| 1. |
- Bergstrom, U, et al.
(författare)
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Drug targeting to the brain: Transfer of picolinic acid along the olfactory pathways
- 2002
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Ingår i: Journal of Drug Targeting. - : Informa UK Limited. - 1061-186X .- 1029-2330. ; 10:6, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [H-3]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [H-3]PA. After 4h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [H-3]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [H-3]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium, is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.
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| 2. |
- Dahlström Wester, Maria, et al.
(författare)
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Targeting malignant glioma cells in vitro using platelet-derived growth factor AA-based conjugates
- 2009
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Ingår i: Journal of drug targeting. - : Informa UK Limited. - 1029-2330 .- 1061-186X. ; , s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is an unusually aggressive brain tumor; it is also highly heterogeneous. Poor prognosis and a median survival of less than 1 year, using conventional treatment, calls for development of new treatment strategies. Overexpression and/or amplification of platelet-derived growth factor alpha receptors (PDGFalphaRs) in GBM might act as potential targets for a novel therapeutic approach. In this study, conjugates based on PDGFAA-ligand and dextran, of different sizes (10 and 40 kDa dextran), were prepared and investigated regarding targeting properties in vitro. Three human malignant glioma cell lines, U343MGa31L, U343MGaCl2:6, and U563MG, were used because of their previously reported differences in receptor expression and behavior. PDGFAA-based 10 kDa dextran iodine-125 radiolabeled conjugates showed the most favorable properties according to results achieved in accumulation, retention, and localization of cell-associated radioactivity. In comparison with dextran-(125)I-tyrosine delivered radioactivity, the PDGFAA-based dextran conjugates confirm the potential of receptor targeting.
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| 3. |
- Fondell, Amelie, et al.
(författare)
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In vitro evaluation and biodistribution of HER2-targeted liposomes loaded with an 125I-labelled DNA-intercalator
- 2011
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Ingår i: Journal of drug targeting (Print). - 1061-186X .- 1029-2330. ; 19:9, s. 846-855
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increasing attention is currently focussed on the issue of finding strategies for the delivery of Auger-electron emitting radionuclides into tumour cell nuclei. Nuclear localisation is a prerequisite for these radionuclides, since their radiotoxic properties are functional only in close vicinity to DNA.Purpose: In this study we investigated tumour-cell uptake and cell killing ability in vitro, as well as in vivo biodistribution of an 125I-labelled anthracycline derivative administered by means of HER2-targeted liposomes.Methods: Anthracycline derivative Comp1 was radiolabelled with Auger-emitting 125I and encapsulated in liposomes (DSPC:Chol:DSPE-PEG) using pH-gradient loading. Single-chain fragment F5 was anchored to the liposomes as targeting device for HER2. Uptake and specificity of 125I-Comp1 delivered via targeting and non-targeting liposomes were analysed in cultured HER2-overexpressing SKOV3 and SKBR3 cells. Cell-killing efficacy was evaluated in SKOV3 cells and biodistribution for up to 48 hours was studied after intra-peritoneal injection in tumour-bearing female Balb/c nu/nu mice.Results: 125I-Comp1 was specifically taken up by the cultured cells when administered by means of HER2-targeted liposomes and a clear dose-effect correlation in survival of cells was seen with increasing specific activity. The biodistribution studies revealed that 125I-Comp1 accumulated in tumours when distributed using HER2-targeted liposomes and that this effect was absent when using non-targeting liposomes.Conclusion: The HER2-targeted liposomes possess the properties needed to bring about tumour-specific delivery and therapeutic effect of 125I-Comp1.
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| 4. |
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| 5. |
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| 6. |
- Hojjat-Farsangi, Mohammad
(författare)
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Targeting non-receptor tyrosine kinases using small molecule inhibitors : an overview of recent advances
- 2015
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Ingår i: Journal of Drug Targeting. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1061-186X. ; 24:3, s. 192-211
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Tidskriftsartikel (refereegranskat)abstract
- Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.
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| 7. |
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| 8. |
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| 9. |
- Kokhaei, Parviz, et al.
(författare)
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Ibrutinib-A double-edge sword in cancer and autoimmune disorders
- 2015
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Ingår i: Journal of Drug Targeting. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1061-186X. ; 24:5, s. 373-385
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Tidskriftsartikel (refereegranskat)abstract
- Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton’s tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.
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| 10. |
- Larhed, Agneta, et al.
(författare)
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Starch microparticles as oral vaccine adjuvant : antigen-dependent uptake in mouse intestinal mucosa
- 2004
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Ingår i: Journal of drug targeting (Print). - : Informa UK Limited. - 1061-186X .- 1029-2330. ; 12:5, s. 289-296
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Tidskriftsartikel (refereegranskat)abstract
- An oral vaccine formulation comprised of starch microparticles with conjugated antigens is being developed. In this report we have examined the uptake of such microparticles by the intestinal mucosa and examined whether the conjugated antigen can influence the uptake. Two model antigens were used: recombinant cholera toxin B subunit (rCTB), which is known to bind to the ubiquitous GM1-receptor, and human serum albumin (HSA) which is not known to have any specific binding properties. The uptake was studied in mouse ligated intestinal loops into which the microparticles were injected. The intestinal loops were excised, fixed in ice-cold 95% ethanol. Entire specimens were mounted, exposed to fluorescence-labeled reagents staining the cytoskeleton, the particles and/or M cells and examined in a confocal laser-scanning microscope. A qualitative difference in the uptake of the rCTB- and HSA-conjugated microparticles was seen. The rCTB-conjugated microparticles were found both in villi and in the follicles of the Peyer's patches. HSA-conjugated microparticles could only be detected in the follicles of the Peyer's patches and not in villi. The rCTB conjugated to the microparticles did not lose its ability to bind the GM1-receptor, as shown with a GM1-ELISA, and the uptake of rCTB-conjugated microparticles in villi is most probably facilitated by the rCTB binding to the GM1-receptor. The qualitative difference in uptake could be of importance for the development of an immune response as the cytokine and chemokine microenvironment during antigen presentation will decide the differentiation of the immune response induced.
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| 11. |
- Lindmark, T, et al.
(författare)
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Absorption enhancement in intestinal epithelial Caco-2 monolayers by sodium caprate : Assessment of molecular weight dependence and demonstration of transport routes
- 1998
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Ingår i: Journal of drug targeting (Print). - : Informa UK Limited. - 1061-186X .- 1029-2330. ; 5:3, s. 215-223
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Tidskriftsartikel (refereegranskat)abstract
- Sodium caprate (CIO), a medium chain fatty acid, is used clinically to enhance rectal absorption of the low molecular weight (MW) drug ampicillin. The main aim of this study was to investigate whether CIO also enhances the permeability of high MW model drugs in a model of the intestinal epithelium. The second aim was to present visual evidence of the route of enhanced transport across the epithelial cell layer. The studies were performed in Caco-2 monolayers cultured on permeable supports. The effects of non-toxic concentrations (≤ 13 mM) of CIO on drug transport across the monolayers was studied using monodisperse 14C-polyethylene glycols (MW 238-502; 14C-PEGs), 125I-Arg8-vasopressin (MW 1,208), 125I-insulin (MW 6,000) and FITC-labelled dextrans (MW 4,400 and 19,600; FD4 and FD20 respectively) as model drugs. Electron and confocal laser scanning microscopy were used to demonstrate transport routes across the epithelium. 10 mM C10 increased the permeability of all 14C-PEGs to approximately the same extent. 13 mM C10 increased the permeability of 125I-Arg8-vasopressin 10-fold. Only small increases in FD4 and FD20 permeabilities were observed. After C10 exposure, both tight junctions with normal morphology and those with dilatations showed an increased permeability to ruthenium red, indicating that C10 enhanced the paracellular transport of molecules with a MW < 1,000. Confocal microscopy showed that C10 increased the transport of FD4 and FD20 by the paracellular route. In conclusion, nontoxic concentrations of C10 can be used to enhance the permeability of drugs of MW up to approximately 1,200. Enhancement of the absorption of molecules larger than 4,000 is quantitatively insignificant. The enhanced permeability occurred via the paracellular pathway.
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| 12. |
- Masquelier, M, et al.
(författare)
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Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy : Study of stability of drug-carrier complexes in blood
- 2000
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Ingår i: Journal of drug targeting (Print). - 1061-186X .- 1029-2330. ; 8:3, s. 155-164
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Tidskriftsartikel (refereegranskat)abstract
- Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL, In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.
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| 13. |
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| 14. |
- Pärnaste, Ly, et al.
(författare)
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Methods to follow intracellular trafficking of cell-penetrating peptides
- 2016
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Ingår i: Journal of drug targeting (Print). - 1061-186X .- 1029-2330. ; 24:6, s. 508-519
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Tidskriftsartikel (refereegranskat)abstract
- Cell-penetrating peptides (CPPs) are efficient vehicles to transport bioactive molecules into the cells. Despite numerous studies the exact mechanism by which CPPs facilitate delivery of cargo to its intracellular target is still debated. The current work presents methods that can be used for tracking CPP/pDNA complexes through endosomal transport and show the role of endosomal transport in the delivery of cargo. Separation of endosomal vesicles by differential centrifugation enables to pinpoint the localization of delivered cargo without labeling it and gives important quantitative information about pDNA trafficing in certain endosomal compartments. Single particle tracking (SPT) allows following individual CPP/cargo complex through endosomal path in live cells, using fluoresently labled cargo and green fluoresent protein expressing cells. These two different methods show similar results about tested NickFect/pDNA complexes intracellular trafficing. NF51 facilitates rapid internalization of complexes into the cells, prolongs their stay in early endosomes and promotes release to cytosol. NF1 is less capable to induce endosomal release and higher amount of complexes are routed to lysosomes for degradation. Our findings offer potential delivery vector for in vivo applications, NF51, where endosomal entrapment has been allayed. Furthermore, these methods are valuable tools to study other CPP-based delivery systems.
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| 15. |
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