Targeted Nanoparticles for Cancer Therapy

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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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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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 tissues44

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

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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

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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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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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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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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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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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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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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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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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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Polymer backbonePolymer backbone

DrugDrug

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Biodegradable linkerBiodegradable linkerTargeting Moiety Targeting Moiety

(optional)(optional)

Schematic representation of Drug polymer Conjugate Schematic representation of Drug polymer Conjugate

Design of Polymer ConjugatesDesign of Polymer Conjugates1.1. 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 1919

1.Polymer1.Polymeri.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 acid2020

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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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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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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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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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) INTEGRININTEGRIN2525

Chemotherapeutic AgentChemotherapeutic Agent

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1.Antimetabolites1.AntimetabolitesI.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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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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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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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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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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Topoisomerase InhibitorsTopoisomerase InhibitorsI.I. CamptothecinCamptothecin

II.II. DoxorubicinDoxorubicin

III.III. Daunorubicin Daunorubicin

IV.IV. EpirubicinEpirubicin

Alkylating AgentsAlkylating AgentsI.I. CyclophosphamideCyclophosphamide

II.II. IfosphamideIfosphamide

III.III. MelphalanMelphalan

IV.IV. BusulphanBusulphan

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v. Carmustinev. Carmustine

vi. Cisplatinvi. Cisplatin

vii. Caboplatinvii. Caboplatin

Antitumor AntibioticsAntitumor Antibiotics

I.I. BleomycinBleomycin

II.II. Mitomycin CMitomycin C

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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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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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