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Nanoparticles

Applications in Cancer Therapy and


Diagnosis

By: M. Shafiee

PhD student, Biochemistry Department, Shiraz


University of Medical Sciences, November 2008.
Nanotechnology
• 1st trigger: by the Nobel Laureate, R. Feynman in
1959:

“Using larger machines to manufacture smaller ones”

• N. Taniguchi, 1974: used the term “nano”, meaning


“dwarf”.

• The principle: engineering and manufacturing of


systems or device at the molecular level.
Nanotechnology (cont…)
Nanotechnology (cont...)
• Understanding and control of matter at
dimensions of 1 to 100 nanometer, sometimes up
to 500 nm.
• Multidisciplinary, using bio-nonomaterials in
engineering or engineered nanomaterials in
biology and medicine.
• Different aspects:
• Nanomaterials
• Nanodevices
• Nanosystems
Nanoparticles in medicine

Using nanoscale-sized structures for:

• Treatment (drug/gene delivery, etc.)

• Diagnosis and screening

• Tissue engineering
Basic concepts of NPs

• Bulk properties of materials in nano-sized


structure differ significantly from the original
material.

• Altering the size of building blocks can


controle internal and surface chemistry,
electrical conductivity, magnetic properties
etc…
NPs and Cancer
• Apply the interaction of NPs with cellular and
molecular components for:

1-Cancer diagnosis
2-Cancer therapy:
a. Systemic administration
b. Local administration
Targeting to Cancer
• Targeting to neovasculature

• Targeting to cancer cells:

1- Passive targeting

2- Active targeting
Passive targeting
• Is related to different characteristics of
neoplasm tissue:
1-Open gaps through interendothelial channels.

2-Less lymphatic drainage.

• NPs Cause enhanced permeability and


retention effect (EPR).
• So in the reticuloendothelial system (RES) the
uptake should be avoided.
Active targeting
• By specific interactions:
Antigen-antibody
Ligand-receptors

• Targeted to:
Angiogenesis
Tumor vasculature
Cancer cells specific antigen
Common targets in Active
targeting
• VEGF receptors.
• Integrins, e.g. αvβ3 by NPs with RGD.
• Folate receptor (overexpressed in various
epithelial cancer cells).
• EGF receptor.
• Specific tumor Ag, such as PSA.
• Surface carbohydrates, using lectins.
Various types of NPs
• From last 2 decades:
Gelatin, Ceramic, Liposomes, Micelles
• More recently:
Conventional polymeric NPs
Long-circulating polymeric NPs
Quantum Dots (QDs)
Dendrimers
Aptamers
Metallic and Magnetic NPs
Conventional polymeric NPs
Conventional polymeric NPs for passive
drug delivery

• Incorporation of drugs to polymers.

e.g PIHCA [poly(isohexylcyanoacrylate] with


doxorubicin.

Hydrophobicity causes the uptake by liver,


spleen and lung and higher conc. in these
organs in compare with free doxorubicin.
Conventional polymeric NPs advantages

• Hepatocarcinomas and metastasis to liver.

Drug accumulation in Kupffer cells’ lysosomes


makes a reservoir for gradient and gradual
release.

• Treatment of some lymphomas.


Conventional polymeric NPs disadvantages

• By targeting the BM cause myelosuppressive


effects.

• Renal toxicity due to mesengial cells uptake and


glomerolar damage.

• Cardiotoxicity.

• Short circulating time due to uptake by RES.


Long-circulating NPs
Hydrophilic coat

Modifications in long-circulating polymeric NPs


Long-circulating NPs
• “Stealth” particles invisible to macrophages.
• Directly target tumors outside of MPS.
• Modifications: Size < 100 nm
Hydrophilic Surface

• Repel plasma proteins and prevent


opsonization.
• Improving circulation time.
• More extravasation and retention.
Long-circ. NPs(…(cont
• A dynamic cloud of hydrophilic chains is
made by:

1-Adsorption of surfactants.
e.g. Poloxamine, Polysorbate 80

2-Use of block or branched polymers.


e.g. polyethylene glycol (PEG) and Pluronic.
Schematic of enhanced permeability and retention
effect.
Quantum Dots
QDs
Quantum Dots
• Nanocrystals composed of a core of a
semiconductor material (CdSe), enclosed within
a shell of another semiconductor (ZnS) that has
a larger spectral band gap.

Spectral band gap: the separation between electronic energy

levels of a material.
QDs characteristics
• Diameter of about 2–10 nm, allows one-on-one
interaction with biomolecules such as proteins.
• Inorganic fluorophores that have size-tunable
emission.
• Strong light absorbance.

• Bright fluorescence.

• High photostability.
QDs’ applications
• Imaging and detection

• Therapy
Multicolor quantum dot (QD) capability of QD imaging in live animal,
using 3 different QDs with the same wavelength in deep organs.
specific mAb attachment to the QD
QDs for imaging and diagnosis
• QDs emit in the IR and near-IR regions, imaging
and diagnostic of cells deep within tissues.

• Long-term and real time imaging due to stability.

• mAb conjugated QDs to detect specific tumor Ags


and tumor site detection.
FRET
Excitation
488 nm

Emission Cy5
670 nm
Emission (QD)
nm 605

Schematic concept of single-QD-based DNA probe.


FRET= Fluorescence resonance energy transfer
C) Fluorescent images of QDs (top), Cy5 (middle) and)
merged colors (bottom) with complementary DNA
.target and (D) non-complementary DNA target
Dendrimers
Generations in a dendrimer
Dendrimers
• The Greek word dendron, meaning "tree".
• Repeatedly branched, monodisperse, and
usually highly symmetric globular compounds.

• The branching units are described by


generation.
• Characterized by their terminal generation, e.g.
a G5 dendrimer refers to a polymer with four
generations.
Dendrimers

(1) PAMAM. (polyamidoamine dendrimer).


(3) Bow tie dendrimer based on 2,2-bis(hydroxymethyl) propionic acid.
.Interaction of PAMAM dendrimers with lipid bilayers
Dendrimers’ pharmacokinetics
• Can be tuned by varying generation size and
the rate of PEGylation, esp. in bow tie forms.
Drug delivery by dendrimers
• Non-covalent encapsulation in the interior
of the dendrimer.

• Covalently conjugation to form


macromolecular prodrugs.
Dendrimer-drug conjugates

• Antineoplastic agent covalently attached to


the peripheral groups of the dendrimer.

e.g. carboxylate-terminated G3 PAMAM


conjugated with MTX, is 24-fold more effective
than free MTX on MTX resistant cell lines.
Dendrimers for targeted drug delivery
and imaging
Drug

A G5-PAMAM conjugated anti-HER2 mAb targets tumors that overexpress


.HER2
Dendrimers for photothermal therapy
• Gold-based NPs strongly absorb light in the near-
IR region.
• Facilitating deep optical penetration into tissues.
• Generating a localized lethal dose of heat at the
site of a tumor.
• Only within the last year (2007), dendrimer-
encapsulated gold nanoparticles prepared and
identified for the photothermal treatment of
malignant tissue.
Photothermal therapy

.Photothermal therapy using dendrimer-entrapped gold nano-particles


Aptamers
Aptamers
• The Latin word “aptus”, means “to fit.”

• Single-stranded DNA, RNA, or unnatural


oligonucleotides that fold into unique structures
capable of binding to specific targets with high
affinity and specificity.

• Unlike anti-sense oligonucleotides (siRNA), bind


and inhibit different types of targets directly.
Aptamers’ advantages

• Small size (~5 nm for 30–60 base pair


of aptamer).
• Highly stable in wide range of
temperature and pH (~4-9).
• No batch-to-batch variations in
compare with mAbs.
Aptamers production
• SELEX
“ Systematic evolution of ligands by exponential
enrichment”

• A selection and amplification protocol to


isolate single-stranded nucleic acid ligands
that bind to their target with high affinity
and specificity.
Aptamer–NP conjugates

Long-circ. NP
Aptamer–NP conjugates for targeted
cancer therapy and diagnosis
• Conjugation to drug encapsulated NPs.
• Binding to optical imaging agents
including:
Fluorophores
QDs (nanocrystals)
MRI imaging agents such as magnetic
nanoparticles.
Aptamer-drug conjugates for
targeted drug delivery

Interaction
+

Doxorubicin

PSA aptamer

Physical conjugate
Conclusion
• NP-based therapeutics for clinical use:

1. Approved for clinical use.


e.g. PEGylated NPs such as PEG-anti VEGF aptamer
2. In clinical trial period.
e.g. Pluronic block-copolymer doxorubicin, in phase II
3. In preclinical development period.
e.g. foliate-PAMAM dendrimers
• Main references:
1. Lisa Brannon-Peppas, James O. Blanchette, Nanoparticle and
targeted systems for cancer therapy, Advanced Drug Delivery
Reviews 56 (2004) 1649– 1659.

2. Jesse B. Wolinsky, Mark W. Grinstaff, Therapeutic and diagnostic


applications of dendrimers for cancer treatment, Advanced
Drug Delivery Reviews 60 (2008) 1037–1055.
3. Hassan M.E. Azzazy , Mai M.H. Mansour , Steven C. Kazmierczak,
From diagnostics to therapy: Prospects of quantum dots,
Clinical Biochemistry 40 (2007) 917–927.
4. Omid C. Farokhzad, Sangyong Jon, and Robert Langer, Aptamers
and Cancer Nanotechnology, 2006 by Taylor & Francis Group,
LLC, pp 289-306.
5. Tania Betancourt, Amber Doiron,and Lisa Brannon-Peppas,
Polymeric Nanoparticles for Tumor-Targeted Drug Delivery,
2006 by Taylor & Francis Group, LLC, pp 215-226.
• Main references (cont…):
6. Sushma Kommareddy, Dinesh B. Shenoy, and Mansoor M. Amiji,
Long-Circulating Polymeric Nanoparticles for Drug and Gene
Delivery to Tumors, 2006 by Taylor & Francis Group, LLC, pp
231-239.

7. Hassan M.E. Azzazy , Mai M.H. Mansour , Steven C. Kazmierczak,


From diagnostics to therapy: Prospects of quantum dots,
Clinical Biochemistry 40 (2007) 917–927.
8. Noritada KAJI, Manabu TOKESHI, and Yoshinobu BABA, Quantum
Dots for Single Bio-Molecule Imaging, ANALYTICAL
SCIENCES JANUARY 2007, VOL. 23, pp 21-24.
9. Lisa Brannon-Peppas, James O. Blanchette, Nanoparticle and
targeted systems for cancer therapy, Advanced Drug Delivery
Reviews 56 (2004) 1649– 1659.
Thank You

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