Dendrimers for cancer therapy

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Dendrimers for cancer therapy Presented by V.Vijayalakshmi M.Tech

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V.Vijayalakshmi

Transcript of Dendrimers for cancer therapy

Page 1: Dendrimers for cancer therapy

Dendrimers for cancer therapy

Presented by V.VijayalakshmiM.Tech

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Dendrimers for cancer therapy

Dendrimers

Synthesis method

Properties

Structure- drug delivery

Dendrimers- requirements for cancer targeting

Dendrimers applications in cancer treatment

conclusion

Outline

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Dendrimers

A synthetic polymer with a branching, tree-like structure

The name comes from the Greek word δένδρον (dendron), which translates to

"tree"

Dendrimers are highly branched, star-shaped macromolecules with

nanometer-scale dimensions.

Dendrimers are defined by three components:

• a central core

• an interior dendritic structure (the branches)

• an exterior surface with functional surface groups

The varied combination of these components yields products of different shapes

and sizes with shielded interior cores that are ideal candidates for applications in

both biological and materials sciences.

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Dendrimer structure

Figure 1: Schematic representation of dendrimer – G2 generation. Dendrimers are formed by

three components a central core ,an interior dendritic structure (the branches), an exterior

surface with functional surface groups, an internal cavity for drug loading

http://www.sigmaaldrich.com/materials-science/nanomaterials/dendrimers/dendrons.html

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Dendrimer- Synthesis method

Figure 2.2: Schematic of convergent synthesis of dendrimers. Dendrimers are built from small molecules that end up at the surface of the sphere, and reactions proceed inward building inward and are eventually attached to a core.

Figure 2.1: Schematic of divergent synthesis of dendrimers. The dendrimer is assembled from a multifunctional core, which is extended outward by a series of reactions, commonly a Michael reaction. 

http://en.wikipedia.org/wiki/Dendrimer

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Dendrimers- Properties

monodisperse macromolecules.

size and molecular mass of dendrimers can be specifically controlled during

synthesis.

Molecular mass increases - viscosity decreases.

Dendrimers’ solubility is strongly influenced by the nature of surface groups.

Dendrimers terminated in hydrophilic groups are soluble in polar solvents, while

dendrimers having hydrophobic end groups are soluble in nonpolar solvents.

Dendrimers have some unique properties because of their globular shape and the

presence of internal cavities.

The most important one is the possibility to encapsulate guest molecules in the

macromolecule interior.

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dendrimers can play the role of photoswitchable hosts. Photochemical

modifications of the dendritic surface cause encapsulation and release of guest

molecules

Hydrolysing the outer shell could liberate the guest molecules

dendrimers which can act as extremely efficient light-harvesting antennae

Subha sankar Ghosh “ Dendrimers new hope for cancer” science reporter, August 2010

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Figure 3. Structural options for dendrimer based drug delivery. Dendrimers can be synthesized with neutral surfaces (1) and positive (2) or negative (3) charges at the periphery; moreover, dendritic macromolecules, generally when larger than G3, can harbor non covalently encapsulated guest/drug molecules (4). An alternative strategy for drug delivery is through covalent conjugation of ligands to the surface of the dendrimer.(5) The versatility of dendrimers for drug delivery is illustrated by considering that ‘‘A’’ could be a targeting ligand and the active drug could be encapsulated within the same macromolecule (6). Synthetic strategies are now available for providing dendritic clusters with extremely high densities of surface ligands (7) and for providing more than one type of surface ligand, either in a random orientation (8), or in blocks (9). The latter dendrimers are now being exploited in sophisticated cancer cell targeting and drug release strategies where A, B, and C can be any combination of targeting agents, drugs, contrast agents, or functional groups that improve pharmacological properties.Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-”

Dendrimers in Cancer Treatment and Diagnosis”.

Dendrimers- drug delivery

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Figure 4: Requirements for dendrimer-based,cancer-targeted drug delivery. (a) Dendrimers with multiple surface functional groups can be directed to cancer cells by tumor-targeting entities that include folate or antibodies specific for tumor-associated antigens (TAAs). (b) The next step is intake into the cell, which in the case of folate targeting occurs by membrane receptor mediated Endocytosis. (c) Once inside the cell, the drug generally must be released from the dendrimer, which, for the self-immolative method results in the simultaneous disintegration of the dendritic scaffold (d).

Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”.

Dendrimers targeting cancer- Requirements

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Applications of dendrimers in cancer

therapy

• Cancer imaging• Photodynamic therapy• Boron Neutron capture therapy• DNA- Dendrimer conjugate• Tectodendrimer- Nanodevice• Gene therapy

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1) Dendrimers- cancer imagingDendrimers conjugated to fluorochromes and shown to enter cells - imaging

Possible to characterize

• cell tergeting, surface binding

• uptake and internalization

• even sub cellular localization

Gadolinium, a contrasting agent conjugated to folate receptor or TAA dendrimer to

target cancer cells

Gd- macromolecular system, limited success

Eg:

PAMAM-based MR contrast agents was their long residence time in the body; this

problem, however, can be met by modifying both the surface properties and basic

chemical composition of the dendrimer

Diaminobutane (DAB) dendrimer-based chelators were more rapidly excreted

from the body, illustrating that the development of clinically-acceptable dendrimer

MR platforms.

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2) Photodynamic therapy

PDT- drug- Photosensitizer or photosensiting agent and particular type of light.

When photosensitizer exposed to specific wavelength of light they produce form

of oxygen which kills cancer cells

Problem:

Long rentention time, radiation exposed after a gap period 24-72 hours, to left

normal cells – drugs

Dendrimers in PDT- designed to deliver the agent only to affected tissues by

recognizing the specific molecules on cancer cells

Fasten the rate of treatment

No need to wait for elimination of photo sensitizer from normal cells

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3) Boron Neutron capture therapy

BNCT- require selective delivery of sufficient number of stable non radioactive

isotope of boron – successful treatment

Beam of low energy neutrons is given to a stable isotope of boron(boron-10) after

they have accumulated in tumour cells

Boron present in or adjacent to the tumour cells disintegrates after capturing

neutrons produce high energy heavy charged particles that destroy only cells in

close proximity to it leaving adjacent normal cells

Problem:

Conventional BNCT- polymer like polylysine were used which can deposit 1700

boron derivatives to the targeted site

Lesser number of boron depositions

Eg:

Dendrimers like PAMAM – transfer 5000 Boron derivatives

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Figure 5:DNA–dendrimer conjugates as potential cancer targeting imaging agents or therapeutics. Differentially functionalized dendrimers covalently conjugated to complementary deoxyoligonucleotides can readily form duplex combinatorial nanoclusters that possess cancer cell-specific ligands hybridized to an imaging agent or drug. Cell-specific targeting ligands (e.g., folic acid in one study) are appended to Dendrimer A, and Dendrimer B is conjugated with an imaging agent or drug.

4) DNA – Dendrimer conjugate for cancer targeting

Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in Cancer Treatment and Diagnosis”.

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5) Multifunctional nanodevice- Tectodendrimers

Figure6.1:Tectodendrimers. Tectodendrimers are multifunctional devices built from a core dendrimer, surrounded by shell dendrimers. Each shell dendrimer performs one function.

Figure 6.2: Nanodevice tergetting. To target the nanodevice specifically to the cancer cells and not to other cells, we make use of the fact that cells have on their surfaces receptors for specific molecules. By attaching the proper moiety (target of active receptor), the specificity can be precisely controlled.

http://www.nano.med.umich.edu/Platforms/Dendrimers-Introduction.html 3/

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6) Dendrimers based gene therapy- cancer treatment

Dendrimers offer many advantage over viruses as vehicles of genes

Less toxic, cost, ease of production, ability to transfer long genes

Eg:

Polypropyleneimine dendrimer nanoparticles – capacity for tumour

transfection- the process of introducing nucleic acids into cells by non viral

methods in tumour bearing mice.

once inside the cell gene enclosed in the particle recognises the cancer cells

and kills them

Human trial- not yet

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Conclusion

Dendrimers, chemically-defined entities with tunable biological properties,

have advanced over the past two decades to the point where they stand on

the cusp of major contributions to the treatment of cancer in a meaningful

way.

Dendrimers – improve the therapeutic index of cytotoxic drugs by direct

delivery of drugs to cancer drugs

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References

Srinivasa-Gopalan Sampathkumar, and Kevin J. Yarema-” Dendrimers in

Cancer Treatment and Diagnosis”.

Subha sankar Ghosh “ Dendrimers new hope for cancer” science reporter,

August 2010.

James R. Baker Jr. Dendrimer-based nanoparticles for cancer Therapy

American Society of Hematology,2009.

Barbara Klajnert and Maria Bryszewska, Dendrimers: properties and

applications Acta biochimica Polanica ;2001(48):199-208.

http://www.sigmaaldrich.com/materialsscience/nanomaterials/dendrimers/den

drons.html

http://www.nano.med.umich.edu/Platforms/Dendrimers-Introduction.html 3/

http://en.wikipedia.org/wiki/Dendrimer

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Thank You