1. Nanotechnology in Cancer
Treatment

2. Background and Introduction
 Cancer
Development of abnormal cells that divide uncontrollably which have
the ability to infiltrate and destroy normal body tissue
 Chemotherapy
Use of anti-cancer (cytotoxic) drugs to destroy cancer cells.
Work by disrupting the growth of cancer cells
 Nonspecificity
 Toxicity
 Adverse side effects
 Poor solubility

3.  Cancer Nanotechnology
interdisciplinary research, cutting across the disciplines of
 Biology
 Chemistry
 Engineering
 Physics
 Medicine
Nanoparticles
 Semiconductor quantum dots (QDs)
 Ion oxide nanocrystals
 Carbon nanotubes
 Polymeric nanoparticles
Liposomes
Unique Properties
 Structural
 Optical
 Magnetic

4. • Tumors generally can’t grow beyond 2 mm in size without
becoming angiogenic (attracting new capillaries) because
difficulty in obtaining oxygen and nutrients.
• Tumors produce angiogenic factors to form new capillary
structures.
• Tumors also need to recruit macromolecules from the blood
stream to form a new extracellular matrix.
• Permeability-enhancing factors such as VEGF (vascular
endothelial growth factor) are secreted to increase the
permeability of the tumor blood vessels.

5. Tissue selectivity
Tissues with a leaky endothelial wall contribute to a
significant uptake of NP. In liver, spleen and bone
marrow, NP uptake is also due to the macrophages
residing in the tissues.

7. • In tumors the uptake depends on the so-called
enhanced permeability and retention effect
(EPR).

8. TUMOR-TISSUE TARGETING

9. Schematic of EPR (enhanced
permeability and retention) effect in
solid tumors:
1- nanovehicles passively target to vasculature
and extravasate through fenestrated tumor
vasculature.
2- the extended circulation time (stealth
features) allows accumulation in tumor tissue
3- lack of lymphatic drainage prevents removal
of nanoparticles after extravasation
This passive targeting process facilitates tumor
tissue binding, followed by drug release for cell
killing.
Nanovehicles which fail to bind to tumor cells
will reside in the extracellular (interstitial)
space, where they eventually become
destabilized because of enzymatic and
phagocytic attack. This results in extracellular
drug release for eventual diffusion to nearby
tumor cells and bystander cell.

12. In vivo distribution of long-circulating radiolabeled liposomes
i.v. injected into C26 tumour-bearing mice
Liposomes : DPPC ( a saturated lipid)/ 20%GM1 ganglioside ( a
stealth Glycolipid)

14. Targeting tumours vasculature

15. Vascular targets
Vascular endothelial GF
Vascular cell adhesion molecule
Matrix metalloproteinases
Tumour targets
Human epidermal receptor
Transferrin receptor
Folate receptor

16. Affinity-based targeting of tumors.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
© 2010 Ruoslahti et al.

17. Saturation of receptors affects the specificity of targeting.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
© 2010 Ruoslahti et al.

18. Treating tumors with cooperative nanoparticles.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
© 2010 Ruoslahti et al.

19. Molecular Cancer Imaging (QDs)
 Tumor Targeting and Imaging
Emission wavelengths are size
tunable (2 nm-7 nm) 4
High molar extinction coefficients
Conjugation with copolymer
improves size-tunable optical properties of ZnS-capped CdSe QDs
biocompatibility, selectivity and
decrease cellular toxicity 5

20.  Correlated Optical and X-Ray Imaging
High resolution sensitivity in detection of small
tumors 6
x-rays provides detailed anatomical locations
Polymer-encapsulated QDs
 No chemical or enzymatic degradations
 QDs cleared from the body by slow filtration
or excretion out of the body

21. ANTICANCER DRUG
•Passive diffusion •Poorly vascolarized tumor
PHYSIOLOGICAL BARRIERS
•EPR non cellular based mechanisms
region
•Acidic enviroments in
tumors
DRUG DRUG RESISTANCE
•Biochemical alterations
cellular based mechanisms
•Endocytosis/phagocytosis
by the cells
•Overcome MDR
DISTRIBUTION, CLEARANCE OF •Large volume of
DRUG distribution
•Toxic side-effects on
normal cells
Controlled tumoral interstitial
drug release

22. TUMOR-TISSUE TARGETING
Conventional Nanoparticles Long-circulating Nanoparticles
• Size > 100 nm. • Size < 100 nm, “Stealth”, invisible to
• Delivery to RES tissues. macrophages.
• Rapid effect (0.5-3 hr). • Hydrophylic surface to reduce
opsonization (e.g. PEG)
• For RES localized tumors
(hepatocarcinoma, hepatic • Prolonged half-life in blood compartment.
metastasis, non-small cell lung • Selective extravasation in pathological
cancer, small cell lung site.
cancer, myeloma, lymphoma). • For tumors located outside the RES
regions.
• Gradually absorbed by lymphatic system.

23. TUMOR-CELL TARGETING
MDR Reversion
A) Free doxorubicin enters into the
tumor cells by diffusion but is effluxed by
Pgp, resulting in the absence of
therapeutic efficacy.
B) Doxorubicin-loaded NPs adhere at the
tumor cell membrane where they release
their drug content, resulting in
microconcentration gradient of
doxorubicin at the cell membrane, which
could saturate Pgp and reverse MDR
Brigger et al., 2002

24. V di uscita V di
del farmaco(Attività Pgp) ingresso
farmaco
Conc intracellulare farmaco Diff di conc farmaco esterno/interno

25. Zhang et al., 2008

26. Caelyx® is a form of doxorubicin| that is enclosed in liposomes.
It is sometimes known as pegylated doxorubicin hydrochloride
(PLDH). It is used to treat:
•Advanced ovarian cancer that has come back after being
treated with a platinum-based chemotherapy drug.
•Women with advanced breast cancer who have an increased
risk of heart damage from other chemotherapy drugs.
• Aids-related Kaposi’s sarcoma .
Myocet® , another form of liposomal doxorubicin, is used to
treat advanced (metastatic) breast cancer| in combination with
another chemotherapy drug, cyclophosphamide| .

27. Alexis et al., 2009

28. Target: enzimi del rilassamento di DNA
Inibitori delle topoisomerasi
Doxorubicina
• Induce complesso ternario DNA-farmaco-Topoisomerasi
(filamenti di DNA rotti legati in 5’ a una tirosina
dell’enzima)
• Danneggia il filamento formando radicali liberi-

32. Target: microtubuli
Antimitotici
 inibizione di assemblaggio
 stabilizzazione polimeri.
Microtubuli: polimeri di tubulina: crescita richiede GTP alle
estremita’ e sui monomeri.
Idrolisi di GTP a GDP disassembla microtubulo. Per la stabilità
servono MAP