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targeted dds for cancer
1. TARGETED DRUG DELIVERY
SYSTEM FOR CANCER
PRESENTED BY
Neha singh
M.pharm 1 yr.
GUIDED BY
V.B pokharkar
Hod
Pharmaceutics
1
2. WHAT IS CANCER?
• Division – uncontrolled cell division
• Growth – formation of a lump (tumour) or large numbers of
abnormal white cells in the blood
• Mutation – changes to how the cell is viewed by the immune
system
• Spread – ability to move within the body and survive in another
part
3. TYPES OF CANCER
• Carcinomas
• Sarcomas
• Lymphomas
• Leukaemias
• Adenomas
• Often prefixed by the specific cell
14. TUMOR PHYSIOLOGY & EPR EFFECT
• Cancerous growth feeds on the existing supply of blood and nutrients. As the
tumor develops, it can develop it’s own blood vessels.
• The blood vessels developed, are often leaky and porous .
• Interstitial pressure inside the tumor is much higher when compared to the
normal cell and viscosity of blood in tumor is much higher –- slower drug
migration .
• Enhanced Permeability and Retention ( EPR ) effect is the property by
which certain sizes of molecules (typically liposomes, nanoparticles, and
macromolecular drugs) tend to accumulate in tumor tissue much more than
they do in normal tissues.
15. Erb-B1
HER1
EGFR
Erb-B2
HER2
neu
Erb-B3
HER3
The HER Family of Receptors
Tyrosine
kinase
domain
Ligand-
binding
domain
Erb-B4
HER4
TGF-α
EGF
Epiregulin
Betacellulin
HB-EGF
Amphiregulin Heregulin
Heregulin (neuregulin-
Epiregulin
HB-EGF
Neuregulins-3, -4
No ligand-
binding
activity*
Ligands
*HER2 dimerizes with other members of the HER family.
Roskoski. Biochem Biophys Res Commun. 2004;319:1.
Rowinsky. Annu Rev Med. 2004;55:433.
18. TREATMENT OPTIONS FOR CANCER
SURGERY
• Surgery: before 1955
• Radiotherapy: 1955-1965
• Hyperthermia: 1958-1967
• Chemotherapy: after 1965
• Immunotherapy and Gene therapy
• The design of tumor specific delivery of chemotherapeutic agents is a
means, to address the issues of the dose-limiting toxic side effects of
these agents, by enhancing the fraction of dose actually reaching the
tumor while, reducing the amount of drug that reaching the non-
targeted organs.
19. Issues with traditional chemotherapy
• Act on all rapidly dividing cells
- non-selective
- toxic to normal cells
- often IV treatments
- finite number of cycles
21. Chemotherapy
Two basic types of agents are recognized
1. Cell Cycle Specific Agents
2. Cell Cycle Nonspecific A gents
Cell Cycle Specific Agents : Act during a specific phase of
the cell cycle –
• S Phase Specific Drug: Anti metabolites, Topoisomerase
Inhibitors
• M Phase Specific Drug: Vinca Alkaloids, Taxanes –
• G2 Phase Specific Drug: Bleomycin
Cell Cycle Nonspecific A gents: Active throughout the cell
cycle –
• Alkylating Agents
• Platinum Compounds
• Antibiotics
22. TARGETED THERAPIES
• Targeted cancer therapies block the growth and spread of cancer by
interfering with specific molecules involved in tumour growth and
progression
Mechanisms of action of targeted therapies
• Interfere with cell growth signalling
• Interfere with tumour blood vessel development
• Promote specific death of cancer cells
• Stimulate the immune system to destroy cancer cells
• Deliver toxic drugs to cancer cells
23.
24. MOLECULAR MARKERS
Gene Cancer Drug
KRAS Colorectal Cetuximab
BRAF Melanoma Vemurafenib
EGFR NCSLC Gefitinib and erlotinib
HER2 Breast Trastuzumab
CKIT GIST Imatinib
25. Role of molecular markers
• Early detection/diagnosis
• Prognosis
• Prediction of toxicity, response, relapse
26. Methods developed to enhance specificity of
chemotherapeutic agents
• First order targeting
• Second order targeting
• Third order targeting
• Passive targeting
• Active targeting
• Physical targeting
27. Anti neoplastic agents can be formulated as…
• Pro-drugs
• Simple Soluble Macro Molecular Systems
• Soluble Synthetic Polymer Systems
• Polymer–Drug Conjugates
• Complex Particulate Multicomponent Systems
28. PRODRUG - Challenging factors
1. Requires an activatable version of the drug, and research in
its development is comparable in cost to drug development.
2. The technology does not necessarily place the drug where it
is needed .
• This may be improved by a targeting carrier system.
29. GLYCOPROTEINS
• The family of glycoproteins includes many enzymes, acute
phase reactant proteins and plasma proteins.
• Mannose, galactose and sialic acid are the principle sugars
that form the carbohydrate components of this simple
macromolecules and tend to confer receptor specificity .
• Use of glycoproteins as a delivery system for antineoplastic
diseases is attractive conceptually due to the targeting
specificity afforded by the ligand - receptor interaction
principle.
30.
31. MONOCLONALANTIBODIES
• Monoclonal antibodies are very specific to their immunological
ligands and are thus very appealing drug carriers.
• Monoclonal antibodies have been coupled to cytotoxic anti cancer
agents such as doxorubicin and the carrier substrate dextran. The
Mabs used in these formulations were directed in theory against
epitopes found only on cancer cells . Antibodies tend to be very
confirmationally stable and usually retain their binding specificity
when combined with other molecules.
34. BISPECIFIC ANTIBODIES
• In carcinoma patients the combination treatment of IL-2 and Bis-
1F bispecific antibody directed against epithelial glycoprotein -2
and TcR/CD3 complex on T-Lymphocytes elicited an immune
response measured by elevated plasma levels of TNF- α and
interferon – γ . Through cross linking of T-cell receptor and CD3
complex on the cytotoxic T-lymphocytes and epithelial
glycoprotein-2 on the target cell , the lymphocyte tends to be
capable of actively lysing the target cells .
35.
36. ANTIBODY DIRECTED ENZYME- PRO DRUG
THERAPY (ADEPT )
• The need for antibody internalization, which is one of the problems
associated with immunoconjugates is a addressed in this
strategy, known as Antibody directed enzyme- pro drug therapy
(ADEPT).
• Enzymosomes are liposomal constructs engineered to provide a mini
bio environment . Enzymes are covalently immobilized or coupled to
the surface of liposomes, therefore, when a non toxic product is
administered simultaneously, it is converted by the immobilized
enzyme to a potent anti-tumor agent in the vicinity of tumor cell lines.
37.
38. IMMUNOTOXIN CONJUGATE
• Toxins are molecules that inactivate Viral cytosolic components
of the protein synthesis machinery in catalytic manner.
• Reaching cytosol is the major requirement.
• Immuno-toxins are the conjugates of antibodies (Mab)/ (Fab)
fragments and toxins in which the cell binding moieties of the
toxins are replaced by the binding specific chain of Ab.
39.
40. SOLUBLE SYNTHETIC POLYMER SYSTEMS
• The synthetic polymeric carriers are large enough to avoid filtration and
removal by the kidneys but small enough to avoid trapping by the liver and
spleen.
• Many natural and synthetic biodegradable polymers have been investigated
as implants, microcapsules, micro particles and nanocapsules in order to
achieve prolonged release and targeting of a variety of drugs.
• Apart from targeting, the backbone of a polymeric carrier molecule provides
both controlled, sustained release pattern and a means of protecting the drug
form the physiological environment.
41. DESIGN OF POLYMER CONJUGATES
POLYMER
• Should degrade into non-toxic, non immunogenic, water soluble
metabolites that are eliminated easily via renal filtration but be
of sufficiently high molecular weight to allow entrapment in the
tumor by EPR effect. E.g.: Dextrin (2000-55,000) Poly glutamic
acid (30,000 -60,000)
• Polymer should possess functional groups which are amenable
to conjugation with a drug directly or through a linker.
• Polymer should possess high drug carrying capacity.
42. COMPLEX PARTICULATE MULTI-
COMPONENT SYSTEMS
• Liposomes
• Niosomes
• Nanoparticles
• Cells as carriers
• Microspheres
• Magnetic microspheres
• Emulsions
• Implantable drug delivery systems
43.
44. LIPOSOMES
• Targeting strategies using liposomes can be designed
as: Natural targeting of conventional liposomes.
Long circulatory liposomes (Stealth liposomes)
Ligand mediated targeting.
45. STERICALLY STABILIZED LIPOSOMES
• It avoid scavenging through receptor mediated uptake by
mononuclear phagocytic cells of RES rich organs. A fraction of
the lipids present, have a polyethylene glycol polymer bound to
their head groups. This polymer binds a lot of water creating a
water cloud around the liposome, which hides it from the immune
system and provide long circulatory behavior . Hence the
name, Stealth liposomes.
46. Liposome targeting to tumors using vitamin
and growth factor receptors
Advances in liposome technology have resulted in the development of
ligand targeted liposomes capable of selectively increasing the efficacy
of carried agents against receptor bearing tumor cells.
Receptors for vitamins and growth factors have become attractive targets
for ligand-directed liposomal therapies due to their high expression
levels on various forms of tumor and their ability to internalize after
binding to the liposomes conjugated to receptors’ natural ligands
(vitamins).
47. Release of drug from liposomes…A Constraint ?
• The design of liposomes can be such that, they can become
leaky a few degrees above the body temperature hence letting
the encapsulated material flow out. By tuning the lipid
composition to become leaky at a certain temperature above
the body temperature.
• it is possible to heat the tumor locally by either
microwave, ultrasound or radio-frequency radiation resulting
in a very fast release of the anti-cancer drug, typically a
million times faster than from conventional liposomes.
48. IMMUNOLIPOSOMES
• Immunoliposomes are generated by conjugating antibodies
either directly to lipid bilayer of liposomes in presence or
absence of PEG chains (type I immunoliposomes) or to the
distal end of the PEG chain (type II immunoliposomes).
• Immunoliposomes, make use of use of hyperthermia.
• Liposomal systems appear to be the most promising carrier
systems, for photo sensitizers in the photodynamic therapy of
tumors agnetic field for the induced release of it’s contents
49. NANOPARTICLES
• The loading of drug into ultrafine colloidal particles in the
nanometer size range (10-1000nm)is done, for optimization of
drug delivery to the desired site with the either the drug
encapsulated, dissolved, adsorbed or covalently attached.
• They can be prepared using natural hydrophilic polymers.
• They can entrap various agents in stable and reproducible fashion.
• Stabilizers such as dextran and its derivatives can be incorporated
into nanoparticle surface to modify it’s surface characteristics.
50. SOLID IMPLANTS :
• Cylindrical monolithic devices of mm or cm dimensions, implanted
by a minor surgical incision or injected through a large bore needle
into subcutaneous or intra muscular tissue .
• The drug in implants may be dissolved or dispersed or embedded in a
matrix of polymers.
• Implantable drug-delivery systems can detect chemical signals in the
body and release appropriate therapeutic dosages for treatment with
the help of biosensors .
• Improved control of drug levels at the specific site of action is
possible, for prolonged duration with significantly small dose.
51. IN-SITU FORMING IMPLANTS :
• In-situ gels consists of biodegradable polymers dissolved in a
biocompatible carrier ( DMSO or NMP ). When the liquid
polymer system is placed in the body, it solidifies upon contact
with aqueous body fluids to form a solid implant. The gel-
matrix, thus formed will release the incorporated drug slowly
over a period of weeks to months, and ultimately biodegrade
depending on the composition used
52. INTRA-TUMORAL DRUG DELIVERY
• The concept of administration of drug directly into the tumor arise
from the non uniform and in adequate accumulation of drug or drug
carrier in the tumor.
• Prodrug approach has been successfully utilized for intra tumoral
chemotherapy for a variety of drugs. Mitomycin C, conjugated with
dextran and subcutaneously implanted in B 16 melanoma, resulted in
reduction in tumor growth.
• It can also be optimized using polymeric implants . Cisplatin-Collagen
matrix, Vinblastine-Collagen matrix, Methotrexate-Polylactide
implant, all have resulted in suppression of tumor.
53. CHEMOEMBOLIZATION
• Embolization is widely acknowledged form of endovascular therapy.
• It consists of delivering an embolic material locally through a catheter
that has been previously inserted in the vessels supplying the
pathological area.
• Chemoembolization involves the selective arterial embolization of a
tumor together with a simultaneous or subsequent local delivery of
chemotherapeutic agents. Microcapsule bound intra-arterial
chemotherapy has the greatest potential in treating most of the tumors.
54. Summary of targeted therapy actions
Mechanism Drug
Interfere with cell growth signalling Erlotinib, Gefitinib, Crizotinib
Interfere with tumour blood vessel
development
Bevacizumab, Pazopanib
Promote specific death of cancer cells Olaparib
Stimulate the immune system to
destroy cancer cells
Ipilimumab
Deliver toxic drugs to cancer cells Trastuzumab emtansine
55. CANCER VACCINES
• Prophylactic vaccines e.g. Gardasil®, Cervarix®
• Therapeutic vaccines:
- delay or stop cancer cell growth
- cause tumour shrinkage
- prevent cancer from recurring
- eliminate cancer cells not killed by other forms of treatment
56. PROVENGE® VACCINE
• Licensed for metastatic prostate cancer in USA
• Designed to stimulate an immune response by T-cells
to prostatic acid phosphatase, an antigen found on
most prostate cancer cells
57. Vaccines in development...
• Telo Vac: immune response against the protein telomerase
which is widely expressed in pancreatic cancer
• IMA901 in combination with sunitinib in renal cell carcinoma
to see if overall survival is improved
• TroVax stimulates the immune system to destroy cancer cells
that express the 5T4 tumour antigen, which is present in
approximately 85% of solid tumours
58. IMPACT OF TARGETED THERAPIES
• Personalised medicine
- given until progression
- additional to existing therapy
- extending life
- improving quality of life
