NEDD

1. Nano Enabled Drug Delivery
S Manna
M.Sc. II Sem IV

2. Sizes in Biological Systems and Comparison
• Nanotechnology includes study of carriers and elements of size range 1-1000 nm.
• Size of nanoparticle should large enough to prevent their leakage into blood vesicles but small
enough to escape capture by macrophage [1]
• Must have a hydrophilic surface to avoid macrophage capture. This problem is overcome with
PEGylation.
(Nature Scitable 2010)

3. The Big Picture
• Nanoparticle
extravasate into the
tumor stroma because
of the permeation
enhancer and they
carry antibodies which
targets and binds to
the epitope of tumor
cells.
• Nanoparticles are
activated and they
release their cytotoxic
compound directly into
the tumor cell leading
to cell death.
[2] Ferrari, M. (2005).Nature Reviews Cancer, 5(3), 161.

4. Rationale behind Nano enabled Drug delivery
• Between 1 and 10 part per 100,000 of
intravenously administered monoclonal
antibodies reach their parenchymal targets in
vivo [3]
• To increase its targeting selectivity and to
endow the agent(s) comprising the therapeutic
formulation with the means to overcome the
biological barriers that prevent it from reaching
its target [4]
1. By improving delivery of drugs that are
poorly water soluble
2. Targeting the drug delivery to tissue or cell
3. Transporting or transcytosis of large and
small drugs/macromolecules across tight
epithelial and endothelial barriers
4. Co-delivery of two drugs and checking
their effect in combination
5. Visualizing the sites of drug delivery by
combing the drug with imaging modalities
and obtaining a real time read on the in
vivo efficacy

5. Fundamental Structure
1. The Drugs – one or more can be conjugated on the core
constitute material which shows the ability of the
nanoparticle to carry one or more therapeutic agent.
2. Targeting a specific cell or tissue through one or more
antibodies attached to the core material
3. To visualize the sites of delivery and obtain a real time read
in vivo, the core constituent is added with imaging
modalities and co-encapsulated contrast enhancers. Also
helps in signal amplification.
4. For transcytosis through tight epithelial and endothelial
barriers the core is added with a permeation enhancer. for
tight junction opening. Examples are MMP 9
5. And PEG for the avoidance of macrophage engulfment or
uptake.
[2] Ferrari, M. (2005). Nature Reviews
Cancer, 5(3), 161.

6. Nanoparticles play at being RBC – The Stealth Mode
[5] Hu, C. M. J., Zhang, L., Aryal, S., Cheung, C., Fang, R. H., &
Zhang, L. PNAS (2011).
Erythrocyte membrane-
camouflaged polymeric
nanoparticle for long-circulating
cargo delivery.

7. Types of Nanocarriers and Cargoes
• Liposome
• Micelle
• Dendrimer
• Metal Nanoparticles
• Polymeric Nanoparticles
• Carbon nanotubes
[6] Glaser, T., Han, I., Wu, L., & Zeng, X. Frontiers in pharmacology, 8, 166 (2017)

8. Chemistry behind the Core Material of the Nanoparticle
• These are all water soluble
polymers
• Polymers can be synthetic,
natural or man made(amino
acids)
[7] Duncan, R. (2003). Nature reviews Drug discovery, 2(5), 347.

9. Chemistry behind the Core Material of the Nanoparticle
• HPMA is poly N(2-Hydroxypropyl
Methacryamide) which is an inorganic
polymer. Conjugated with doxorubicin.
• Non covalent bonding
• Non toxic and non - immunogenic way.
• Shows EPR - Enhanced permeablity
retention effect
[7] Duncan, R. (2003). Nature reviews Drug discovery, 2(5), 347.

10. Targeting vs Triggering – Two different aspects
[8] Wang, Y., & Kohane, D. S. Nature Reviews Materials, 2(6), 17020 (2017).

11. What are the External Stimulus?? That activates the release of drugs
• Light and lasers
• Ultrasound
• Magnetic field
• Electric Pulses
• Pharmaceutical
methods
[8] Wang, Y., & Kohane, D. S. Nature Reviews Materials, 2(6), 17020 (2017).
Above shows phototargeting release of the caged (4,5-
dimethoxy-2-nitrobenzyl) molecule which leads to activated
nanoparticle.
Right image shows the use of Laser to open up gold nanocage
which then releases the drug into the tissue.
[9] Dvir, T., Langer, R (2009). Nano letters, 10(1), 250-
254.

12. Drug delivery Strategies
[8] Wang, Y., & Kohane, D. S. Nature Reviews Materials, 2(6), 17020
(2017).
• Low frequency magnetic field 10kHz triggers
liposomal membrane disruption caused by the
motion of nanoparticle chain
• Dual system
• Ultrasound releases the drug paclitaxel from the
liposome.

13. • Drugs are contained inside 25nl wells
covered by Titanium platinum membrane
• Membrane dissolves as an oxidative potential
is applied <10V
• Novobiocin is a bacterial gyrase inhibitor
• Vaccine is trapped inside the hydrogel made
up of PEG and dimerization of gyrase
[10] Farra, R. et al. Sci. Transl. Med. 4,
122ra121 (2012).
[11] Gübeli, R. J. et al. Sci. Rep. 3, 2610
(2013).
Drug delivery Strategies

14. Disadvantages [12]
Exacerbated respiratory, Cardiovascular deaths, is attributed to the ability of Nanoparticles to cause inflammation.
(Traffic, diesel exposure)
Pulmonary inflammation is due to resulting in membrane permeation capacity of nanoparticles.
Toxicity is reported in many cases causing mitochondrial damage.
ROS induction and oxidative stress is high in many cases and has resulted in neurodegenerative diseases
Another problem related to cationic metal nanoparticle such as Gold Nanoparticles is that, they haemolysis along with
blood clotting.
Another huge cause of worry lies in the blood brain barrier crossing ability of nanoparticles. BBB is there to protect the
brain from blood borne infections.
Viral particles can use this as an advantage and cause significant brain damage.
Conclusion : Nanotechnology drug delivery should not to be implemented rapidly as the hazards associated are rising
as we gain more insights into the matter, hazards posed are beyond the conventional hazards we see in daily life.
Before using Nanoparticles as a standard Medical care - One must obtain a holistic and comprehensive
understanding of the subject matter.
Rigorous clinical trials must be conducted to access the safety of nanoparticles.
Furthermore a close collaboration between scientists working on drug delivery and particle toxicology is a must.

15. Summary
• Nanotech is the study of devices that are themselves useful or the devices that carry essential
components 1-1000 nm in range
• Two main subfields are nanocarriers and determining the precise surface pattern of a molecule.
• Nanovectors/carriers are utilized for the delivery of therapeutic agents and imaging moieties.
• Example is Liposome encapsulated doxorubicin for Treatment of Kaposi Sarcoma.
• Nanocantilever, nanowire and Nanotubes are used to detect broad multiplicity of molecular signals
and biomarkers in real time
• Nanovectors has multifunctionalty- By avoiding biobarriers and biomarker based targeting
• By systematically combining nanovectors with preferred therapeutic and biological targeting moieties
it might be possible to obtain a very large number of novel, personalized therapeutic agents.

16. References
[1] Moghimi, S. M., & Szebeni, J. (2003). Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding
properties. Progress in lipid research, 42(6), 463-478.
[2] Ferrari, M. (2005). Cancer nanotechnology: opportunities and challenges. Nature Reviews Cancer, 5(3), 161.
[3] Li, K. C. P., Pandit, S. D., Guccione, S., Bednarski, M. D. (2004).Molecular imaging applications in nanomedicine. Biomed. Microdevices 6, 113–116 (2004).
[4] Jain, R. K. (1998). The next frontier of molecular medicine: delivery of therapeutics. Nature Med. 4, 655–657.
[5] Hu, C. M. J., Zhang, L., Aryal, S., Cheung, C., Fang, R. H., & Zhang, L. (2011). Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic
delivery platform. Proceedings of the National Academy of Sciences, 108(27), 10980-10985.
[6] Glaser, T., Han, I., Wu, L., & Zeng, X. (2017). Targeted nanotechnology in glioblastoma multiforme. Frontiers in pharmacology, 8, 166
[7] Duncan, R. (2003). The dawning era of polymer therapeutics. Nature reviews Drug discovery, 2(5), 347.
[8] Wang, Y., & Kohane, D. S. (2017). External triggering and triggered targeting strategies for drug delivery. Nature Reviews Materials, 2(6), 17020.
[9] Dvir, T., Banghart, M. R., Timko, B. P., Langer, R., & Kohane, D. S. (2009). Photo-targeted nanoparticles. Nano letters, 10(1), 250-254
[10] Farra, R. et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci. Transl. Med. 4, 122ra121 (2012).
[11] Gübeli, R. J. et al. Pharmacologically triggered hydrogel for scheduling hepatitis B vaccine administration. Sci. Rep. 3, 2610 (2013).
[12] De Jong, W. H., & Borm, P. J. (2008). Drug delivery and nanoparticles: applications and hazards. International journal of nanomedicine, 3(2), 133.

17. THANK YOU 