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Nanocell: Mechanism of action. Soraya Aroonvilairat Inter-U program, AIT. Scope: Mechanism of Nanocell. Mechanism s of chemotherapeutic agents C onventional drugs for liver cancer & drug resistance problems Mechanisms of FTY720, doxorubicin & 5FU.

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nanocell mechanism of action

Nanocell: Mechanism of action

Soraya Aroonvilairat

Inter-U program, AIT

scope mechanism of nanocell
Scope: Mechanism of Nanocell
  • Mechanisms of chemotherapeutic agents
  • Conventional drugs for liver cancer& drug resistance problems
  • Mechanisms of FTY720, doxorubicin& 5FU
slide3

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

types of chemotherapeutic drugs 1
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
types of chemotherapeutic drugs 2
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
cisplatin
Cisplatin
  • IUPAC name : dichloroplatinum;azanide
  • Chemical formula : Cl2H4N2Pt
  • Platinum based chemotherapeutic drug & Alkylating agent
  • Application: solid tumors (testis, ovary, head & neck, bladder)
cisplatin dna interaction
Cisplatin-DNA interaction

Inter-strand cross-links

Intra-strand adduct

N7-guanine

http://www.iupac.org/publications/pac/1987/pdf/5902x0181.pdf

mitomycin c
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
what are the problems of chemotherapeutics usage
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
slide10

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

nanocell design for liver cancer

100 nm

200 nm

Nanocell design for liver cancer

Lipid vesicle with integrated

antiangiogenics

Fast release kinetics

Nanocore

Loaded with Chemotherapeutics

Slow release kinetics

anti angiogenic fty720
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
fty720 sphingosine analogue
FTY720: sphingosine analogue

http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

angiogenic process
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

fty720 mechanism of action
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)
fty720 mechanism of action16
FTY720: mechanism of action

http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

doxorubicin adriamycin
Doxorubicin (Adriamycin)
  • Chemical formula : C27H29NO11
  • Cytotoxic anthracycline antibiotic
  • Noncovalent DNA binding drug
  • Application: treatment of solid tumors (breast, ovarian, lymphoma, HCC, soft tissue sarcoma)
doxorubicin mechanism of action
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
doxorubicin dna complex
Doxorubicin-DNA complex

http://chemistry.clemson.edu/ChemDocs/

5 fluorouracil 5 fu
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)
5 fu pyrimidine analogue
5-FU: pyrimidine analogue
  • 5-FU resembles the pyrimidine bases uracil and thymine (components of RNA & DNA)

Uracil Thymine 5-Fluorouracil

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

5-FU: mechanism of action

5-FU

summary
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