DENDRIMERS – A RECENT DRUG DELIVERY SYSTEM

Under the guidance ofDr. K. H. Ramteke(M.Pharm, Ph.D.)

Dept. of Pharmaceutics

PE Society’sModern college of pharmacy (for ladies), Moshi, Pune 1

Presented By,Varsha V. AwasarkarM Pharm 1st semister

Contents • Aim• Introduction• Properties• Types of dendrimers• Mechanism of drug release• Synthesis of dendrimers• Characterization• Advantages• Cytotoxicity• Applications of dendrimers• Literature survey• Conclusion• References

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AIM

• To emphasize on dendrimeric drug delivery system.

• To focus on current applications of dendrimers.

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INTRODUCTION

• A suitable drug delivery system would protect the drug against degradation and ensure that drug reaches proper permeability properties and further provides a combined transportation and protection system against the natural barriers, as done by the dendrimers. Dendrimers are highly defined nanoparticles:

– Size: 1 -15 nanometers

– Very versatile surface functionalisation

– Synthetic: Practical and cost effective

– Well tolerated pharmaceutica.

• The term “Dendrimer” arise from two Greek word :

- “Dendron” meaning tree’

-“Meros” meaning part

• The dendrimers are also called as CASCADE MOLECULES or ARBOROLS.

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CONT….

• Dendrimers are hyper-branched, globular, monodisperse, three dimensional nanoscale synthetic polymers, having very well defined size, shape and definite molecular weight.

• Dendrimer is a nanoparticle (10-9) and so has advantages over microparticles or others due to its small size, easy uptake by cells (through endocytosis).

• They are branched macromolecules have a central core unit having a high degree of molecular uniformity, narrow molecular weight, distribution, specific size and shape characteristics, and a highly- functionalized, terminal surface.

• Dendrimers exhibit characteristics features of both molecular chemistry and polymer chemistry. Molecular chemistry like properties are due to their step by step controlled synthesis while it shows polymer chemistry like properties as it is made up of monomers.[1]

Components of a Dendrimer Structure:

Generation, Shell, Pincer, End group. 5

CONT….

• Goals behind developing the dendrimers:

A) Modify/Improve the pharmacokinetic and pharmacodynamic properties of a drug so that there is also an accretion in bioavailability.

B) Achieve the controlled and targeted release of drug restricted to the area desired. [2]

• STRUCTURE: Dendrimers are built from a starting atom, such as nitrogen, to which carbon and other elements are added by a repeating series of chemical reactions that produce a spherical branching structure.

• As the process repeats, successive layers are added, and the sphere can be expanded to the size required by the investigator. The result is a spherical macromolecular structure whose size is similar to albumin and hemoglobin, but smaller than such multimers as the gigantic IgM antibody complex.

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1.1 STRUCTURE OF DENDRIMERS

7Figure 1: Schematic representation of the dendrimer typical structure.

Structure of Dendrimers possesses 3 distinct units: A Central core unit. Generations i.e. branches, which are radically “Meros” meaning part attached to

the central core. Terminal functional group attached to the outermost series of branches.

1.2 HISTORY

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Table 1: Properties of Dendrimer And Linear Polymers [5]

Serial

NumberProperty Dendrimers Linear Polymers

1 Structure Compact and Globular Not compact

2 Shape Spherical Random coil

3 Architecture Regular Irregular

4 Synthesis Stepwise growth Single step

polycondensation

5 Crystallanity Non-crystalline and amorphous Materials Lower glass

temperatures

Semi crystalline/crystallineMaterials -Higher glass

temperatures

6 Aqueous solubility High Low

7 Nonpolar solubility High Low

8Compressibility Low High 9

3. TYPES OF DENDRIMERS

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PAMAM Dendrimer

• PAMAM [Poly (amido amine)] dendrimers are spheroidal or ellipsoidal in shape. These are most studied macromolecules and are commercially available.

• The divergent method is used for their synthesis where ammonia or ethylenediamine is used as starting material.

• The high solubility and reactivity of these are due to presence of a number of functional end groups and empty internal cavities.

• The conventional macromolecules have low amino group density as compared to PAMAM dendrimers. [1]

• Products up to generation 10 (a molecular weight of over 9,30,000 g/mol) have been obtained (by comparison, the molecular weight of human hemoglobin is approximately 65,000 g/mol). PAMAM dendrimers are commercially available, usually as methanol solutions

• Starburst dendrimers is applied as a trademark name for a sub-class of PAMAM dendrimers based on a tris-aminoethylene-imine core. The name refers to the star like pattern observed when looking at the structure of the high-generation dendrimers of this type in two-dimensions.

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Figure 2: 3 dimentional projection of dendrimer core shell architecture for G-Figure 2: 3 dimentional projection of dendrimer core shell architecture for G-4.5 PAMAM Dendrimers4.5 PAMAM Dendrimers

Table 2: Types of dendrimers [5]

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Types Definition Synthesis Example Applications

PamamDendrimer

Poly (amidoamine) dendrimers possess amino groups on theSurface.

Divergent Dendritech(USA) Material Science and Biomedicine

Computer toners

PamamosDendrimer

Inverted unimolecular micelles consists of hydrophilic nuclephilicPAMAM interiors and hydrophobic organosilicon(OS) Exteriors.

Convergentand Divergent

SARSOX Nano-lithography Electronics, Photonics Chemical catalysisPrecursor for honeycomb like network preparations.

PPIdendrimer

Poly-alkyl amines having primary amines as end groups and itsInterior consists of numerous tertiary trispropylene amines.

Divergent Asramol by DSM(Netherlands)

Material science and biology

Tectodendrimer

Composed of a core dendrimer with multiple dendrimers at its periphery

Divergent Stratus® CS Acute Care TM, Starburst®, Mercapto

Diseased cell recognition Diseased state drug delivery diagnosisReporting location to outcome of therapy

Types Definition Synthesis Example Applications

Amphiphilicdendrimers

Unsymmetical globular dendrimers built with two segregated sites ofchain end.

Divergent SuperFect, HydraamphiphilesAnd bola-amphiphiles

Structure-directing agent, Use as polar part, cell and gene transfection.

Micellardendrimers

Unimolecular micelle structure of Water soluble hyperbranched polyphenylene

Divergent Beclomethazonedipropionate, NX-200,Magnevist®

Biological and medical applications,Drug delivery, Imaging agent.

Multiple antigenpeptidedendrimers

Dendron-like molecular constructbased upon a polylysine skeleton.

Convergent VivaGel Used in vaccines and diagnostic research. Biological applications.

Frechettypedendrimers

Dendrimes having carboxylic acid groups as surface groups andcontaining poly-benzylether hyperbranced skeleton.

Convergent Frechet type dendron azides, Priostar

Drug carrier, Purifiers, Organic synthesis, detecting agent, drug

delivery.

Liquidcrystallinedendrimers

Consists of mesogenicmonomers

divergent Polycanter liquid crystals, Mesogen functionalizedCarbosilane dendrimers

Science and Engineering.

Metallodendrimers

Dendrimers with incorporated metalatoms

Convergent Zinc Porphyrindendrimers(M=Zn)

Sensing Catalytic applications, mimicbiomolecules, lightharvesting,

Biomarkers.

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MECHANISM OF DRUG DELIVERY THROUGH DENDRIMERS

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Fig. A Dendrimer molecule with Drug molecules loaded at terminal

surface of branches. (electrostatic interactions or

covalent conjugate) . [2]

Fig. A Dendrimer molecule with terminal drug molecules

encapsulated within branches.(simple encapsulation) . [2]

SYNTHESIS OF DENDRIMERS

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Divergent Synthesis• The dendrimer is assembled from a multifunctional core, which is extended

outward by a series of reactions, commonly a Michael reaction. Each step of the reaction must be driven to full completion to prevent mistakes in the dendrimer, which can cause trailing generations (some branches are shorter than the others). Such impurities can impact the functionality and symmetry of the dendrimer, but are extremely difficult to purify out because the relative size difference between perfect and imperfect dendrimers is very small.

Convergent synthesis• 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. This method makes it much easier to remove impurities and shorter branches along the way, so that the final dendrimer is more monodisperse. However dendrimers made this way are not as large as those made by divergent methods, because crowding due to steric effects along the core is limiting.

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Figure 9: Divergent synthesis of dendrimer [4]

Figure 10: Convergent synthesis of dendrimer [4]

Double Exponential and Mixed Method: This is amixture of both divergent and convergent method. In this method a single starting material is taken from which two monomers are prepared by divergent and convergent

method. Then these two monomers are reacted together to give an orthogonally protected trimer. This protecter trimer

may be use to repeat the growth process again. [1]

Figure 12: Combined Divergent-Convergent Method [12]

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CHARACTERIZATION OF DENDRITIC POLYMERS [4, 1]

• Spectroscopy UV-Visible, IR, NMR.• Microscopy TEM , AFM, SEC.• Rheology, physical properties DSC• Miscellaneous• Scattering techniques• Electrical techniques• Solubility • Determination of Melting Point • Elemental Analysis (Nitrogen)

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ADVANTAGES

A) Medication to the affected part inside a patient's body directly

B) Controlled and sustained release of drugs can also be obtained

C) Drugs can be easily made to remain within layers of skin and not penetrate in systemic circulation

D) Bypassing the gastric medium and hence the eschewing the variation due to effect of gastric secretions.

E) Increase in therapeutic efficacy, decrease in side effects: decreased clearance of drug via altered distribution of drug in organs at site of localization and transportation due to controlled and sustained release of the drug.

F) Relatively high drug loading.

G) Preservation of drug activity: as drugs can be incorporated into the systems without any chemical reaction.

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CYTOTOXICITY

Dendrimer having – NH2 termini shows and generation dependent

cytotoxicity, hemolytic activity. Which are associated with their cationic

nature. The cytotoxicity is a function of surface charge, size and

concentration. The cytotoxicity and hemolytic activity of cationic.

Non-charged dendrimer are non-toxic and bioavailable.

• A) Dendrimers with positively charged surface groups-prone to destabilize

cell membranes and cause cell lysis.

• B) Generation dependent toxicity-higher generation dendrimers being the

most toxic.

• C) Degree of substitution, type of amine functionality is important- primary

amines being more toxic than secondary or tertiary amines. [2]

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APPLICATIONS OF DENDRIMERS 1. Therapeutic Application:

-Dendrimer in photodynamic therapy-Dendrimers for Boron Neutron capture therapy 2. Diagnostic Application:-Dendrimers as MRI contrast agent-Dendrimers as X-Ray contrast agent-Dendrimer as molecular probe 3. Pharmaceutical Application: -Dendrimers in pulmonary drug delivery-Dendrimers in Transdermal drug delivery-Dendrimers in ocular drug delivery-Dendrimers in oral drug delivery-Dendrimers for controlled release drug delivery-Dendrimers in targeted drug delivery-Dendrimers in gene delivery-Dendrimers as solubility enhancer-Cellular delivery using Dendrimers carrier-Dendrimers based product in cosmetics-Dendrimers based commercial products

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4. Dendrimers in Gene Delivery

5. Dendrimers as Solubility Enhancer

6. Dendrimers as Cellular Drug Delivery CarrierDendrimers in Targeted and Controlled Release Drug Delivery

7. Dendrimers in Cosmetics

8. Dendrimers as a light harvesting antennae [1]

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CONT….

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Fig. Dendrimers in ocular drug delivery

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Literature surveyAuthor Aim Method and materials Result

R. Ritawidya, A. Pujiyanto,

Mujinah

Synthesis and Characterization ofPoly(Amidoamine) Dendrimers Encapsulated198Au Nanoparticles.

PAMAM G3.0, bovine serum albumin (BSA), gold chloride (HAuCl4.3H2O), methanol, and Au foil.Method- Bottom – up method.

PAMAM G3.0 dendrimer encapsulated 198Aunanoparticles were synthesized which was used as brachytherapy agents.

Gregory Spataro,Francois Malecaze,Cedric-Olivier Turrin

Designing dendrimers for

ocular drug delivery.

tris(2-chloroethyl) amine hydrochloride 3 as analogue of benzalkonium chloride, hydroxybenzaldehyde with NaOH in ethanol, carteolol. Divergent Method

New series of PH-containing dendrimers, having one quaternary ammonium salt as core and carboxylic acid terminal groups have been synthesized from generation 0 (3 carboxylic acid terminal groups) to generation 2 (12 carboxylic acid terminal groups).26

Literature surveyAuthor Aim Method and materials Result

Anna Luganinia, Andrea Giulianib, Giovanna Pirri.

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection byblocking virus binding to cell surface heparan sulfate.

Peptide grade reagents, resins and solvents were used for SPPS (solid phase peptide synthesis)Method- M6 prototype, a tetrabranched dendrimer synthesized on a lysine core which tethers four 10-mer peptide chains in lysine and positions

The two peptide dendrimers, SB105 and SB105 A10, to directly and almost completely inhibit human cytomegalovirus (HCMV) replication in both primary fibroblasts and endothelial cells.

Mona A., Abdel-Rahman

Et al

Thermoresponsive dendrimers based on oligoethylene glycols: Design, synthesis and cytotoxic activity against MCF-7 breast cancercells.

Tetrabromohydroquinone,Tetrahydrofuran (THF),

lithium aluminum hydride(LAH) and

dichloromethane (DCM)Method- Divergent

method

D2 dendrimer gave the best result; it showed cytotoxicity against MCF-7 cellline with IC50 of 1.07 mg/mL and resistant fraction equals 1.97%, the other two dendrimers showed amodest cytotoxic profile.

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CONCLUSION

 

• PAMAM dendrimers are presented as nanocarriers drugs promising for the coming years, since the multiple properties related to their three-dimensional structure, as mono dispersity, versatility, biocompatibility and other characteristics intrinsic which increase the solubility and activity of these drugs linked these polymers, improving the bioavailability and reduce the toxicity potential of many drugs.

• The drug can be linked to the dendrimers by covalent bonds, electrostatic interactions, or by encapsulation, and the choice of the interaction fits the drug needs.

• As a flexible and excellent carrier, the dendrimers can be carefully designed for the delivery of biomolecules to the desired target tissue, which allows the use of lower doses, although effective in therapy.

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REFERENCES

1. A. Malik, S. Chaudhary, G. Garg and A. Tomar, A review on “Dendrimers: A Tool for Drug Delivery”, Advances in Biological Research ,6th edition (4), IDOSI Publications, page no. 165-169, 2012.

 

2. I. Mishra et al, “Dendrimer: A novel drug delivery system”, Journal of Drug Delivery & Therapeutics, 1st publication, 2nd edition, 2011, page no. 70-74.

3. V. Babu, V. Mallikarjun, S. Nikhat and G. Srikanth, “Dendrimers: A New Carrier System For Drug Delivery”, International Journal of Pharmaceutical and Applied Sciences, 1st edition, 2010, page no. 1-10.

4 M. Toraskar, V. Pande and V. Kadam, “Dendrimer: a new approach in pharmacy”, International journal of research in pharmacy and chemistry, VOL.1(4), 2011, page no. 1100-1107.

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CONT…..5. B. Hari, K. Kalaimagal, R. Porkodi, P. Gajula, “Dendrimer: Globular

Nanostructured Materials for Drug Delivery”, International Journal of Pharmtech Research, Vol.4, No.1, Jan-Mar 2012, page no. 432-451.

 

6. Y. Cheng, Z. Xu, T. Mingluma, Tongwen Xu, “Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration”, Published online in Wiley InterScience, March 2007, page no. 123-143.

 

 7. O. Flomenbom, R. Amir et al, “ Some New Aspects of Dendrimer Applications”, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Israel.

 

8. Donald A. Tomalia, K. Mardel, Scott A. Henderson, R. Esfand, “Dendrimers — An Enabling Synthetic Science to Controlled Organic Nanostructures”, page no. 1- 34.

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