Dendrimers for cancer therapy
-
Upload
vijitha-j -
Category
Technology
-
view
586 -
download
2
description
Transcript of Dendrimers for cancer therapy
Dendrimers for cancer therapy
Presented by V.VijayalakshmiM.Tech
Dendrimers for cancer therapy
Dendrimers
Synthesis method
Properties
Structure- drug delivery
Dendrimers- requirements for cancer targeting
Dendrimers applications in cancer treatment
conclusion
Outline
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.
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
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
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.
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
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
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
Applications of dendrimers in cancer
therapy
• Cancer imaging• Photodynamic therapy• Boron Neutron capture therapy• DNA- Dendrimer conjugate• Tectodendrimer- Nanodevice• Gene therapy
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.
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
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
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”.
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/
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
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
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
Thank You