TPP-alantolactone conjugates and their nanotherapeutic forms for antitumor application.
| Title: | TPP-alantolactone conjugates and their nanotherapeutic forms for antitumor application. |
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| Authors: | Nemtarev AV; Alexander Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, Kremlevskaya St., 18, Kazan 420008, Russia; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia. Electronic address: a.nemtarev@mail.ru.; Shemakhina ME; Alexander Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, Kremlevskaya St., 18, Kazan 420008, Russia.; Pashirova TN; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia.; Voloshina AD; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia.; Souto EB; UCD School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4 D04 V1W8, Ireland. Electronic address: eliana.souto@ucd.ie.; Lyubina AP; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia.; Amerkhanova SK; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia.; Idrisova LR; Alexander Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, Kremlevskaya St., 18, Kazan 420008, Russia.; Semakov AV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd, 1, Chernogolovka 142432, Russia.; Mironov VF; Alexander Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, Kremlevskaya St., 18, Kazan 420008, Russia; Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia. Electronic address: mironov@iopc.ru. |
| Source: | Colloids and surfaces. B, Biointerfaces [Colloids Surf B Biointerfaces] 2026 Jan; Vol. 257, pp. 115127. Date of Electronic Publication: 2025 Sep 08. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9315133 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4367 (Electronic) Linking ISSN: 09277765 NLM ISO Abbreviation: Colloids Surf B Biointerfaces Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam ; New York : Elsevier, c1993- |
| MeSH Terms: | Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Lactones*/chemistry ; Lactones*/pharmacology ; Nanoparticles*/chemistry ; Sesquiterpenes, Eudesmane*/chemistry ; Sesquiterpenes, Eudesmane*/pharmacology ; Organophosphorus Compounds*/chemistry ; Organophosphorus Compounds*/pharmacology; Apoptosis/drug effects ; Liposomes/chemistry ; Membrane Potential, Mitochondrial/drug effects ; Cell Proliferation/drug effects ; Reactive Oxygen Species/metabolism ; Mitochondria/drug effects ; Mitochondria/metabolism ; Cell Survival/drug effects ; Humans ; Cell Line, Tumor ; HeLa Cells ; Drug Screening Assays, Antitumor |
| Abstract: | Delocalized positive charge and high hydrophobicity of triarylphosphonium (TPP) groups facilitate a penetration of the TPP-conjugated molecules through the cell and mitochondrial membranes, which result in their accumulating in tumor cells. Combining mitochondrial strategies with nanotechnology-based delivery systems is a challenge to the new cancer therapy approaches. Using synthetic approach for targeted delivery of small molecules with antitumor activity into mitochondria, the quaternary γ-oxoalkylphosphonium salts (TPP-alantolactone, TPP-AL) were synthesized under mild conditions with high yields. First time mitochondria-targeted lipid nanosystems, namely, liposomes and solid lipid nanoparticles (SLN) modified with TPP-AL were prepared and characterized. TPP-alantolactones showed a high in vitro cytotoxicity. The highest cytotoxicity against human duodenal adenocarcinoma cell lines (HuTu 80) occurred at IC50 = 0.4 µM with a high selectivity of 17.5. Cytotoxicity is increased up to 520-fold when tested TPP-alantolactone-SLN (TPP-AL-SLN) against M-HeLa cancer cell lines. The enhanced cellular uptake and accumulation of curcumin-labeled-TPP-AL-SLN were shown by confocal microscopy. TPP-AL caused a significant depolarization of mitochondrial membrane in the HuTu 80 cancer cells, increased ROS production and over expression of caspase-9, suggesting an intrinsic mitochondrial mechanism for triggering apoptosis. A significant delay of cells in the G0/G1 phase compared to the control was revealed. In addition to the anti-tumor effect TPP-AL exhibit a bactericidal activity, i.e. they are dual-action drugs. TPP-AL are noticeably active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), with a minimum bactericidal concentration (MBC) of 7.8 µM, which is close to the antibiotic norfloxacin. TPP-derived sesquiterpene lactones-decorated nanosystems showed a high potential as antitumor agents for the targeted delivery to the mitochondria of tumor cells.; (Copyright © 2025 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Alantolactone; Cytotoxity; Drug Delivery Systems; Phosphonium salt; Solid Lipid Nanoparticles; TPP-conjugate |
| Substance Nomenclature: | 0 (Antineoplastic Agents); 0 (Lactones); M7GSN5Q1M6 (alantolactone); 0 (Sesquiterpenes, Eudesmane); 0 (Liposomes); 0 (Organophosphorus Compounds); 0 (Reactive Oxygen Species) |
| Entry Date(s): | Date Created: 20250913 Date Completed: 20251113 Latest Revision: 20251113 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.colsurfb.2025.115127 |
| PMID: | 40945407 |
| Database: | MEDLINE |
Journal Article