This document discusses the use of nanotechnology for cancer treatment. It begins with background on cancer and challenges with chemotherapy. It then introduces various nanoparticles being explored for cancer applications, such as quantum dots, iron oxide, and gold nanoparticles. The document discusses the enhanced permeability and retention effect that allows nanoparticles to passively target tumors. It provides the example of Doxil, an FDA-approved liposomal drug delivery system. Other nanomedicine examples discussed include Abraxane protein-bound paclitaxel nanoparticles. The document covers topics like tumor tissue targeting, overcoming drug resistance, vascular and cellular targets, and using heat-generating nanoparticles for thermal ablation of cancer cells.

1. Nanotechnology for 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
 Nonspecificity
 Toxicity
 Adverse side effects
 Poor solubility
Use of anti-cancer (cytotoxic) drugs to destroy cancer cells. Work by
disrupting the growth of cancer cells
Defects

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

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 solid tumors the uptake of NP 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:
EPR, in principle, is based
on passive targeting
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.

10. How EPR works
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

13. Clinical Example of EPR
.
Marketed by Ben Venue Laboratories of J&J.
Approved by the FDA for treatment of ovarian cancer and multiple myeloma
and an AIDS-related cancer.
Doxil is a polyethylene glycol
(PEG)-coated
liposomal formulation
of doxorubicin

14. In vivo distribution of long-circulating radiolabeled liposomes
i.v. injected into C26 tumour-bearing mice
DOXORUBICIN pharmacokinetics

16. How Doxil works?
Doxorubicin interacts with DNA by
intercalation and inhibition of
macromolecular biosynthesis.
This inhibits the progression of the
enzyme topoisomerase II, which relaxes
supercoils in DNA for transcription.
Doxorubicin stabilizes the topoisomerase
II complex after it has broken the DNA
chain for replication, preventing the DNA
double helix from being resealed and
thereby stopping the process of
replication.

17. Liposome-encapsulated doxorubicin is less cardiotoxic than free
doxorubicin.
Polyethylene glycol results in preferential concentration of Doxil in
the skin-----a side effect known as hand-foot syndrome:
Small amounts of the Dox can leak from capillaries in the palms of
the hands and soles of the feet.
>50% of patients treated with Doxil developed hand-foot
syndrome.
Doxil Side Effects

19. Example of an Approved Anticancer Agent
ABRAXANE : Protein-bound paclitaxel is an injectable formulation of paclitaxel,
a mitotic inhibitor drug used in the treatment of breast cancer, lung
cancer and pancreatic cancer.
Paclitaxel
Albumin

20. ABRAXANE Clinical Trial Results
recTLRR (PRIMARY END POINTS) VS. PACLITAXEL INJECTION FOR ALL
RANDOMIZED PATIENTS IN THE PHASE III TRIAL IN METASTATIC BREAST CANCER
SIGNIFICANTLY SUPERIOR TUMOR RESPONSE RATE IN ALL RANDOMIZED PATIENTS
EFFICACY DEMONSTRATED IN SECOND-LINE METASTATIC PATIENTS AND PATIENTS WHO
RELAPSED WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY

22. 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

23. Is Abraxane Safe?
• On Jan, 25, 2014: 1,893 people reported to have side effects when
taking Abraxane. Among them, 25 people (1.32%) have Renal
Failure.
< 1
month
1 - 6
months
6 - 12
months
1 - 2
years
2 - 5
years
5 - 10
years
10+
years
Renal
failure
83.33% 16.67% 0.00% 0.00% 0.00% 0.00% 0.00%
Time on Abraxane when people have Renal failure :

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

25. Active Targeting
• On the horizon are nanoparticles that will actively target drugs to
cancerous cells, based on the molecules that they express on their cell
surface.
• Molecules that bind particular cellular receptors can be attached to a
nanoparticle to actively target cells expressing the receptor. Active
targeting can even be used to bring drugs into the cancerous cell, by
inducing the cell to absorb the nanocarrier.
• Active targeting can be combined with passive targeting to further reduce
the interaction of carried drugs with healthy tissue.
• Nanotechnology-enabled active and passive targeting can also increase
the efficacy of a chemotherapeutic, achieving greater tumor reduction
with lower doses of the drug.
http://nano.cancer.gov/learn/impact/treatment.asp

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

27. TUMOR-CELL TARGETING
MDR Reversion
Brigger et al., 2002
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

28. V di uscita
del farmaco(Attività Pgp)
[Conc. intracellulare farmaco]
V di
ingresso
farmaco
[farmaco esterno]-[farmaco interno]

29. Vascular targets
Vascular endothelial GF
Vascular cell adhesion molecule
Matrix metalloproteinases

30. Tumour targets
Human epidermal receptor
Transferrin receptor
Folate receptor
Specific tumour cell surface markers

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

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

33. Zhang et al., 2008

34. Alexis et al., 2009

35. Destruction from Within
• Moving away from conventional chemotherapeutic agents that activate
normal molecular mechanisms to induce cell death, researchers are
exploring ways to physically destroy cancerous cells from within.
• One such technology—Gold Np—is being used in the laboratory to
thermally destroy tumors from the inside. GOLD NP can be designed to
absorb light of different frequencies, generating heat (hyperthermia).
Once the cancer cells take up the NP scientists apply near-infrared light
that is absorbed by the nanoshells, creating an intense heat inside the
tumor that selec tively kills tumor cells without disturbing neighboring
healthy cells.
http://nano.cancer.gov/learn/impact/treatment.asp

36. Thermal ablation of cancer is gaining
increasing attention as an alternative to
standard surgical therapies , especially for
patients with contraindications.
Potential benefits of thermal ablation include
reduced morbidity and mortality
in comparison with standard surgical resection
and the ability to treat nonsurgical patients.
There is a wide range of ablation techniques
that include : cryoablation, radiofrequency
ablation, microwave ablation, ultrasound
ablation and laser ablation.

37. Plasmonic photothermal therapy (PPTT) is a technique
of cancer thermal therapy based on the laser heating
of gold nanoparticles. One of the main advantages of this
therapeutic technology is its high spatial selectivity
that prevents surrounding healthy tissues
from thermal damage.

40. By changing the shape of nanoparticles from spheres to nanorods, the absorption or
scattering wavelength changes from the visible to the near-IR (NIR) region and offers the
advantages of larger absorption and scattering cross-sections and much deeper penetration in
tissues. Recent studies have shown that gold nanorods (GNRs) attached to antibodies and viral
vectors could be used for selective and efficient photothermal therapy,.
The resonant wavelength is redshifted from the visible (for spherical nanoparticles,
with R=1) to near-IR (for nanorods, with R > 1). R: Aspect ratio. NIR: Near-IR.

41. Dependence of the temperature increment ∆T on the concentration of gold
nanorods in the suspension after irradiation with laser light (810 nm, 1
W/сm2 ) during 5 min.

42. 2 D distribution of temperature over the surface of mice skin before the laser
irradiation, in 1 min and in 5 min.
before laser irradiation 1 min 5 min

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

44.  Correlated Optical and X-Ray Imaging
High resolution sensitivity in detection of small
tumors
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