1. Drug Delivery: Tumor-Targeted Systems
Ali Badiee (Pharm. D., Ph.D.)

3. The hurdles Goal of cancer therapy is
will selectively destroy cancer cells,
sparing the normal tissues of the patient
BUT
Unsatisfactory therapeutic efficacy
Substantial systemic toxicity

4. Approach to overcome hurdles
Developing drugs that only target tumor cells without altering normal tissues.
Herceptin (Trastuzumab)
Gleevec (Imatinib mesylate)

6. Rituximab (MabThera)

7. Approach to overcome hurdles
Developing tumor-targeted drug delivery systems to enhance the efficacy of existing anticancer drugs
……..

9. Overview of targeting mechanisms Overview of tumor-targeted DDS
Two major sections:
Overview of targeting mechanisms
Overview of tumor-targeted DDS

10. Classification of targeting mechanisms
Passive Targeting
Active Targeting
External Stimuli Triggering

11. Passive Targeting

12. Passive targeting of TTDDS
Bypass natural Barriers
Find anatomical and pathological differences

16. Kidney glomerulus, Pulmonary region

17. Passive targeting of TTDDS
Overexpression of
Vascular permeability factor (VPF)
Vascular endothelial growth factor (VEGF)

18. Passive targeting of TTDDS
Resulting in:
Leaky vasculature ( nm pore size vs. 2-6 nm)
Lymphatic system (No lymphatic inside=> retention)
Enhanced Permeability and Retention effect

19. Passive targeting of TTDDS
blood circulation time
renal clearance
RES uptake
Size (~50 – ~150 nm)
Charge control
Using hydrophilic polymer (PEG)

20. Negative Points

21. Active Targeting

24. Active targeting
DDS containing binding moieties to the receptors expressed in tumors
DDS
drug carrier,
cytotoxic molecules,
drug release triggers,
tumor-specific ligands
physical interaction or chemical bonds
drug release can be triggered by
abnormal low pH
high temperature
presence of tumor-specific enzymes

25. Tumor antigens are expressed on
The major challenge is
Identification of tumor-specific ligands
Ideal is to have tumor-specific ligands, but in practice degree of overexpression (density) in tumor is very critical
More over, EPR effect will cover this low specificity
Tumor antigens are expressed on
the cell surface OR the vasculature
Long blood-circulation, critical for active targeting
coupling targeting ligands => increase BCT (size => renal Cl)
coupling targeting ligands => increase RES uptake
50% of injected Immunoliposomes vs 10% of liposomes in liver 2h after use
using hMAbs or fragments

26. Examples of tumor targets
Folate receptor
Transferin receptor
Integrins (αv β3)
Fibronectin
VEGF
Tumor- specific Mabs
Nucleic acids (Aptamers)
ECM receptors (heparin sulphate, chondroitin sulphate, hyaluronan )
Sugars (galactose)

27. Folate receptor
A membrane protein with high binding affinity to folates
Receptor-mediated endocytosis
Negligible in most normal tissues but are over-expressed in many human tumors
ovarian, endometrial, colorectal, breast, lung, renal cell carcinomas
Folic acid as ligand for targeting

28. Transferin receptor A cell membrane glycoprotein
Binds to transferrin to transport iron ion into cells
By receptor-mediated endocytosis
Over-expressed in rapidly dividing cells
that are in need for an increased intake for iron
Treatment of brain tumors
high level of transferrin receptors on glioma cells

29. Integrins
Expressed in the neovasculature during the angiogenesis of tumor
key role in cell signaling
Binding to integrins signals cell proliferation or
Suppression
Heterodimeric glycoproteins containing a and b chains
avb3 integrin is recognized as a target on endothelial cells of metastatic cancers
Arg-Gly-Asp (RGD) tripeptide

30. Fibronectin Expressed in and around neoplastic blood vessels
An extracellular adhesion glycoprotein
Binds to integrin receptors and mediates interactions between cells and extracellular matrix components
Antibodies against fibronectin

31. VEGF Is an angiogenesis stimulating protein
Causes tumor blood vessels to become more permeable
Antibodies against VEGF interfering with VEGF functions

32. Classification of TTDDS
Macromolecular conjugates
Covalently bound drugs
Drugs need to be freed to exert antitumor activity
Drug release by selecting appropriate linkers
Particulate drug delivery systems
Drugs embedded in the particles
Drug release by particles destabilization

35. Macromolecular conjugates
PEG conjugates
N-(2-hydroxypropyl) methacrylamide conjugates
Styrene- co- maleic acid- half- butylate
Poly(glutamic acid)
Immunocojugates

36. PEG conjugates Conjugation of PEG to a small molecule yields a
more water soluble
a lesser tendency for protein binding
enzymatic degradation
reduce renal clearance
reduce RES uptake
prolong blood circulation time
MW is critical in achieving tumor targeting
150 kDa a longer circulation half-life and accumulation (17.7hr, 13.8%) than a 40KDa (5.4 hr, 5%)
PEG-paclitaxel, folate-targeted PEG-DOX

37. PEG conjugates Limited efficacy Using branched PEGs
limited sites for conjugation
low drug pay-load
immunogenicity ??
Using branched PEGs
HPMA
SMA
pGA

39. Immunoconjugates
Covalently conjugation of drug to a MAb specific for tumor antigen
combination of targeting power of Mabs and cytotoxic activity of drugs
uptake to the cell via receptor mediated endocytosis
BR96-DOX ( DOX+ anti-lewis Y Mab)
limited by
potential immunogenicity
heterogeneity of tumor tissues
rapid mutation of tumor antigen

40. TTDDS Macromolecular conjugates Particulate drug delivery systems …
Passively targeted liposomes
Actively targeted liposomes
Immunoliposomes
Polymeric micelles
Polymeric nanoparticles
Biological ghost delivery systems

50. External Stimuli triggering

51. Biological Ghost DS
Derived natural particles from endogenous cells, bacteria, or viruses
Biocompatible, biodegradable, and non-immunogenic
Obtained by removing the enclosed contents of cells, bacteria, and viruses
Membrane surfaces maintain the original binding elements
Additional targeting ligands can also be added
Erythrocyte and bacterial ghosts for the delivery of anticancer drugs and gene delivery
Virus envelops have been used as vehicles for gene delivery
Folate-targeted erythrocyte ghosts