Transcript Nanocell design for liver cencer

Nanocell:
Mechanism of action
Soraya Aroonvilairat
Inter-U program, AIT
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Scope: Mechanism of Nanocell
• Mechanisms of chemotherapeutic agents
• Conventional drugs for liver cancer & drug resistance
problems
• Mechanisms of FTY720, doxorubicin & 5FU
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http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/phar
msite/98-409/Cancer/Anticancer_drugs1.html
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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
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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
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Cisplatin
H3N
Pt
H3N
• IUPAC name :
Cl dichloroplatinum;azanide
• Chemical formula : Cl2H4N2Pt
• Platinum based
Cl
chemotherapeutic drug &
Alkylating agent
• Application: solid tumors (testis,
ovary, head & neck, bladder)
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Cisplatin-DNA interaction
Inter-strand
cross-links
Intra-strand
adduct
N7-guanine
http://www.iupac.org/publications/pac/1987/pdf/5902x0181.pdf
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Mitomycin C
O
NH
N
O
H 2N
O
O
H 2N
O
• 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
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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
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Mechanisms of drug resistance
ABC transporters
(P-gp)
•Binding of drugs
Altered drug
accumulation within
cells
•Activate ATPbinding domain
•ATP hydrolysis
causes drug release
into extracellular
space
•Mutation of receptors
or transporters involving
drug uptake
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Annu Rev Med 53:615-27, 2002
Nanocell design for liver cancer
Lipid vesicle with integrated
antiangiogenics
Fast release kinetics
100 nm
Nanocore
200 nm
Loaded with Chemotherapeutics
Slow release kinetics
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Anti-angiogenic: FTY720
OH
NH2
HO
• IUPAC name: 2-amino-2-[2-(4-octylphenyl)ethyl] propane1,3 diol
• Synthetic analogue of natural compound derived from
fungus Isaria sinclairii.
• Originally developed as novel immunosuppressant in organ
transplantation
• Sphingosine analogue
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FTY720: sphingosine analogue
http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm
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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
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www.amplab.de/3D-Images/angiogenesis-scheme.gif
FTY720: mechanism of action
• FTY720 phosphate (FTY-P) acts a high-affinity
agonist at the G protein-coupled sphingosine 1phosphate receptor
• Decreased Rac expression of tumor cells (related to
endothelial cells migration, chemotaxis)
• Inhibited VEGF expression induced vascular
permeability (anti-angiogenesis)
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FTY720: mechanism of action
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http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm
Doxorubicin (Adriamycin)
O
O
OH
OH
OH
O
O
OH
O
O
NH2
OH
• Chemical formula :
C27H29NO11
• Cytotoxic anthracycline
antibiotic
• Noncovalent DNA binding
drug
• Application: treatment of solid
tumors (breast, ovarian,
lymphoma, HCC, soft tissue
sarcoma)
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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
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Doxorubicin-DNA complex
http://chemistry.clemson.edu/ChemDocs/
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5-Fluorouracil (5-FU)
O
HN
O
N
H
• IUPAC name : 5-fluoro-1Hpyrimidine-2,4-dione
F • Chemical formula : C H FN O
4 3
2 2
• Anti-metabolite drug
• Pyrimidine base analogue
• Application: treatment of solid
tumors (breast & colon
carcinoma)
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5-FU: pyrimidine analogue
O
O
O
CH3
HN
HN
N
H
Uracil
O
O
N
H
Thymine
F
HN
O
N
H
5-Fluorouracil
• 5-FU resembles the pyrimidine bases uracil and
thymine (components of RNA & DNA)
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5-FU: mechanism of action
5-FU
FdUMP
Inhibit thymidylate
synthase
FUTP
Mistakenly
incorporate to RNA
Depletion of dTMP
alter RNA processing
(required for DNA systhesis) and protein synthesis
Apoptosis
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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
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