Nanocell: Mechanism of action

1. Nanocell: Mechanism of action Soraya Aroonvilairat Inter-U program, AIT

2. Scope: Mechanism of Nanocell • Mechanisms of chemotherapeutic agents • Conventional drugs for liver cancer& drug resistance problems • Mechanisms of FTY720, doxorubicin& 5FU

3. http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Cancer/Anticancer_drugs1.htmlhttp://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Cancer/Anticancer_drugs1.html

4. Types of chemotherapeutic drugs (1) • Antimetabolites • Structurally related to naturally occurring compounds (vitamins, amino acids, nucleotides) • Result: interfere DNA & RNA synthesis, cell proliferation • Covalent DNA-binding drugs (Alkylating agents) • Drugs (electrophilic) covalently bind to alkyl groups of bases of DNA & protein (nucleophilic) • Result: single strand break, base mispairing, cross linkage

5. Types of chemotherapeutic drugs (2) • Noncovalent DNA-binding drugs • Intercalating drugs forming tight drug-DNA interaction • Free radical damage cause single strand break • Drugs affecting endocrine function • Steroid hormones (estrogen) or their antagonists • Inhibitors of chromatin function • Drugs which disrupt the chromosomal dynamic necessary to carry out DNA replication and mitosis • 2 subgroups: topoisomerase inhibitors & microtubule inhibitors

6. Cisplatin • IUPAC name : dichloroplatinum;azanide • Chemical formula : Cl2H4N2Pt • Platinum based chemotherapeutic drug & Alkylating agent • Application: solid tumors (testis, ovary, head & neck, bladder)

7. Cisplatin-DNA interaction Inter-strand cross-links Intra-strand adduct N7-guanine http://www.iupac.org/publications/pac/1987/pdf/5902x0181.pdf

8. Mitomycin C • Chemical formula : C15H18N4O5 • Antitumor antibiotic, alkylating agent • Application: malignant neoplasm (oral cavity, pharynx, breast, and urinary bladder) • Mechanism: binding to DNA, cross-linking, inhibit DNA synthesis

9. What are the problems of chemotherapeutics usage • Side effects: nausea & vomiting, hair loss, bone marrow suppression, mouth sores, skin changes, diarrhea • Drug resistance: • Decrease drug accumulation ( drug influx, drug efflux) • Altered drug metabolism • Altered drug targets • Increased repair of drug-induced damage

10. ABC transporters (P-gp) Mechanisms of drug resistance Altered drug accumulation within cells • Binding of drugs • Activate ATP-binding domain • ATP hydrolysis causes drug release into extracellular space • Mutation of receptors or transporters involving drug uptake Annu Rev Med 53:615-27, 2002

11. 100 nm 200 nm Nanocell design for liver cancer Lipid vesicle with integrated antiangiogenics Fast release kinetics Nanocore Loaded with Chemotherapeutics Slow release kinetics

12. Anti-angiogenic: FTY720 • IUPAC name: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3 diol • Synthetic analogue of natural compound derived from fungus Isaria sinclairii. • Originally developed as novel immunosuppressant in organ transplantation • Sphingosine analogue

13. FTY720: sphingosine analogue http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

14. Angiogenic process • Angiogenesis induced by VEGF (tumor) • Degradation of basement membrane • Invasion & migration of endothelial cells to tumor • Elongation of new vessel by proliferation • Vessel maturation by synthesis of ECM www.amplab.de/3D-Images/angiogenesis-scheme.gif

15. FTY720: mechanism of action • FTY720 phosphate (FTY-P) acts ahigh-affinity agonist at the G protein-coupled sphingosine 1-phosphate receptor • Decreased Rac expression of tumor cells (related to endothelial cells migration, chemotaxis) • Inhibited VEGF expression induced vascular permeability (anti-angiogenesis)

16. FTY720: mechanism of action http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

17. Doxorubicin (Adriamycin) • Chemical formula : C27H29NO11 • Cytotoxic anthracycline antibiotic • Noncovalent DNA binding drug • Application: treatment of solid tumors (breast, ovarian, lymphoma, HCC, soft tissue sarcoma)

18. Doxorubicin: mechanism of action • DNA intercalation: binding to DNA, inhibit the progression of topoisomerase II which unwinds DNA for transcription,consequent in cell cycle disruption & cell death • Free radical damage involving reactive oxygen species (ROS) ss breakage

19. Doxorubicin-DNA complex http://chemistry.clemson.edu/ChemDocs/

20. 5-Fluorouracil (5-FU) • IUPAC name : 5-fluoro-1H-pyrimidine-2,4-dione • Chemical formula : C4H3FN2O2 • Anti-metabolite drug • Pyrimidine base analogue • Application: treatment of solid tumors (breast & colon carcinoma)

21. 5-FU: pyrimidine analogue • 5-FU resembles the pyrimidine bases uracil and thymine (components of RNA & DNA) Uracil Thymine 5-Fluorouracil

22. FdUMP FUTP Inhibit thymidylate synthase Mistakenly incorporate to RNA Depletion of dTMP (required for DNA systhesis) alter RNA processing and protein synthesis Apoptosis 5-FU: mechanism of action 5-FU

23. Summary • Nanocell is designed to solve the problems of side effects & drug resistance • Design of nanocell: anti-angiogenics (outer), chemotherapeutics (inner) • Anti-angiogenesis of FTY720: via Rac-VEGF mediated pathway • Chemotherapy of Doxorubicin: DNA intercalation, 5FU:apoptosis, alter RNA processing & protein synthesis