Smart nanocarriers as novel drug delivery systems in cancer therapy
1.
2. Smart Nanocarriers
As Novel Drug Delivery Systems In Cancer Therapy
Presented by: Farshad Mirzavi
Ph.D candidate in clinical biochemistry
1-November-2018
3. Introduction
Types of nanocarriers
oMicelles
oDendrimers
oGold nanocarriers
oSuper paramagnetic iron oxide nanoparticles (SPIONs)
oCarbon nanotubes (CNTs)
oLiposomes
• Composition of liposomes
• Classification of liposomes
• Current Approved liposomal products
Drug Delivery Systems
oPassive targeting
oActive targeting
4. Nanoparticles:
Particles between 1 and 100 nanometers.
Nanocarriers:
When nanoparticles are used as transport module for another
substance, such as a drug.
4Colloids and Surfaces B: Biointerfaces
https://doi.org/10.1016/j.colsurfb.2014.05.027
5. Smart nanocarriers should possess the following characteristics:
1) Avoid the cleansing process of the body’s immune system.
2) Accumulated at the targeted site only.
3) Release the cargo at the targeted site.
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6. 1) Nanocarriers face many biological barriers, including cleansing
by the reticuloendothelial system (RES).
The RES takes the nanocarrier out of circulation shortly and
accumulates those anti-cancer drug-carrying nanocarriers in the liver,
spleen or bone marrow.
PEGylation is a unique solution to avoid this cleansing process.
PEGylation helps nanocarriers escape the RES.
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7. 2) Nanocarriers can be functionalized to identify the cancer cells.
The surface of cancer cells overexpresses some proteins.
Nanocarriers are modified with ligands matching the overexpressed
proteins.
3) Releasing the drug under stimulation is the next big challenge.
To make nanocarriers responsive to the stimulus system, various
chemical groups can be grafted on the surface of the nanocarriers.
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10. Micelles may face immature drug release by crossing the critical micelle concentration.
The solution to this problem is a smart micelle.
Micelles are usually cross-linked; that is, linking two polymer chains by disulfide formation.
PG-PCL, PEEP-PCL, PEG-PCL and PEG-DSPE are examples of some micelles.
10Journal of Advanced Research
https://doi.org/10.1016/j.jare.2018.06.005
11. To actively target cancer cells, different types of ligands are used to decorate the
micelle surface:
Folic acid, peptides, carbohydrates, antibodies, aptamers, etc.
To release the anti-cancer drug at
the right concentration, the core
or the corona of the micelle can
be functionalized.
The stimuli used in micelle based
SDDSs are pH gradients, enzymes,
temperature changes, and oxidation.
11International Journal of Pharmaceutics
https://doi.org/10.1016/j.ijpharm.2017.09.005
14. To actively target the cancer site, the surface of dendritic structures can be
modified by peptides, proteins, carbohydrates, aptamers, antibodies, etc.
The dendrimer surface can also be modified for various stimuli responsive
systems, such as heat, pH change, protein, and enzyme transformation.
The dendritic contrast agent for tumor imaging is very promising.
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Journal of Advanced Research
doi.org/10.1016/j.jare.2018.06.005
Metallic nanocarriers are a matter of significant interest because of their:
Customizable size,
Large surface to volume ratio,
Easy synthesis,
Noble optical properties,
Easy surface functionalization.
• GNPs are metallic nanocarriers available in custom shapes and sizes.
16. • GNPs without modification are unstable in blood and face higher uptake by the
RES. To overcome these limitations, gold nanocarriers need to be PEGylated.
• For targeted drug delivery, the surface
of GNPs can be modified by various
ligands. For example, transferrin (TF)
can be grafted onto the surface of
GNPs, as many tumors overexpress the
TF receptor on their surface.
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17. GNPs are also interesting due to the surface plasmon resonance (SPR)
phenomenon, which enable them to convert light to heat and scatter the
produced heat to kill the cancer cells.
The grafting of the surfaces of GNPs with proper ligands could significantly
overcome the blood brain barrier (BBB).
GNPs modified with fluorescently labeled heparin could be used to diagnose
the cancer site.
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18. • The magnetic materials include the widely studied SPIONs.
• Small synthetic maghemite and magnetite (Fe3O4) particles with cores
ranging between 10 and 100 nm in diameter are two SPIONs.
• Mixed iron oxides with transition metals, such as copper, cobalt, and nickel
also belong to the category of SPIONs.
• This carrier can be controlled by an external magnetic field.
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20. When a graphene sheet is rolled up into a seamless cylindrical tube, the
shape is known as a CNT.
There are two types of CNTs:
Single walled (SWCNT) and multi-walled (MWCNT).
20Carbon letters
DOI: 10.5714/CL.2014.15.4.219}
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MWCNTs can pass through the barrier of various cellular compartments,
and PEGylated SWCNTs are able to localize in a specific site.
Due to the better defined walls of SWCNTs and relatively more structural
defects of MWCNTs, SWCNTs are more efficient than MWCNTs in drug
delivery.
CNTs should be functionalized to make them smart.
PEGylation is a very important step to increase solubility, avoid the RES
and to lower the toxicity.
22. Recent studies exhibit that functionalized CNTs can overcome the BBB.
CNTs have shown promise in carrying plasmid DNA, siRNA,
oligonucleotides, and aptamers.
Functionalized CNTs can be used as diagnostic tools for the early
detection of cancer.
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23. Liposomes, are naturally occurring phospholipid-based nanocarriers.
Conventional liposomes have many problems including instability,
insufficient drug loading, faster drug release and shorter circulation times
in the blood; therefore, they are not smart.
Like other nanocarriers, liposomes also need to overcome the challenge
presented by the RES. PEGylation helps liposomes escape the RES.
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27. Products Drug Indications
AmBisome Amphotericin B
Fungal infections
Leishmaniasis
Doxil/Caelyx Doxorubicin
Ovarian cancer
Breast Cancer
Multiple myeloma
DaunoXome Daunorubicin Kaposi's sarcoma
Myocet Doxorubicin Breast cancer
DepoCyt Cytarabine AML
Marqibo Vincristine ALL
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29. • Hossen S et al. Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies:
A review. J Adv Res (2018), https://doi.org/10.1016/j.jare.2018.06.005.
• T.M. Allen, et al. Liposomal drug delivery systems: From concept to clinical applications. Advanced
Drug Delivery Reviews (2013), http://dx.doi.org/10.1016/j.addr.2012.09.037.
• Li et al. Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma. International
Journal of Nanomedicine (2016),. http://dx.doi.org/10.2147/IJN.S115727.
• Rohit Kolhatkar et al. Active Tumor Targeting of Nanomaterials Using Folic Acid, Transferrin and
Integrin Receptors, Current Drug Discovery Technologies(2011), DOI:10.2174/157016311796799044
• Daniel A. Richards et al. Antibody fragments as nanoparticle targeting ligands: a step in the right
direction. The Royal Society of Chemistry (2016), DOI: 10.1039/c6sc02403c.
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Transferrin receptor (TfR) has been one of the primary targets investigated for receptor-mediated transcytosis across the BBB because of its high expression on BBB endothelium
Liposomes that can carry both therapeutics and imaging agents are known as theranostic liposomes.
This leaky vasculature is thought to have several causes, including insufficient pericytes and a malformed basement membrane
enhanced permeability effect.
enhanced retention effect.
EPR effect