Gives brief outline of various strategies that are being followed to home in to tumor spot in the treatment of cancer.

1. Tumor targeting through Nanomedicine-
based Therapeutics
Presentation by:
Vijay Kumar Ekambaram ∣ M.Pharm. Pharmaceutics

2. Contents
1. Introduction
2. Nanomedicine –based therapeutics
3. Goals of Tumor targeting through nanocarriers
4. Tumor targeting strategies
5. Multifunctional nanocarriers
6. Toxicities of Nanoformultion
7. Conclusion
8. References

3. Introduction
• Cancer is a leading cause of death around the world. The WHO
estimates that 84 million people will die of cancer between
2005 and 2015
• Cancer is a term used for diseases in which abnormal cells
divide without control and are able to invade other tissues
• Conventional chemotherapeutic agents are distributed non-
specifically in the body affecting both normal and tumor cells.

4. Nanomedicine-based Therapeutics
DEFINITION:
The ESFFLN defined Nanomedicines (NMs) as “nanometer size
scale complex systems, consisting of at least two components, one of
which being the active ingredient”[1]. Different NMs are shown in
Fig.no.1
Figure No.1: Nanomedicines in Drug delivery

5. • Polymeric Nanoparticles are solid and spherical structures, ranging
around 100 nm in size, in which drugs are encapsulated within the
polymeric matrix[1].
• Liposomes are closed spherical vesicles formed by one or several
phospholipid bilayers surrounding an aqueous core in which drugs can
be entrapped[1].
• Dendrimers are highly branched macromolecules with controlled three-
dimensional architecture[1,2]
• Polymeric micelles are spheroidal structure with hydrophobic core which
increases the solubility of poorly-water soluble drugs[1]
• Polymer–drug conjugates are polymeric macromolecules constituted by
a polymer backbone on which drugs are conjugated via linker regions.

6. GoalsofTumortargetedNanoscaledrugdelivery
system[1]
Increase drug concentration in the tumor through-(a) passive targeting
(b) active targeting
Decrease drug concentration in normal tissue
Improve pharmacokinetics and pharmacodynamics profiles
Improve the solubility of drug to allow i.v administration
Release a minimum of drug during transit and maximum at target
site
Increase drug stability
Improve internalization and intracellular delivery

7. Tumor targeting strategies[2]
Figure 2: Tumor targeting strategies

8. Passive Targeting
• Passive targeting exploits the anatomical differences between
normal and diseased tissues to deliver the drugs as inFig.no.3
• Passive targeting involves transport of nanocarriers through
leaky tumor capillary fenestrations into the tumor interstitium
and cells by convection or passive diffusion, Selective
accumulation of Nanocarriers and drug then occurs by the EPR
effect (gold standard in cancer-targeting drug designing)[2]
Figure 3: Anatomical difference between Normal and Tumor tissue

9. EnhancedPermeabilityandRetentioneffect
• Tumor blood vessels are characterized by abnormalities such as
high proportion of proliferating endothelial cells, pericyte
deficiency and aberrant basement membrane formation
leading to an enhanced vascular permeability, lymphatic vessels
are absent or non-functional in tumor tissue results in EPR
effect as shown in fig no.4
Figure 4: EPR effect

10. Table1:Passivelytumor-targeted nanocarriersincancertherapy

11. Active Targeting
• Active targeting, requires the conjugation of receptor specific
ligands that can promote site specific targeting[1,2]
• The active targeting can be achieved by molecular recognition
of the diseased cells by various signature molecules
overexpressed at the diseased site as shown in Fig. no.5
Figure 5: Active targeting

12. Table2:Examplesof nanocarriers using theactiveTumoraltargetingstrategy[1]

13. Active targeting approaches

14. Transferrin receptor(TR)
• Transferrin, a serum glycoprotein, transports iron through the
blood and into cells by binding to the transferrin receptor and
subsequently being internalized via receptor-mediated
endocytosis[2]
• 100 folds higher expression in tumor cells
Figure 6:Transferrin receptor

15. Folate receptor(FR)
• Folate receptor-α(Fig.no.7) is overexpressed on 40% o f
human cancers. folate receptor-β is expressed on activated
macrophages and also on the surfaces of malignant cells of
hematopoietic origin
• FR binds to the vitamin folic acid and folate –drug conjugates
or folate-grafted nanocarriers with a high affinity and carries
these bound molecules into the cells via receptor-mediated
endocytosis.[1,2]
Figure 7: FR

16. Glycoproteins
• Lectins bind to carbohydrate moieties attached to glycoproteins
expressed on cell surface
• Direct lectin targeting- Lectins can be incorporated into
nanoparticles as targeting moieties that are directed to cell-
surface carbohydrates [1,2]
• Reverse lectin targeting- carbohydrates moieties can be coupled
to nanoparticles to target lectins

17. Targeting of Tumoral endothelium
• In this strategy, ligand-targeted nanocarriers bind to and kill
angiogenic blood vessels and indirectly, the tumor cells that
these vessels support[3]
Advantages
• No need of extravasation of nanocarriers
• Binding to their receptors is directly possible after i.v
• Resistance is decreased because of the genetically stability of
endothelial cells

18. VascularEndothelialGrowthFactorReceptors(VEGF)
• Tumor hypoxia and oncogenes up regulate VEGF levels in the
tumor cells, resulting in an up regulation of VEGF receptors on
tumor endothelial cells[3]
• Approaches to target angiogenesis via the VEGF
i) Targeting VEGFR -2 to decrease VEGF binding
ii) Targeting VEGF to inhibit ligand binding to VEGFR-2

19. αvβ3 Integrin
• It is an endothelial cell receptor for extracellular matrix
proteins such as fibrinogen (fibrin) , vibronectin ,
thrombospondi n , osteopontin and fibronectin, responsible
for cell adhesion[1]
• Highly expressed on neovascular endothelial cells but poorly
expressed in resting endothelial cells and most normal organs
• Ligand= Cyclic or linear derivatives of RGD (Arg –Gly– Asp)
oligopeptide [3,4]

20. Stimuli based Nanocarriers
• pH-sensitive polymeric carriers includes poly(l-histidine) or
polysulfonamide
• Poly (histidine) acts as a weak base that has the ability to
acquire a cationic charge when the pH of the environment
drops below 6.5, destabilistation , drug release occurs
• Polysulfonamides are negatively charged, exposure to acidic
environment results in neutralisation, destabilisation, drug
release[1,2]
• Redox/thiol sensitive polymers
• supromolecular polymer surfactant complexes can form
micelles susceptible to thiol-induced dissociation

21. Multifunctional Nanocarriers
• Multifunctional drug carriers may combine the targetabilit y
and the stimuli sensitivity[1,2]
• Cyclic NGR peptide targeted thermally sensitive liposome was
designed for binding preferentially to CD13/aminopeptidase N
overexpressed in tumor vasculature.

22. Toxicitiesrelatedto Nanoformulation
• Bio-degradable/ non-degradable nanocarriers gets
accumulated in the tissues, triggering inflammation
• Cationic NPs including Au and polystyrene have been shown
to cause hemolysis and blood clotting
• Carbon-derived nanomaterials showed that platelet
aggregation
• Cell surface molecules may shed from cancer cell with
progress of time, resulting in reduced efficiency[2]

23. Conclusion
• Nanocarriers can escape from tumor vasculature through the leaky
endothelial tissue that surrounds the tumor and then accumulate in certain
solid tumors by the EPR effect.
• The basis for increased tumor specificity is the differential accumulation of
drug-loaded nanocarriers in tumor tissue versus normal tissue
• In “active targeting ” of tumors, some nanocarriers target tumor endothelial
cells while others targets cancer
• The limitation impeding the entry of targeted nanomedicines onto the market
is that innovative research ideas within academia are not exploited in
collaboration with the pharmaceutical industrycells

24. References
1. J.D. Byrne, T. Betancourt, L. Brannon-Peppas, Active
targeting schemes for nanopartic le systems in cancer
therapeutics, Adv. Drug Deliv. Rev. 60 (2008) 1615–
1626.
2. J.H. Park, S. Lee, J.H. Kim, K. Park, K. Kim, I.C. Kwon,
Polymeric nanomedecine for cancer therapy, Prog.
Polym. Sci. 33 (2008) 113 – 137.
3. S.M. Moghimi, A.C. Hunter, J.C. Murray, Nanomedicine :
current status and future prospec ts, FASEB J. 19
(2005) 311–330.

25. Thank You