Most cited article - PubMed ID 30605747
Folic acid-mediated re-shuttling of ferritin receptor specificity towards a selective delivery of highly cytotoxic nickel(II) coordination compounds
PURPOSE: The present study deals with the in vitro evaluation of the potential use of coordination compound-based zinc oxide (ZnO) nanoparticles (NPs) for the treatment of triple negative breast cancer cells (TNBrCa). As BrCa is one of the most prevalent cancer types and TNBrCa treatment is difficult due to poor prognosis and a high metastasis rate, finding a more reliable treatment option should be of the utmost interest. METHODS: Prepared by reacting zinc carboxylates (formate, acetate, propionate, butyrate, isobutyrate, valerate) and hexamethylenetetramine, 4 distinct coordination compounds were further subjected to two modes of conversion into ZnO NPs - ultrasonication with oleic acid or heating of pure precursors in an air atmosphere. After detailed characterization, the resulting ZnO NPs were subjected to in vitro testing of cytotoxicity toward TNBrCa and normal breast epithelial cells. Further, their biocompatibility was evaluated. RESULTS: The resulting ZnO NPs provide distinct morphological features, size, biocompatibility, and selective cytotoxicity toward TNBrCa cells. They internalize into two types of TNBrCa cells and imbalance their redox homeostasis, influencing their metabolism, morphology, and ultimately leading to their death via apoptosis or necrosis. CONCLUSION: The crucial properties of ZnO NPs seem to be their morphology, size, and zinc content. The ZnO NPs with the most preferential values of all three properties show great promise for a future potential use in the therapy of TNBrCa.
- Keywords
- carboxylate, hexamethylenetetramine, nanoparticles, redox homeostasis imbalance, triple negative breast cancer, zinc oxide coordination compounds,
- MeSH
- Apoptosis drug effects MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nanoparticles chemistry MeSH
- Zinc Oxide chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Triple Negative Breast Neoplasms pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Zinc Oxide MeSH
- Antineoplastic Agents MeSH
INTRODUCTION: The present study reports on examination of the effects of encapsulating the tyrosine kinase inhibitors (TKIs) vandetanib and lenvatinib into a biomacromolecular ferritin-based delivery system. METHODS: The encapsulation of TKIs was performed via two strategies: i) using an active reversible pH-dependent reassembly of ferritin´s quaternary structure and ii) passive loading of hydrophobic TKIs through the hydrophobic channels at the junctions of ferritin subunits. After encapsulation, ferritins were surface-functionalized with folic acid promoting active-targeting capabilities. RESULTS: The physico-chemical and nanomechanical analyses revealed that despite the comparable encapsulation efficiencies of both protocols, the active loading affects stability and rigidity of ferritins, plausibly due to their imperfect reassembly. Biological experiments with hormone-responsive breast cancer cells (T47-D and MCF-7) confirmed the cytotoxicity of encapsulated and folate-targeted TKIs to folate-receptor positive cancer cells, but only limited cytotoxic effects to healthy breast epithelium. Importantly, the long-term cytotoxic experiments revealed that compared to the pH-dependent encapsulation, the passively-loaded TKIs exert markedly higher anticancer activity, most likely due to undesired influence of harsh acidic environment used for the pH-dependent encapsulation on the TKIs' structural and functional properties. CONCLUSION: Since the passive loading does not require a reassembly step for which acids are needed, the presented investigation serves as a solid basis for future studies focused on encapsulation of small hydrophobic molecules.
- Keywords
- drug delivery, lenvatinib, nanomedicine, vandetanib,
- MeSH
- Biocompatible Materials chemistry MeSH
- Cell Death drug effects MeSH
- Clone Cells MeSH
- Cell Line MeSH
- Quinazolines chemistry pharmacology MeSH
- Quinolines chemistry pharmacology MeSH
- Diffusion MeSH
- Phenylurea Compounds chemistry pharmacology MeSH
- Ferritins chemistry MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Hydrogen-Ion Concentration MeSH
- Horses MeSH
- Folic Acid chemistry MeSH
- Drug Delivery Systems * MeSH
- Humans MeSH
- Drug Carriers chemistry MeSH
- Piperidines chemistry pharmacology MeSH
- Cell Movement drug effects MeSH
- Surface Properties MeSH
- Antineoplastic Agents pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Biocompatible Materials MeSH
- Quinazolines MeSH
- Quinolines MeSH
- Phenylurea Compounds MeSH
- Ferritins MeSH
- Protein Kinase Inhibitors MeSH
- Folic Acid MeSH
- lenvatinib MeSH Browser
- Drug Carriers MeSH
- Piperidines MeSH
- Antineoplastic Agents MeSH
- vandetanib MeSH Browser
Allyl- and propargyl ethers of umbelliferone are sensitive probes for palladium and platinum, including anticancer compounds cisplatin, carboplatin and oxaliplatin, and effective for direct visualization of protein and DNA complexes with organometallic compounds in polyacrylamide gels allowing easy detection of interactions with analyzed protein or nucleic acid. Both probes can be used for fast evaluation of Pd/Pt binding to nanocarriers relevant in drug targeted therapy or specific clinically relevant target macromolecules.
- MeSH
- Acrylic Resins MeSH
- DNA chemistry MeSH
- Organoplatinum Compounds chemistry MeSH
- Palladium chemistry MeSH
- Platinum chemistry MeSH
- Proteins chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acrylic Resins MeSH
- DNA MeSH
- Organoplatinum Compounds MeSH
- Palladium MeSH
- Platinum MeSH
- polyacrylamide gels MeSH Browser
- Proteins MeSH
BACKGROUND: Currently, the diagnosis and treatment of neuroblastomas-the most frequent solid tumors in children-exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. RESULTS: The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (< - 228 kJ/mol). The peptides were comprehensively characterized by computational and spectroscopic methods showing ~ 21% β-sheets/aggregation for GASNGINAYL and ~ 27% α-helix for SLWERLAYGI. After decorating 12-nm ferritin-based nanovehicles with cysteinated peptides, both peptides exhibited high potential for use in actively targeted neuroblastoma nanotherapy with exceptional in vitro biocompatibility and stability, showing minor yet distinct influences of the peptides on the global expression profiles. Upon binding to hNET with fast binding kinetics, GASNGINAYLC peptides enabled rapid endocytosis of ferritins into neuroblastoma cells, leading to apoptosis due to increased selective cytotoxicity of transported payload ellipticine. Peptide-coated nanovehicles significantly showed higher levels of early apoptosis after 6 h than non-coated nanovehicles (11% and 7.3%, respectively). Furthermore, targeting with the GASNGINAYLC peptide led to significantly higher degree of late apoptosis compared to the SLWERLAYGIC peptide (9.3% and 4.4%, respectively). These findings were supported by increased formation of reactive oxygen species, down-regulation of survivin and Bcl-2 and up-regulated p53. CONCLUSION: This novel homing nanovehicle employing GASNGINAYLC peptide was shown to induce rapid endocytosis of ellipticine-loaded ferritins into neuroblastoma cells in selective fashion and with successful payload. Future homing peptide development via lead optimization and functional analysis can pave the way towards efficient peptide-based active delivery of nanomedicines to neuroblastoma cells.
- Keywords
- Ferritin, Homing peptide, Neuroblastoma, Norepinephrine transporter, Targeted therapy,
- MeSH
- Endocytosis genetics MeSH
- Ferritins chemistry MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nanomedicine MeSH
- Nanostructures chemistry MeSH
- Neuroblastoma metabolism MeSH
- Peptides chemistry genetics metabolism MeSH
- Norepinephrine Plasma Membrane Transport Proteins * chemistry genetics metabolism MeSH
- Antineoplastic Agents chemistry pharmacokinetics pharmacology MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Ferritins MeSH
- Peptides MeSH
- Norepinephrine Plasma Membrane Transport Proteins * MeSH
- Antineoplastic Agents MeSH
The electrochemical redox behavior of three trinuclear Ni(II) complexes [Ni3(abb)3(H2O)3(µ-ttc)](ClO4)3 (1), [Ni3(tebb)3(H2O)3(µ-ttc)](ClO4)3·H2O (2), and [Ni3(pmdien)3(µ-ttc)](ClO4)3 (3), where abb = 1-(1H-benzimidazol-2-yl)-N-(1H-benzimidazol-2-ylmethyl)methan-amine, ttcH3 = trithiocyanuric acid, tebb = 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole, and pmdien = N,N,N',N″,N″-pentamethyldiethylenetriamine is reported. Cyclic voltammetry (CV) was applied for the study of the electrochemical behavior of these compounds. The results confirmed the presence of ttc and nickel in oxidation state +2 in the synthesized complexes. Moreover, the antibacterial properties and cytotoxic activity of complex 3 was investigated. All the complexes show antibacterial activity against Staphylococcus aureus and Escherichia coli to different extents. The cytotoxic activity of complex 3 and ttcNa3 were studied on G-361, HOS, K-562, and MCF7 cancer cell lines. It was found out that complex 3 possesses the cytotoxic activity against the tested cell lines, whereas ttcNa3 did not show any cytotoxic activity.
- Keywords
- cyclic voltammetry, nickel complexes, trimercaptotriazine, trithiocyanuric acid,
- Publication type
- Journal Article MeSH