aspect ratio of the polyplexes caused an increase in PCR efficiency with a concomitant decrease in cellular uptake.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01498DOI Listing
November 2019

Development of pH-Responsive Hyaluronic Acid-Based Antigen Carriers for Induction of Antigen-Specific Cellular Immune Responses.

ACS Biomater Sci Eng 2019 Nov 25;5(11):5790-5797. Epub 2019 Oct 25.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

Cancer immunotherapy has gained much attention because of the recent success of immune checkpoint inhibitors. Nevertheless, clinical therapeutic effects of immune checkpoint inhibitors remain limited, probably because most patients have other immune checkpoint molecules or because they lack cancer-specific cytotoxic T lymphocytes. Induction of cancer-specific cytotoxic T lymphocytes requires efficient antigen delivery systems that can convey cancer antigens specifically to antigen presenting cells, promote the endosomal escape of antigen into cytosol, and activate immune cells. Earlier, we reported cytoplasmic delivery systems of antigen using pH-sensitive polymer-modified liposomes. Adjuvant molecules were further incorporated into these liposomes to provide activation properties of cellular immune responses. This study further introduced cell specificity to these liposomal systems using hyaluronic acid-based pH-sensitive polymers, which are recognized by CD44 expressing on antigen presenting cells. pH-Sensitive hyaluronic acid derivative-modified liposomes showed much higher cellular association to antigen presenting cells than to fibroblasts with less CD44 expression. These liposomes achieved the delivery of model antigenic proteins into cytosol of dendritic cells and promoted Th1 cytokine production from the cells. Subcutaneous administration of these liposomes to mice induced antigen-specific cellular immune response in the spleen, leading to tumor regression in tumor-bearing mice. The results show that pH-sensitive hyaluronic acid derivative-modified liposomes are promising as multifunctional antigen carriers having cell-specificity, cytoplasmic antigen delivery performance, and adjuvant property to induce antigen-specific cellular immunity.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01278DOI Listing
November 2019

Engineering anti-cancer nanovaccine based on antigen cross-presentation.

Biosci Rep 2019 10;39(10)

Protein Biochemistry Research Laboratory, Dr. D.Y. Patil Biotechnology and Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth (Deemed to be University), Tathawade, Pune 411033, Maharashtra, India.

Dendritic cells (DCs) present exogenous antigens on major histocompatibility complex (MHC) class I molecules, thereby activating CD8+ T cells, contributing to tumor elimination through a mechanism known as antigen cross-presentation. A variety of factors such as maturation state of DCs, co-stimulatory signals, T-cell microenvironment, antigen internalization routes and adjuvants regulate the process of DC-mediated antigen cross-presentation. Recently, the development of successful cancer immunotherapies may be attributed to the ability of DCs to cross-present tumor antigens. In this review article, we focus on the underlying mechanism of antigen cross-presentation and ways to improve antigen cross-presentation in different DC subsets. We have critically summarized the recent developments in the generation of novel nanovaccines for robust CD8+ T-cell response in cancer. In this context, we have reviewed nanocarriers that have been used for cancer immunotherapeutics based on antigen cross-presentation mechanism. Additionally, we have also expressed our views on the future applications of this mechanism in curing cancer.
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http://dx.doi.org/10.1042/BSR20193220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822533PMC
October 2019

Chondroitin Sulfate-Based pH-Sensitive Polymer-Modified Liposomes for Intracellular Antigen Delivery and Induction of Cancer Immunity.

Bioconjug Chem 2019 05 11;30(5):1518-1529. Epub 2019 Apr 11.

Department of Applied Chemistry Graduate School of Engineering , Osaka Prefecture University , 1-1 Gakuen-cho , Naka-ku, Sakai , Osaka 599-8531 , Japan.

Induction of cancer-specific cytotoxic T lymphocytes is crucially important to complement therapeutic effects of immune checkpoint inhibitors and to achieve efficient cancer immunotherapy. To induce cancer-specific cytotoxic T lymphocytes, cancer antigen carriers must have multiple functions to deliver cancer antigens to antigen presenting cells, release antigens into cytosol, and promote the maturation of these cells. We earlier achieved cytosolic delivery of antigens and induction of antigen-specific cytotoxic T lymphocytes using carboxylated polyglycidol or polysaccharide derivative-modified liposomes that can induce membrane fusion with endosomes in response to weakly acidic pH. Furthermore, pH-sensitivity and adjuvant properties of these polymers were enhanced strongly by introduction of hydrophobic carboxylated units to dextran. Against our expectations, these polymer-modified liposomes only slightly induce cancer immunity, probably because of the high hydrophobicity of spacer units. This study used a polysaccharide with charged groups (chondroitin sulfate) instead of dextran as a backbone to reduce hydrophobicity. Chondroitin sulfate derivative-modified liposomes showed almost equal pH-sensitivity to that of dextran derivative-modified liposomes and achieved selective delivery to dendritic cells, whereas dextran derivative-modified liposomes were highly taken up by both dendritic cells and fibroblasts. Chondroitin sulfate derivative-modified liposomes delivered model antigenic proteins into cytosol of dendritic cells and promoted cytokine production from the cells, leading to tumor regression on tumor-bearing mice after subcutaneous administration. Results demonstrate that charged groups having polysaccharide as a backbone can be used in an effective strategy to balance strong hydrophobicity of spacer units with their utilization for immunity-inducing systems.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00221DOI Listing
May 2019

Synthesis, Characterization, and Biomedical Applications of an Alkylated Quercetin-Gadolinium Complex.

ACS Biomater Sci Eng 2019 Mar 14;5(3):1215-1227. Epub 2019 Feb 14.

Centre for Nanotechnology & Advanced Biomaterials, SASTRA Deemed University, Thanjavur 613401, India.

Flavonoids and their derivatives have been extensively studied for their pharmaceutical applications due to their antioxidant and anti-inflammatory properties. The coordination complexes of several flavonoids have demonstrated DNA binding ability that can confer anticancer properties. The structure of the flavonoid has a pronounced influence on its pharmacological properties. Herein we report the synthesis and characterization of alkylated quercetin and its complex with gadolinium. The structure of the complex was confirmed using spectroscopic techniques. The ability of the gadolinium-alkylated quercetin complex to serve as a magnetic contrast agent was compared with gadolinium-quercetin complex. The quercetin-gadolinium complex was found to exhibit better contrast property with a relaxivity of 0.2952 μg mL s when compared to the gadolinium complex of alkylated quercetin. This difference primarily arises due to the greater hydrophobicity of the alkylated quercetin complex that restricts access of water. However, the alkylated quercetin was found to exhibit better enzyme mimic activity as the metal ion served as a redox center that enabled quantification of hydrogen peroxide in the concentration range 50-450 μM within 5 s with a sensitivity of 64 nA/μM and limit of detection of 7.3 μM. The better sensing performance of the alkylated quercetin-gadolinium complex, reported here for the first time, when compared to quercetin-gadolinium complex can be attributed to the enhanced electroactive area on the working electrode.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01254DOI Listing
March 2019

Emerging paradigms in nanotechnology for imaging and treatment of cerebral ischemia.

J Control Release 2019 04 22;300:22-45. Epub 2019 Feb 22.

Centre for Nanotechnology & Advanced Biomaterials (CeNTAB), School of Chemical & Biotechnology, SASTRA Deemed-to-be University, Thanjavur 613 401, India. Electronic address:

Cerebral ischemia is a deadly condition that arises due to blockage of the blood vessels in the brain leading to oxygen deficiency thereby arresting brain functions and resulting in death or permanent impairment. Though a myriad of factors has been proposed to cause cerebral ischemia, it has been generally regarded as an old age-associated malady. However, unhealthy diet, stressful lifestyle and deteriorating environment quality has dramatically reduced the age on onset as well as the number of victims in recent years. Hence, there exists a need for prompt and effective therapeutic strategies for immediate as well as long-term damage control and maintenance of the functions of the brain, as well as early and accurate diagnosis of the risk of stroke or extent of damage after stroke. The physiological barriers further complicate the development of therapeutic and diagnostic interventions for cerebral stroke. The advent of nanotechnology has initiated new vistas for more effective and superior therapeutic and imaging modalities for management of cerebral ischemia. This review provides an overview on the current knowledge on the mechanism and causative factors of cerebral ischemia, drawbacks of conventional therapy as well as molecular targets that are being explored for stroke therapy. The review also discusses in detail the advances made using nano-interventions for therapy and imaging of stroke-affected regions along with their pros and cons. Emergent multi-functional nanoparticles for stroke management have also been reviewed.
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http://dx.doi.org/10.1016/j.jconrel.2019.02.031DOI Listing
April 2019

Sonodynamic Therapeutic Effects of Sonosensitizers with Different Intracellular Distribution Delivered by Hollow Nanocapsules Exhibiting Cytosol Specific Release.

Macromol Biosci 2019 04 1;19(4):e1800365. Epub 2019 Feb 1.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan.

Sonodynamic therapy (SDT) is a novel promising noninvasive therapy involving utilization of low-intensity ultrasound and sonosensitizer, which can generate reactive oxygen species (ROS) by sonication. In SDT, a high therapeutic effect is achieved by intracellular delivery and accumulation at the target sites of sonosensitizer followed by oxidative damage of produced ROS by sonication. Here, pH- and redox-responsive hollow nanocapsules are prepared through the introduction of disulfide cross-linkages to self-assembled polymer vesicles formed from polyamidoamine dendron-poly(l-lysine) for the efficient delivery of sonosensitizer. As sonosensitizer, doxorubicin (DOX), an anticancer drug accumulating into cell nucleus, is selected. Also, the conjugate of DOX and triphenylphosphonium (TPP-DOX) is synthesized as sonosensitizer with mitochondrial targeting ability. DOX and TPP-DOX are delivered to nucleus and mitochondria by nanocapsules. Furthermore, DOX- or TPP-DOX-loaded nanocapsules exhibit in vitro sonodynamic therapeutic effect to HeLa cells with sonication, which might be through oxidative damage to nucleus and mitochondria.
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http://dx.doi.org/10.1002/mabi.201800365DOI Listing
April 2019

Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4 T cells expressing converged T-cell receptor genes .

Oncoimmunology 2018;7(4):e1415687. Epub 2018 Jan 5.

Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto, Japan.

DEP domain containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1) are human cancer testis antigens that are frequently overexpressed in urinary bladder cancer. In a phase I/II clinical trial, a DEPDC1- and MPHOSPH1-derived short peptide vaccine demonstrated promising efficacy in preventing bladder cancer recurrence. Here, we aimed to identify long peptides (LPs) derived from DEPDC1 and MPHOSPH1 that induced both T-helper (Th) cells and tumor-reactive cytotoxic T lymphocytes (CTLs). Stimulation of peripheral blood mononuclear cells (PBMCs) from healthy donors with the synthetic DEPDC1- and MPHOSPH1-LPs predicted to bind to promiscuous human leukocyte antigen (HLA) class II molecules by a computer algorithm induced specific CD4 T cells as revealed by interferon-γ enzyme-linked immunospot assays. Three of six LPs encompassed HLA-A2- or -A24-restricted CTL epitopes or both, and all six LPs stimulated DEPDC1- or MPHOSPH1-specific Th cells restricted by promiscuous and frequently observed HLA class II molecules in the Japanese population. Some LPs are naturally processed from the proteins in DCs, and the capacity of these LPs to cross-prime CTLs was confirmed using HLA-A2 or -A24 transgenic mice. The LP-specific and HLA class II-restricted T-cell responses were also observed in PBMCs from patients with bladder cancer. Repeated stimulation of PBMCs with DEPDC1-LPs and MPHOSPH1-LPs yielded clonal Th cells expressing specific T-cell receptor (TCR)-α and β genes. These DEPDC1- or MPHOSPH1-derived LPs may have applications in immunotherapy in patients with bladder cancer, and the TCR genes identified may be useful for monitoring of Th cells specific to LPs .
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http://dx.doi.org/10.1080/2162402X.2017.1415687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889196PMC
January 2018

Bleomycin-Loaded pH-Sensitive Polymer⁻Lipid-Incorporated Liposomes for Cancer Chemotherapy.

Polymers (Basel) 2018 Jan 15;10(1). Epub 2018 Jan 15.

Joint Department of Veterinary Clinical Medicine, Faculty of Agriculture, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan.

Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM) was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol)-lipid (PEG-PE) for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE) for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.
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http://dx.doi.org/10.3390/polym10010074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415073PMC
January 2018

Evaluation of pH-sensitive fusogenic polymer-modified liposomes co-loaded with antigen and α-galactosylceramide as an anti-tumor vaccine.

J Vet Med Sci 2018 Feb 28;80(2):197-204. Epub 2017 Dec 28.

Division of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka 598-8531, Japan.

pH-Sensitive fusogenic polymer-modified (pH-sensitive) liposomes co-loaded with tumor model antigen, ovalbumin (OVA), and adjuvant, α-galactosylceramide (α-GalCer) were fabricated and administered subcutaneously into mice. The ability of pH-sensitive liposomes containing OVA and α-GalCer to stimulate cellular and humoral immune responses in vivo was compared with OVA-encapsulating pH-sensitive liposomes as well as with OVA alone. After immunization, significant OVA-specific antibodies were detected in the serum. When sera were analyzed for isotype distribution, antigen-specific IgG1 antibody responses were noted in mice immunized with OVA alone, whereas immunization with OVA-containing pH-sensitive liposomes and with pH-sensitive liposomes containing OVA and α-GalCer resulted in the induction of OVA-specific IgG1 and IgG2b antibody responses. Moreover, more substantial production of IFN-γ and IL-4 was demonstrated in spleen cells from mice immunized with pH-sensitive liposomes having OVA and α-GalCer than OVA-containing pH-sensitive liposomes in vitro. Spleen cells from the immunized mice showed strong cytotoxic activity against E.G7-OVA tumor cells. In addition, prophylactic vaccination efficacy against tumor formation was evaluated. In all mice immunized with pH-sensitive liposomes having OVA and α-GalCer, immunization provided substantial protection from tumor formation. The therapeutic efficacy of pH-sensitive liposomes containing OVA and α-GalCer against already established E.G7-OVA tumors was also investigated. Tumor growth was reduced significantly in all mice treated with pH-sensitive liposomes having OVA and α-GalCer. The provided evidence on the advantage of antigen and α-GalCer co-encapsulation into pH-sensitive liposomes should be considered in the design of future cancer vaccines for prophylactic and therapeutic purposes.
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http://dx.doi.org/10.1292/jvms.17-0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836753PMC
February 2018

Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems.

Bioconjug Chem 2018 01 12;29(1):44-55. Epub 2017 Dec 12.

Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

For the enhancement of therapeutic effects and reduction of side effects derived from anticancer drugs in cancer chemotherapy, it is imperative to develop drug delivery systems with cancer-specificity and controlled release function inside cancer cells. pH-sensitive liposomes are useful as an intracellular drug delivery system because of their abilities to transfer their contents into the cell interior through fusion or destabilization of endosome, which has weakly acidic environment. We earlier reported liposomes modified with various types of pH-sensitive polymers based on synthetic polymers and biopolymers as vehicles for intracellular drug delivery systems. In this study, hyaluronic acid (HA)-based pH-sensitive polymers were designed as multifunctional polymers having not only pH-sensitivity but also targeting properties to cells expressing CD44, which is known as a cancer cell surface marker. Carboxyl group-introduced HA derivatives of two types, MGlu-HA and CHex-HA, which have a more hydrophobic side chain structure than that of MGlu-HA, were synthesized by reaction with various dicarboxylic anhydrides. These polymer-modified liposomes were stable at neutral pH, but showed content release under weakly acidic conditions. CHex-HA-modified liposomes delivered their contents into CD44-expressing cells more efficiently than HA-modified or MGlu-HA-modified liposomes or unmodified liposomes, whereas the same liposomes were taken up only slightly by cells expressing CD44 proteins less. Competition assay using free HA or other polymers revealed that HA derivative-modified liposomes might be recognized by CD44. Therefore, HA-derivative-modified liposomes are useful as cell-specific intracellular drug delivery systems.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00551DOI Listing
January 2018
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