Nanoparticles for Cancer Therapy

Nanoparticles in Cancer Therapy

1. Targeted Nanoparticles for Cancer Therapy

2. Nanoparticles
Nanoparticles (NPs), which are solid, colloidal
particles consisting of macromolecular substances
that are being developed to:
 improve drug bioavailability
abrogate treatment-induced drug resistance
Reduce nonspecific toxicity in the field of medicine.
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3. NANOPARTICLES DElIVERY SYSTEM
In order to optimize the therapeutic index of
antitumor drugs, Decreasing their toxicity to normal
tissues
The presence of reactive pendant groups in NPs
make easy their vectorization forward specific cell
motif by binding of ligands.
These include various ligands that bind to specific
target cell surface markers or surfacemarkers
expressed in the disease microenvironment
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4. Responsive systems, such as pH-sensitive polymers,
are also included in this category
Hence, over the past years, efforts have been
focused on the development of nanomedicines
 such as
NPs
 liposomes
 micelles
dendrites for the specific delivery of anticancer
drugs to tumor tissues
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5. Once a tumor cell cluster, whether in its initial stage
as a primary tumor or in later stages.
 when forming metastases, induces an angiogenic
switch, its vasculature and microenvironment
changes dramatically
and abnormal cellular organization, vessel structure,
and physiology function develops (Figure 1).
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2. Physiological characteristics of
solid tumors

6. 66

7. 3. Targeted drug delivery
nanoparticles
Targeted NP therapeutics have shown great
potential for cancer therapy, as they provide
enhanced efficacy and reduced side effects .
 NP drug delivery can be either an active or passive
process.
 Passive delivery refers to NP transport through
leaky tumor capillary fenestrations into the tumor
interstitium and cells by passive diffusion or
convection. 77

8. Selective accumulation of NP and drug then occurs
by the already mentioned characteristics of the
tumor microenvironment
Active targeting involves drug delivery to a specific
site based on molecular recognition. One such
approach is to couple a ligand, such monoclonal
antibodies, lectins, aptamers, folate, and peptides, to
a NP so that the ligand can interact with its receptor
at the target cell site
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9. 99

10. Tumor Specific Delivery of Tumor Specific Delivery of
Chemotherapeutic AgentsChemotherapeutic Agents
Drug delivery to solid tumor scan be classified into Drug delivery to solid tumor scan be classified into
a.a.Primary targettingPrimary targetting
b.b.Secondary targetingSecondary targeting
i.i.Localized DeliveryLocalized Delivery
ii.ii.Intravascular DeliveryIntravascular Delivery
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11. Localized DeliveryLocalized Delivery

This form of drug delivery is used to achieve high This form of drug delivery is used to achieve high
local-regional concentrations of the local-regional concentrations of the
chemotherapeutic agent in specific organs like liver, chemotherapeutic agent in specific organs like liver,
lunglung

These delivery systems are usually polymeric in These delivery systems are usually polymeric in
nature and release the chemotherapeutic agent into nature and release the chemotherapeutic agent into
the tumor interstitium locally, slowly, over extended the tumor interstitium locally, slowly, over extended
periods of time.periods of time.
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12. 
Thus high local concentrations of theagentin the Thus high local concentrations of theagentin the
tumor are achieved resulting in a high cell kill and tumor are achieved resulting in a high cell kill and
extremely low migration of the agent to the other extremely low migration of the agent to the other
non-target organs.non-target organs.

For chemotherapeutic agents such as For chemotherapeutic agents such as
1)1)CisplatinCisplatin
2)2)5-fluorouracil5-fluorouracil
3)3)DocetaxelDocetaxel
4)4)PaclitaxelPaclitaxel
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13. Intravascular DeliveryIntravascular Delivery

This form of delivery makes use ofThis form of delivery makes use of
1)1)Polymeric intravascular delivery systemsPolymeric intravascular delivery systems
2)2)Non-polymeric intravascular delivery systemsNon-polymeric intravascular delivery systems
3)3)Polymer-Drug Conjugates for intravascular Polymer-Drug Conjugates for intravascular
deliverydelivery
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14. Polymeric intravascular delivery Polymeric intravascular delivery
systemssystems

NATURAL POLYMERSNATURAL POLYMERS

High molecular weight biomolecules likeHigh molecular weight biomolecules like
i.i. cytokinescytokines
ii.ii.Topoisimerase inhibitorsTopoisimerase inhibitors
iii.iii.Monoclonal antibodiesMonoclonal antibodies
iv.iv.Thymic hormonesThymic hormones
Etc are natural polymers having anticancer Etc are natural polymers having anticancer
activity. activity.
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15. 
SYNTHETIC POLYMERSSYNTHETIC POLYMERS
i.i.(DEAE) Diethylamineoethyl dextran(DEAE) Diethylamineoethyl dextran
ii.ii.DIVEMADIVEMA
iii.iii.CopivithaneCopivithane
Act by stimulating the host defence mechanismAct by stimulating the host defence mechanism
iv. iv. Poly(Arg-Gly-Asp)Poly(Arg-Gly-Asp)
v.v.(SCM) Chitin(SCM) Chitin
Inhibit metastasis either by preventing migration or Inhibit metastasis either by preventing migration or
attachment of the melanoma cells. attachment of the melanoma cells.
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16. Non-polymeric intravascular Non-polymeric intravascular
delivery systemsdelivery systems
i.i.Liposomal daunorubicinLiposomal daunorubicin
ii.ii.Liosomal doxorubicinLiosomal doxorubicin
iii.iii.Niosomal daunorubicinNiosomal daunorubicin

Niosomes exhibit better chemical stability Niosomes exhibit better chemical stability
than liposomes, the physical instability, than liposomes, the physical instability,
leaking of the entrapped drug and its leaking of the entrapped drug and its
subsequent hydrolysis limits the shelflife of subsequent hydrolysis limits the shelflife of
niosomes. niosomes.
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17. Polymer-Drug Conjugates for Polymer-Drug Conjugates for
intravascular deliveryintravascular delivery

A polymer to which drug is bound A polymer to which drug is bound
chemically(through a covalent linkage) and chemically(through a covalent linkage) and
which releases the drug either by hydrolysis or which releases the drug either by hydrolysis or
enymatic cleavage.enymatic cleavage.

Generally a polymer conjugate consists of a Generally a polymer conjugate consists of a
water-soluble polymer, a chemotherapeutic water-soluble polymer, a chemotherapeutic
agent and a pH-sensitive biodegradable linker agent and a pH-sensitive biodegradable linker
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18. Polymer backbonePolymer backbone
DrugDrug
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Biodegradable linkerBiodegradable linker
Targeting Moiety Targeting Moiety
(optional)(optional)
Schematic representation of Drug polymer Conjugate Schematic representation of Drug polymer Conjugate

19. Design of Polymer ConjugatesDesign of Polymer Conjugates
1.1.The conjugate hasto be recognised by plasma The conjugate hasto be recognised by plasma
membranes of a subset of target cells for membranes of a subset of target cells for
internalizationinternalization
2.2.Lysis of the linker by lysosomal enzymes to Lysis of the linker by lysosomal enzymes to
release the drug. release the drug.

The preparation of polymer conjugate requires a The preparation of polymer conjugate requires a
judicious choice of judicious choice of
a)a)PolymerPolymer
b)b)DrugDrug
c)c)Linker / Targeting ligands Linker / Targeting ligands
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20. 1.Polymer1.Polymer
i.i.Water solubleWater soluble
ii.ii.BiocompatibleBiocompatible
iii.iii.Non-immunogenicNon-immunogenic
iv.iv.Non-toxicNon-toxic
v.v.Low molecular weightLow molecular weight

E.g.E.g.
1)1)DextrinsDextrins
2)2)poly-N-(2-hydroxyl)-L-glutamine (PHEG)poly-N-(2-hydroxyl)-L-glutamine (PHEG)
3)3)polyglutamic acidpolyglutamic acid
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21. 4) 4) Polyethylene glycolPolyethylene glycol
5) 5) N-(2-hydroxypropyl) methacrylamide copolymer N-(2-hydroxypropyl) methacrylamide copolymer
(HPMA)(HPMA)

Synthetic polymer arepreferred as they canbetailor-Synthetic polymer arepreferred as they canbetailor-
made as per the requirements of the conjugate made as per the requirements of the conjugate
system.system.

Synthetic can be either Synthetic can be either
A.A. BiodegradableBiodegradable
B.B. Non- BiodegradableNon- Biodegradable
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22. BiodegradableBiodegradable

Polymer after depletion of the drug degrades into Polymer after depletion of the drug degrades into
biocompatible components and is excreted via biocompatible components and is excreted via
metabolic pathwaysmetabolic pathways
1)1)Poly(amino acids)Poly(amino acids)
2)2)Poly (L-glutamic acid)Poly (L-glutamic acid)
3)3)Styrene-maleic anhydride-neocarzinostatin Styrene-maleic anhydride-neocarzinostatin
(SMANCS) (SMANCS)

The cytotoxic effect of SMANCS by cleavage The cytotoxic effect of SMANCS by cleavage
of DNA and inhibit DNA synthesis of DNA and inhibit DNA synthesis

The access to bone marrow is limited resulting The access to bone marrow is limited resulting
in reduced toxicity. in reduced toxicity.
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23. Non- Biodegradable water-soluble Non- Biodegradable water-soluble
polymers polymers
1)1)Polyetheylene glycolPolyetheylene glycol
2)2)N-(2-hydroxyprpyl)mehacrylamide N-(2-hydroxyprpyl)mehacrylamide
copolymer (HPMA)copolymer (HPMA)

PEG-L-asparginase with marketed PEG-L-asparginase with marketed
advantages for treatment of advantages for treatment of
lymphoma/leukemia such as increased lymphoma/leukemia such as increased
plasma half-life and a diminished antigenic plasma half-life and a diminished antigenic
response of the L-asparginaseresponse of the L-asparginase
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24. 
Non-toxic even up to the doses as high as Non-toxic even up to the doses as high as
30mg/kg30mg/kg

The doxorubicin conjugate prepared with The doxorubicin conjugate prepared with
such cross-linked polymer showed about 25 such cross-linked polymer showed about 25
times increase in circulation half-life and times increase in circulation half-life and
better efficiency in inhibiting tumor growth better efficiency in inhibiting tumor growth
than the lower molecular weight free drug.than the lower molecular weight free drug.
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25. The LINKERSThe LINKERS

The polymer-drug conjugation through linkers The polymer-drug conjugation through linkers
or spacers to control the rate of in vivo or spacers to control the rate of in vivo
hydrolysis .hydrolysis .
1)1)APTAMERSAPTAMERS
2)2)HUMAN EPIDERMAL RECEPTORHUMAN EPIDERMAL RECEPTOR
3)3)TRANSFERRIN RECEPTORTRANSFERRIN RECEPTOR
4)4)FOLATE RECEPTORFOLATE RECEPTOR
5)5) INTEGRININTEGRIN
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26. Chemotherapeutic AgentChemotherapeutic Agent
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27. 1.Antimetabolites1.Antimetabolites
I.I.5-Fluorouracil5-Fluorouracil
II.II.Cytarabine (Ara-C)Cytarabine (Ara-C)
III.III.FludarabineFludarabine
IV.IV.6-Mercaptpurine6-Mercaptpurine
V.V.MethotrexateMethotrexate
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28. 5-fluorouracil5-fluorouracil

MECHANISM OF ACTIONMECHANISM OF ACTION

Inhibition of thymidylatesynthase, an enzyme Inhibition of thymidylatesynthase, an enzyme
important in DNA synthesis, its metabolite fluoro-important in DNA synthesis, its metabolite fluoro-
deoxyuridinetriphosphate gets incorporated in DNA deoxyuridinetriphosphate gets incorporated in DNA
and causes its breakageand causes its breakage
MAJOR TOXICITYMAJOR TOXICITY

Bone marrow suppression,Bone marrow suppression,

Gastrointestinal toxicityGastrointestinal toxicity
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29. 2.Natural alkaloids from plant 2.Natural alkaloids from plant
sourcessources
I.I.VincristineVincristine
II.II.VinblastineVinblastine
III.III.PaclitaxelPaclitaxel
IV.IV.DocetaxelDocetaxel
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30. 1.Vincristine & Vinblastin1.Vincristine & Vinblastin
MECHANISM OFACTIONMECHANISM OFACTION

Inhibition of microtubuleassembly during M Inhibition of microtubuleassembly during M
phase of cell cycle.phase of cell cycle.

MAJOR TOXICITYMAJOR TOXICITY

NeurotoxicityNeurotoxicity
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31. 2.Paclitaxel & Docetaxel2.Paclitaxel & Docetaxel

MECHANISM OF ACTIONMECHANISM OF ACTION

Stabilization of microtubules and prevention Stabilization of microtubules and prevention
of their disassembly. of their disassembly.

MAJOR TOXICITYMAJOR TOXICITY

BradyarrthymiasBradyarrthymias

Chest PainChest Pain

MyelosuppressionMyelosuppression
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32. Topoisomerase InhibitorsTopoisomerase Inhibitors
I.I.CamptothecinCamptothecin
II.II. DoxorubicinDoxorubicin
III.III. Daunorubicin Daunorubicin
IV.IV.EpirubicinEpirubicin
Alkylating AgentsAlkylating Agents
I.I.CyclophosphamideCyclophosphamide
II.II.IfosphamideIfosphamide
III.III.MelphalanMelphalan
IV.IV.BusulphanBusulphan
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33. v. Carmustinev. Carmustine
vi. Cisplatinvi. Cisplatin
vii. Caboplatinvii. Caboplatin
Antitumor AntibioticsAntitumor Antibiotics
I.I.BleomycinBleomycin
II.II.Mitomycin CMitomycin C
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34. Tumor cell targetingTumor cell targeting

Cancer cells express different targets on their Cancer cells express different targets on their
surface, some of them specific of each type of surface, some of them specific of each type of
cancer. cancer.

Active targeting of nanosystems for cancer Active targeting of nanosystems for cancer
treatment has been usually associated with a type of treatment has been usually associated with a type of
cancer and so with a specific target.cancer and so with a specific target.
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35. 3535

36. ReferenceReference

Progress in controlled and Novel Drug Progress in controlled and Novel Drug
delivery System by N.K.JAINdelivery System by N.K.JAIN


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37. 3737