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

4. Types of chemotherapeutic drugs (1)
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
Antimetabolites
Structurally related to naturally occurring compounds (vitamins, amino acids, nucleotides)
Result: interfere DNA & RNA synthesis, cell proliferation

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

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

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. Mechanisms of drug resistance
ABC transporters (P-gp)
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. Nanocell design for liver cancer
Lipid vesicle with integrated
antiangiogenics
Fast release kinetics
200 nm
100 nm
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

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

15. FTY720: mechanism of action
FTY720 phosphate (FTY-P) acts a high-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

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

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

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

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