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Publications (10 of 18) Show all publications
Kadekar, S., Nawale, G. N., Karlsson, K., Ålander, C., Podiyan, O. & Varghese, O. P. (2019). Synthetic design of asymmetric miRNA with engineered 3′-overhang to improve strand selection. Molecular Therapy - Nucleic Acids, 16, 597-604
Open this publication in new window or tab >>Synthetic design of asymmetric miRNA with engineered 3′-overhang to improve strand selection
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2019 (English)In: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 16, p. 597-604Article in journal (Refereed) Published
Abstract [en]

We have developed a novel miRNA design that significantly improves strand selection within the RISC complex by engineering the 3′-end by adding extra nucleotides. Addition of seven nucleotides at the 3′-ends of the miR or miR* strand resulted in a thermodynamic asymmetry at either of the two-ends, which resulted in selective RISC recruitment as demonstrated by the stem-loop quantitative PCR experiment. Such selective recruitment was also corroborated at the protein level by Western blot analysis. In order to investigate the functional effect due to selective recruitment, we performed apoptosis and metastasis studies using human colon carcinoma cells (HCT116) and human osteosarcoma cells (MG63). These experiments indicated that the recruitment of miR strand is responsible for inducing apoptosis as well as to inhibit invasiveness of cancer cells. Recruitment of miR* strand, on the other hand, showed opposite effect. To the best of our knowledge, our strand engineering strategy is the first report of improved strand selection of desired miRNA strand by RISC without using any chemical modifications or mismatches. We believe such structural modifications of miR34a could mitigate some of the off-target effects of miRNA therapy and would also allow a better understanding of sequence-specific gene regulation. Such a design could also be adapted to other miRNA to enhance their therapeutic potential.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
RNA interference, miRNA, miR34a, strand selection, anticancer therapy
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-382299 (URN)10.1016/j.omtn.2019.04.012 (DOI)000470250900053 ()31085353 (PubMedID)
Funder
Swedish Foundation for Strategic Research , SBE13-0028National initiative on Stem Cells for Regenerative Therapy, 2009-1035
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-06-26Bibliographically approved
Roshanbinfar, K., Hilborn, J., Varghese, O. P. & Oommen, O. P. (2017). Injectable and thermoresponsive pericardial matrix derived conductive scaffold for cardiac tissue engineering. RSC Advances, 7(51), 31980-31988
Open this publication in new window or tab >>Injectable and thermoresponsive pericardial matrix derived conductive scaffold for cardiac tissue engineering
2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 51, p. 31980-31988Article in journal (Refereed) Published
Abstract [en]

Scaffolds derived from decellularized cardiac tissue offer an enormous advantage for cardiac applications as they recapitulate biophysical and cardiac specific cues. However, poor electrical conductivity and mechanical properties severely compromise the therapeutic potential of these matrices. Dispersion of multiwall carbon nanotubes (MWCTs) in these scaffolds could improve their mechanical and electrical properties. However, the inherent hydrophobicity and poor dispersibility of these materials under aqueous conditions limit their outcome. We have developed a modified MWCNT functionalized with carbodihydrazide (CDH) residues that significantly improved their dispersibility and suppressed cytotoxicity in HL-1 cardiomyocytes. We found that the doping of CDH functionalized MWCNT (CDH-MWCNT) as low as 0.5 wt% to the pericardial matrix hydrogel (PMNT) induced the necessary electrical conductivity and significantly improved the mechanical properties of the hydrogel. Cardiomyocytes cultured on a PMNT scaffold triggered proliferation and significantly increased the expression of cardiac-specific gap junction protein, namely connexin 43. Such a phenomenon was not observed when cardiomyocytes were cultured on the pericardial matrix derived gels without MWCNT or on gelatin-fibronectin coated 2D cultures. The PMNT gels displayed excellent biophysical characteristics resulting in the clustering of cardiomyocytes with synchronous contraction, which is crucial for the successful integration to the host tissue.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-337097 (URN)10.1039/C7RA03780E (DOI)000404362100021 ()
Available from: 2017-12-20 Created: 2017-12-20 Last updated: 2018-09-19Bibliographically approved
Gurav, D., Varghese, O. P., Hamad, O. A., Nilsson, B., Hilborn, J. & Oommen, O. P. (2016). Chondroitin sulfate coated gold nanoparticles: a new strategy to resolve multidrug resistance and thromboinflammation. Chemical Communications, 52(5), 966-969
Open this publication in new window or tab >>Chondroitin sulfate coated gold nanoparticles: a new strategy to resolve multidrug resistance and thromboinflammation
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2016 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, no 5, p. 966-969Article in journal (Refereed) Published
Abstract [en]

We have developed the first chondroitin sulfate polymer coated gold nanoparticles that can simultaneously overcome mulidrug resistance in cancer cells and suppress thromboinflammation triggered by the chemotherapeutic drug.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-276827 (URN)10.1039/c5cc09215a (DOI)000367614000025 ()26587574 (PubMedID)
Funder
EU, European Research Council, 602699
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
Barman, J., Gurav, D., Oommen, O. P. & Varghese, O. P. (2015). 2 '-N-Guanidino, 4 '-C-ethylene bridged thymidine (GENA-T) modified oligonucleotide exhibits triplex formation with excellent enzymatic stability. RSC Advances, 5(16), 12257-12260
Open this publication in new window or tab >>2 '-N-Guanidino, 4 '-C-ethylene bridged thymidine (GENA-T) modified oligonucleotide exhibits triplex formation with excellent enzymatic stability
2015 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 5, no 16, p. 12257-12260Article in journal (Refereed) Published
Abstract [en]

Here we present the synthesis and characterization of a new 2'-N-Guanidino, 4'-C-ethylene bridged thymidine (GENA-T) modified oligonucleotide possessing North-locked sugar conformation. Incorporation of GENA-T nucleotide though did not change the thermal stability of the oligonucleotides toward the complementary RNA; it significantly increased the stability of the parallel triplex at pH 7. The melting temperature of the triplex was increased by +9.5 degrees C as compared to that of the isosequential unmodified sequence. Moreover this modification imparted exceptional nuclease stability to the oligonucleotides for over 33 h. This study clearly demonstrates that GENA-T modified oligonucleotides could improve triplex formation with phenomenal enzymatic stability and could be used for various biomedical applications.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-247338 (URN)10.1039/c4ra14721a (DOI)000348985400071 ()
Available from: 2015-03-22 Created: 2015-03-17 Last updated: 2017-12-04Bibliographically approved
Yan, H., Podiyan, O., Yu, D., Hilborn, J., Qian, H. & Varghese, O. P. (2015). Chondroitin Sulfate-Coated DNA-Nanoplexes Enhance Transfection Efficiency by Controlling Plasmid Release from Endosomes: A New Insight into Modulating Nonviral Gene Transfection. Advanced Functional Materials, 25(25), 3907-3915
Open this publication in new window or tab >>Chondroitin Sulfate-Coated DNA-Nanoplexes Enhance Transfection Efficiency by Controlling Plasmid Release from Endosomes: A New Insight into Modulating Nonviral Gene Transfection
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2015 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 25, no 25, p. 3907-3915Article in journal (Refereed) Published
Abstract [en]

Degradation of plasmid DNA (pDNA) in the endosome compartment and its release to the cytosol are the major hurdles for efficient gene transfection. This is generally addressed by using transfection reagents that can overcome these limitations. In this article, the first report is presented which suggests that controlling the release of pDNA from endosome is the key for achieving efficient transfection. In this study, chondroitin sulfate (CS)-coated DNA-nanoplexes are developed using a modular approach where CS is coated post-pDNA/PEI nanoplex formation. To ensure good stability of the nanoplexes, imine/enamine chemistry is exploited by reacting aldehyde-modified chondroitin sulfate (CS-CHO) with free amines of pDNA/PEI complex. This supramolecular nanocarrier system displays efficient cellular uptake, and controlled endosomal pDNA release without eliciting any cytotoxicity. On the contrary, burst release of pDNA from endosome (using chloroqine) results in significant reduction in gene expression. Unlike pDNA/PEI-based transfection, the nanoparticle design presented here shows exceptional stability and gene transfection efficiency in different cell lines such as human colorectal cancer cells (HCT116), human embryonic kidney cells (HEK293), and mouse skin-derived mesenchymal stem cells (MSCs) using luciferase protein as a reporter gene. This new insight will be valuable in designing next generation of transfection reagents.

Keywords
chondroitin sulfate, endosomal escape, gene delivery, mesenchymal stem cells, nanoparticles
National Category
Physical Sciences Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-259095 (URN)10.1002/adfm.201500695 (DOI)000357268900013 ()
Funder
EU, FP7, Seventh Framework Programme
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Wang, S., Gurav, D., Oommen, O. P. & Varghese, O. P. (2015). Insights into the Mechanism and Catalysis of Oxime Coupling Chemistry at Physiological pH. Chemistry - A European Journal, 21(15), 5980-5985
Open this publication in new window or tab >>Insights into the Mechanism and Catalysis of Oxime Coupling Chemistry at Physiological pH
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 15, p. 5980-5985Article in journal (Refereed) Published
Abstract [en]

The dynamic covalent-coupling reaction involving alpha-effect nucleophiles has revolutionized bioconjugation approaches, due to its ease and high efficiency. Key to its success is the discovery of aniline as a nucleophilic catalyst, which made this reaction feasible under physiological conditions. Aniline however, is not so effective for keto substrates. Here, we investigate the mechanism of aniline activation in the oxime reaction with aldehyde and keto substrates. We also present carboxylates as activating agents that can promote the oxime reaction with both aldehyde and keto substrates at physiological pH. This rate enhancement circumvents the influence of alpha-effect by forming H-bonds with the rate-limiting intermediate, which drives the reaction to completion. The combination of aniline and carboxylates had a synergistic effect, resulting in a similar to 14-31-fold increase in reaction rate at pD 7.4 with keto substrates. The biocompatibility and efficiency of carboxylate as an activating agent is demonstrated by performing cell-surface oxime labeling at physiological pH using acetate, which showed promising results that were comparable with aniline.

Keywords
ketones, kinetics, coupling reaction, oxime, reaction mechanisms
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-252690 (URN)10.1002/chem.201406458 (DOI)000352506500042 ()25737419 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
Tengdelius, M., Gurav, D., Konradsson, P., Pahlsson, P., Griffith, M. & Oommen, O. P. (2015). Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles. Chemical Communications, 51(40), 8532-8535
Open this publication in new window or tab >>Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles
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2015 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 51, no 40, p. 8532-8535Article in journal (Refereed) Published
Abstract [en]

Gold nanoparticles coated with fucoidan-mimetic glycopolymers were synthesized that displayed good colloidal stability and promising anti-cancer properties. Fucoidan mimetic glycopolymers on their own were nontoxic, while glycopolymer coated gold nanoparticles displayed selective cytotoxicity to human colon cancer cell lines (HCT116) while it was non-toxic to mouse fibroblast cells (NIH3T3).

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-256558 (URN)10.1039/c5cc02387d (DOI)000354043200034 ()25892661 (PubMedID)
Available from: 2015-06-24 Created: 2015-06-24 Last updated: 2017-12-04Bibliographically approved
Lal, S., Mallick, L., Rajkumar, S., Oommen, O. P., Reshmi, S., Kumbhakarna, N., . . . Namboothiri, I. N. N. (2015). Synthesis and energetic properties of high-nitrogen substituted bishomocubanes. Journal of Materials Chemistry A, 3(44), 22118-22128
Open this publication in new window or tab >>Synthesis and energetic properties of high-nitrogen substituted bishomocubanes
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2015 (English)In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 3, no 44, p. 22118-22128Article in journal (Refereed) Published
Abstract [en]

Synthesis, thermodynamic characterization, and energetic properties of three novel high-nitrogen bishomocubane-based compounds DADMBHC, DTetzBHC and DPTrizDMBHC are reported here. These compounds have higher heats of formation (HoFs) and higher energy densities as compared to traditional hydrocarbon fuels. Densities, gas phase HoF and their optimized molecular structure geometries were calculated with various levels of theory. In general, the calculated HoFs of these compounds turn out to be extremely high. Ballistic properties such as vacuum specific impulse and density vacuum specific impulse were calculated using the NASA Chemical Equilibrium and Applications utility. Propulsive properties were compared with liquid bipropellants (RP1) and solid propellants (AP) and explosive properties were compared with RDX. The density specific impulse demonstrated an improvement of 35 s for DADMBHC and DTetzBHC over standard liquid hydrocarbon HTPB, thus showing promise as possible monomers to replace HTPB as a fuel-binder. The density specific impulses of these compounds were also found to be significantly higher than that of RP1, e.g. that of DADMBHC was found to be higher by 84 s, making them potentially good candidates as propellants for use under volume-limited conditions. The detonation properties showed that these compounds have low potential as explosives. TGA, coupled with IR spectroscopy, revealed that DADMBHC and DPTrizDMBHC evaporate readily while DTetzBHC decomposes partially.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-268727 (URN)10.1039/c5ta05380c (DOI)000364080400021 ()
Available from: 2015-12-09 Created: 2015-12-09 Last updated: 2017-12-01Bibliographically approved
Podiyan, O., Garousi, J., Sloff, M. & Varghese, O. (2014). Tailored Doxorubicin-Hyaluronan Conjugate as a Potent Anticancer Glyco-Drug: An Alternative to Prodrug Approach. Macromolecular Bioscience, 14(3), 327-333
Open this publication in new window or tab >>Tailored Doxorubicin-Hyaluronan Conjugate as a Potent Anticancer Glyco-Drug: An Alternative to Prodrug Approach
2014 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 14, no 3, p. 327-333Article in journal (Refereed) Published
Abstract [en]

Releasibility of doxorubicin from drug-conjugates is believed to be a prerequisite for its anti- cancer activity. Here, a new glyco-drug approach that circumvents the releasibility restriction is reported, opening a new possibility to design efficient, target specific drug delivery system. It is discovered that stable amide coupling of doxorubicin (DOX) tohyaluronan (HA) shows dose dependent cytotoxicity to CD44 positive human coloncancer cells (HCT116) as compared to human breast cancer cells(MCF-7) and mouse fibroblast cells (NIH-3T3), which express less CD44 receptor. This direct conjugation approach is an easy scalable strategy that could be adopted to design innocuous anti-tumor nanoparticle formulations.

National Category
Polymer Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-214496 (URN)10.1002/mabi.201300383 (DOI)000332932200004 ()
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2017-12-06Bibliographically approved
Teramura, Y., Podiyan, O., Olerud, J., Hilborn, J. & Nilsson, B. (2013). Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers. Biomaterials, 34(11), 2683-2693
Open this publication in new window or tab >>Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers
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2013 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 11, p. 2683-2693Article in journal (Refereed) Published
Abstract [en]

The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra-thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal-PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi-permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum.

Keywords
Microencapsulation, Bioartificial pancreas, Islets, Poly(ethylene glycol)-lipid (PEG-lipid), Cell surface modification, Diabetes
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-197955 (URN)10.1016/j.biomaterials.2013.01.015 (DOI)000315748200011 ()
Available from: 2013-04-10 Created: 2013-04-08 Last updated: 2017-12-06Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2768-0133

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