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Nanotechnology Critical Endeavor incancer

ByBy

P.P. ChandrasekharChandrasekhar(M.Pharm)(M.Pharm)

Guided byGuided by

Mr. Subhasis Debnath (M.Pharm,Mr. Subhasis Debnath (M.Pharm,Ph.D)Ph.D)

Seven Hills College of Pharmacy,Seven Hills College of Pharmacy,

http://www.google.co.in/imgres?imgurl=http://www.shcptirupati.com/Images/Logo.jpg&imgrefurl=http://www.shcptirupati.com/Home1.aspx&usg=__L1iZmEzyUHNHa9vR4WOlZmiHFUU=&h=200&w=200&sz=20&hl=en&start=1&zoom=1&tbnid=ipvGyAbBfdo2SM:&tbnh=104&tbnw=104&ei=MBZeT7_4DMKtrAfKmOSiCw&prev=/search%3Fq%3Dseven%2Bhills%2Bcollege%2Bof%2Bpharmacy%26um%3D1%26hl%3Den%26sa%3DN%26gbv%3D2%26tbm%3Disch&um=1&itbs=1

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Introduction:Introduction:

NeoplasmsNeop

lasms: are defined as a new formation of cell: are defined as a new formation of cellclusters, which have lost their ability to control cellclusters, which have lost their ability to control celldivision.division.

Neoplasms can either be benign or malignant.Neoplasms can either be benign or malignant. Benign tumorsBenig

n tumors::

1. Differentiated.1. Differentiated.

2. Slow rate of proliferation.2. Slow rate of proliferation.

3. Encapsulated.3. Encapsulated.4. Do not infiltrate surrounding tissue.4. Do not infiltrate surrounding tissue.

5. Usually do not result in patient death.5. Usually do not result in patient death.http://www.scienceclarified.com/images/uesc_10_img0586.jpg

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Introduction (cont.):Introduction (cont.):

Malignant tumors:Malig

nant tumors:1. High rate of cell1. High rate of cell

proliferation.proliferation.

2. Loss of contact2. Loss of contact

inhibition.inhibition.3. Lack of differentiation.3. Lack of differentiation.

4. Grow by invading and4. Grow by invading andinfiltrating.infiltrating.

5. Loss of cohesiveness.5. Loss of cohesiveness.

6. Resistance to6. Resistance toapoptosis.apoptosis.

http://www.news-medical.net/images/breast%20cancer%20cell.jpg

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Estimated Number of Persons Alive in the U.S.

Diagnosed With Cancer by Site (N = 10.5 M)

Prevalence of Cancer type in the US. Data source: 2005 Submission. U.S. estimated cancer prevalence counts were estimated by applying U.S.

populations to SEER 9 and historical Connecticut Limited Duration Prevalence proportions and adjusted to represent complete prevalence.

Populations from January 2003 were based on the average of 2002 and 2003 population estimates from the U.S. Bureau of the Census.www.cancer.gov.

http://www.seer.cancer.gov/registries/terms.htmlhttp://www.seer.cancer.gov/registries/terms.html

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The Cell Cycle and CancerThe Cell Cycle and Cancer::

Cell proliferation is a tightly controlledCell proliferation is a tightly controlled

process that ensures the accurateprocess that ensures the accurate

replication and transcription of geneticreplication and transcription of genetic

information.information.

Genetic mutations can either be repaired, orGenetic mutations can either be repaired, or

result in the induction of apoptosis.result in the induction of apoptosis. Mutations in certain genes, calledMutations in certain genes, called

oncogenes, can result in dysregulation ofoncogenes, can result in dysregulation of

the cell cycle, resistance to apoptosis, andthe cell cycle, resistance to apoptosis, and

in the development of cancer.in the development of cancer.

A large number of todays most effectiveA large number of todays most effective

cancer treatments are cytotoxic agents thatcancer treatments are cytotoxic agents that

target the cell cycle.target the cell cycle.http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html

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HISTORY OF CANCER THERAPYHISTORY OF CANCER THERAPY ::

(Chabner and Roberts, 2005)

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Current Cancer Treatment Strategies:Current Cancer Treatment Strategies:

SurgerySurgery: T: The first line ofhe first line oftreatment for solid tumors, andtreatment for solid tumors, andmay be curative if the tumormay be curative if the tumorhas not metastasized.has not metastasized.

Radiation TreatmentsRadiation Treatments:: UsesUsesionizing radiation.ionizing radiation.

Chemotherapeutic AgentsChemotherapeutic Agents::Three main classes ofThree main classes ofcytotoxic drugs used to treatcytotoxic drugs used to treatneoplastic disease. Theneoplastic disease. Thealkylating agents, thealkylating agents, theantimetabolites, and theantimetabolites, and thenatural products.natural products.

http://www2.slac.stanford.edu/vvc/art/schematic.gif

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Current Cancer Treatment Strategies (cont.):Current Cancer Treatment Strategies (cont.):

1)1) Alkylating agents: FAlkylating agents: Form covalentorm covalent

bonds on double stranded DNA,bonds on double stranded DNA,and prevent transcription.and prevent transcription.

Activation of DNA repairActivation of DNA repair

mechanisms result in DNA strandmechanisms result in DNA strand

breaks, and in apoptosis.breaks, and in apoptosis.

2)2) Antimetabolites: Most effectiveAntimetabolites: Most effective

during the S phase of the cell cycle.during the S phase of the cell cycle.

Include the folic acid analogs (ex.Include the folic acid analogs (ex.

methotrexate), pyrimidine analogsmethotrexate), pyrimidine analogs

(ex. fluorouracil), and purine(ex. fluorouracil), and purineanalogs (ex. mercaptopurine). Theiranalogs (ex. mercaptopurine). Their

mechanisms of action are to inhibitmechanisms of action are to inhibit

DNA synthesis, and/or to inhibitDNA synthesis, and/or to inhibit

transcription and translation.transcription and translation.

http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Cancer/Cancer_images/Nitrog_must.gif

http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/methotrexate.gif

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Current Cancer Treatment Strategies (cont.):Current Cancer Treatment Strategies (cont.):

Photodynamic TherapyPhotodynamic Therapy: Uses a: Uses aphotosensitizing drug (porfimerphotosensitizing drug (porfimer

sodium).sodium).

Hormonal treatmentsHormonal treatments: For certain: For certain

types of tumors.types of tumors. Angiogenesis Inhibitors:Angiogenesis Inhibitors: InhibitInhibit

tumor vascularization. The firsttumor vascularization. The first

FDA approved angiogenesisFDA approved angiogenesis

inhibitor was bevacizumab, whichinhibitor was bevacizumab, whichis a humanized monoclonalis a humanized monoclonal

antibody against vascularantibody against vascular

endothelial growth factorendothelial growth factor

(VEGF).(VEGF).

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http://www.orienttumor.com/english/MT/PDT/002_s.jpg

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Current Cancer Treatment Strategies (cont.):Current Cancer Treatment Strategies (cont.):

Tyrosine Kinase Inhibitors:Tyrosine Kinase Inhibitors: InhibitInhibitDNA synthesis and/or geneDNA synthesis and/or genetranscription. There are currentlytranscription. There are currentlythree FDA approved tyrosinethree FDA approved tyrosinekinase inhibitors: Imatinib,kinase inhibitors: Imatinib,

gefitinib, and erlotinib.gefitinib, and erlotinib. Biological Response ModifiersBiological Response Modifiers

(BRMs):(BRMs): Enhance the bodysEnhance the bodysability to effectively fight cancer,ability to effectively fight cancer,or they minimize chemo sideor they minimize chemo side

effects. BRMs include interferons,effects. BRMs include interferons,interleukins, colony-stimulatinginterleukins, colony-stimulatingfactors, monoclonal antibodies,factors, monoclonal antibodies,and vaccines for the prevention ofand vaccines for the prevention ofcertain types of cancer.certain types of cancer.

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Nanotechnology in the Treatment of Cancer:Nanotechnology in the Treatment of Cancer:

Nanotechnology has generated a greatNanotechnology has generated a great

deal of interest in the field ofdeal of interest in the field of

oncology due to its potential tooncology due to its potential to

selectively deliver and concentrateselectively deliver and concentrate

drugs to tumors while minimizingdrugs to tumors while minimizing

damage to healthy cells.damage to healthy cells.

Two FDA approved nanoparticleTwo FDA approved nanoparticle

formulations for the treatment offormulations for the treatment of

cancer:cancer:

1. Abraxane1. Abraxane: a suspension of: a suspension of

albumin-bound paclitaxel (130 nm).albumin-bound paclitaxel (130 nm).

FDA approved in January, 2005.FDA approved in January, 2005.

2. Doxil2. Doxil: liposomal formulation of: liposomal formulation of

doxorubicin (100 nm). Approved indoxorubicin (100 nm). Approved in

February, 2005.February, 2005.

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Nanoparticle drug-delivery systems underNanoparticle drug-delivery systems under

development for the treatment of cancerdevelopment for the treatment of cancer::

AAdriamycin-loaded nanoparticle formulationdriamycin-loaded nanoparticle formulation:: In vivoIn vivo studiesstudies

demonstrated superior efficacy. In this study, rats were implanted withdemonstrated superior efficacy. In this study, rats were implanted with

liver tumors and were later treated with either adriamycin alone, or withliver tumors and were later treated with either adriamycin alone, or with

adriamycin-loaded nanoparticles (average diameters of 93 nm) injectedadriamycin-loaded nanoparticles (average diameters of 93 nm) injected

directly into the hepatic arterydirectly into the hepatic artery (Chen et al., 2004).(Chen et al., 2004). Paclitaxel-loaded gelatin nanoparticlesPaclitaxel-loaded gelatin nanoparticles: These nanoparticles showed: These nanoparticles showed

significant activity against a bladder cancer cell linesignificant activity against a bladder cancer cell line in vitroin vitro (Lu et al.,(Lu et al.,

2004).2004).

Hydrolysable polymeric micelle systemHydrolysable polymeric micelle system: Engineered with a hydrolysable: Engineered with a hydrolysable

segment that confers it a longer degradation half-life, and which makes itsegment that confers it a longer degradation half-life, and which makes it

more stable when administered intravenously. A longer circulation half-more stable when administered intravenously. A longer circulation half-

life may result in greater tumor drug deposition, and in greater cytotoxiclife may result in greater tumor drug deposition, and in greater cytotoxic

effectivenesseffectiveness (Zeng and Pitt, 2006).(Zeng and Pitt, 2006).

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Nanoparticle drug-delivery systems underNanoparticle drug-delivery systems under

development for the treatment of cancerdevelopment for the treatment of cancer(cont.):(cont.):

Dendrimers:Dendrimers: Under investigation for theUnder investigation for thedelivery of oligonucleotides to cancer cells fordelivery of oligonucleotides to cancer cells forgene therapy.gene therapy. Dendrimers, ranging in 130-280Dendrimers, ranging in 130-280nm in size, were demonstrated to increasenm in size, were demonstrated to increaseoligonucleotide uptake by 14 fold in anoligonucleotide uptake by 14 fold in an inin

vitrovitro breast cancer cell linebreast cancer cell line(Santhakumaran et(Santhakumaran etal., 2004).al., 2004). NanocellsNanocells:: A new nanoparticle drug-deliveryA new nanoparticle drug-delivery

system that makes it possible to combinesystem that makes it possible to combinedrugs with different mechanisms of action indrugs with different mechanisms of action inthe same particle, and to design their temporalthe same particle, and to design their temporalrelease. These nanocells have an outerrelease. These nanocells have an outer

pegylated-phospholipid block-copolymerpegylated-phospholipid block-copolymercontaining an antiangiogenic drugcontaining an antiangiogenic drug(combrestastatin), and an inner nanoparticle(combrestastatin), and an inner nanoparticlecore containing a cytotoxic drug (doxorubicin)core containing a cytotoxic drug (doxorubicin)

(Sengupta et al., 2005).(Sengupta et al., 2005).

Nanoparticles: Scientists Work

on an Anti-Cancer Smart Bomb

imagine a cancer drug that can

burrow into a tumour, seal the

exits and detonate a lethal dose

of anti-cancer toxins, all while

leaving healthy cells

unscathed. MIT researchers

have designed

a nanoparticle to do just that.MEDICA.de; Source: Massachusetts Institute of Technology

http://web.mit.edu/http://web.mit.edu/

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Nanoparticles in the Treatment of Cancer:Nanoparticles in the Treatment of Cancer:

Nanoparticles themselves can also be used to destroyNanoparticles themselves can also be used to destroy

cancer cells directly.cancer cells directly.

MMetal nanoparticles, together with near infrared light,etal nanoparticles, together with near infrared light,

have been shown to increase cell death in tumors byhave been shown to increase cell death in tumors bygenerating hyperthermiagenerating hyperthermia (Hirsch et al., 2003).(Hirsch et al., 2003).

Gold nanoparticles inhibit angiogenesis by binding toGold nanoparticles inhibit angiogenesis by binding to

vascular endothelial growth factor and basic fibroblastvascular endothelial growth factor and basic fibroblast

growth factor and preventing them from activating theirgrowth factor and preventing them from activating their

receptorsreceptors (Mukherjee et al., 2006).(Mukherjee et al., 2006).

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Conclusions:Conclusions:

The search for effective cancer treatments has evolvedThe search for effective cancer treatments has evolvedover the years from a non-specific screening approach, toover the years from a non-specific screening approach, toa molecular mechanism-driven targeted approach.a molecular mechanism-driven targeted approach.

Nanoparticles hold great potential as drug-deliveryNanoparticles hold great potential as drug-deliverycarriers, and as selective cytotoxic agents againstcarriers, and as selective cytotoxic agents againstcarcinogenic cells.carcinogenic cells.

Preliminary results indicate that the future of cancerPreliminary results indicate that the future of cancertreatment will include nanoparticles.treatment will include nanoparticles.

However, more studies are still needed to demonstrateHowever, more studies are still needed to demonstratethe superior effectiveness, and diminished toxicity ofthe superior effectiveness, and diminished toxicity ofnanoparticles.nanoparticles.

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Reference

1) Hahn, W. C.; Weinberg, R. A. Nat. Rev. Cancer, 2002, 2, 331341.2) Liotta, L.; Petricoin, E. Nat. Rev Genet, 2000, 1, 4856.3) Henglein, A.; Chem. Rev. 1989, 89, 18611873.4) Alivisatos, P.; Nat. Biotechnol, 2004, 22, 4752.5) Alivisatos, A .P.; Gu, W. W.;Annu. Rev. Biomed. Eng. 2005, 7, 5576.

6) Golub, T .R.; Slonim, D. K.; Tamayo, P.; Huard, C.; Gaasenbeek, M.;Science, 1999, 286, 531537.7) Woolley, A. T.; Guillemette, C.; Cheung, C. L.; Housman, D. E.; Lieber, C.M.; Nat.Biotechnol, 2000, 18, 760763.8) Hahm, J.; Lieber, C. M.; Nano Lett, 2004, 4, 5154.9) Patri, A. K.; Curr. Opin. Chem. Biol, 2002, 6, 466-468.

10) Andresen, T. L.; Prog. Lipid Res, 2005, 44, 68-72.

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