Dendrimers as drug Dendrimers as drug carrierscarriers

Presented by: Chinchole Pravin SonuR. C. Patel collage of pharmacy, Shirpur.

IntroductionIntroduction Dendrimers are the new artificial macromolecules which

have the structure like a tree

Since dendrimers are synthesized from branched monomer units in a stepwise manner hence it is possible to conduct a precise control on molecular size, shape, dimension, density, polarity, flexibility & solubility by choosing different building/branching units & surface functional groups

Dendrimers possess empty internal cavities & open conformations which make it possible to encapsulate hydrophobic drug molecules

Drugs or guest molecules can either be conjugated with these surface functional groups or encapsulated in hydrophobic cavities of dendrimers

Structure, synthesis & properties of Structure, synthesis & properties of dendrimersdendrimers

Dendrimers are globe or ellipsoid shaped & consists of components

A central coreRepeated branchesSurface functional groups

A central core should be a molecule with at least two reactive functional groups

The repeated branches are organized in a series of radically concentric layers called generations

Synthesis of DendrimersSynthesis of DendrimersDivergent method:- starts from the central core &

extends towards the surface

Convergent method:- uses a top down approach & starts from periphery of dendrimers

This method has follow. advantagesEasy purification & characterization the capability of attaching different types of

dendrons to one dendrimer. However there exists steric constraints when one tries attaching large dendrons to central core

PAMAM dendrimers & polpropylenimine dendrimers used in biomedical fields are synthesized by convergent method

The synthesis of PAMAM dendrimers starts with Michael addition between the multifunctional central core (usually ammonia & ethylenediamine) & methylmethacrylate

By repeating the Michael addition & amidation reaction step by step, high generation dendrimers can be obtained

These products with primary amine as terminal functional groups are called as full generation dendrimers

When it comes to the products with carboxylate groups or ester groups they are names as half generation dendrimers

Properties of dendrimersProperties of dendrimers Monodispersity:- monodisperse property of dendrimers has been

characterized by HPLC, size exclusion chromatography mass spectrometry, TEM

Nanoscale dimensions & shapes:- dendrimers have nanoscale dimensions due to their well organized synthesis strategy & size controllable properties. Diameter of dendrimer with an ethylenediamine core increases from 1.1 to 12.4 nm. They have ellipsoidal shapes (PAMAM dendrimers of low generation,G0-G3) whereas PAMAM dendrimers of high generations,G4-G10) with well defined cavities have roughly spherical shapes

Solubility & reactivity:-is determined by the functional groups, dendrimer aggregation, repeated units & even the core. Their high solubility in organic solvents leads to characterize their structures. Also high water solubility enhances its application as solubility enhancer for hydrophobic guest molecules. High density of surface groups(-NH2,-COOH,-OH) conjugates with bioactive molecules

Dynamic structuresDynamic structures

The conformation of dendrimers depends on not only their generation but also the environment where they exist. The structures of dendrimers in solutions are dynamic

The structures of dendrimers were tunable from that of the dense core to that of dense shell by manipulation of the salt conc. or PH in aq. solutions

Interactions between dendrimers & drug Interactions between dendrimers & drug moleculesmolecules

Simple encapsulation:-It directly encapsulates guest molecules into macromolecule interior. Internal hydrophobic cavities interacts with poorly soluble drugs through hydrophobic interactions. Internal cavities have nitrogen & oxygen atoms through which drug molecules interact by hydrogen bonding

Electrostatic interaction:-surface functional groups enhances solubility of hydrophobic drugs by electrostatic interaction e.g. Ibuprofen, ketoprofen, indomethacin

Covalent conjugation:-the drug is covalently bound to dendrimers & its cleavage occurs via chemical or enzymatic cleavage of hydrolytically labile bonds. It allows tissue targeting & controlled delivery as drug-dendrimer conjugate diffuse slower than the free drug in body

Applications in different routes of drug Applications in different routes of drug administrationadministrationDendrimers in intravenous/intraperitoneal

/intratumoural drug delivery dendrimers as targeting carriers in cancer therapy. It was

well studied that the conjugation of special molecules with targeting properties to dendrimers allows the targeting ability of dendrimers. These are sugar, folic acid, specific antibody & peptide & epidermal growth factor. Both intraperitoneal & intratumoural administration of anticancer drugs can increase the exposure of cancer cells within peritoneal cavity or directly to drug & minimizing potential toxic effects to internal organs

The ability of cationic dendrimers to deliver DNA or RNA has been well established. Dendrimer based gene delivery systems have become routine tools in cell biology other biomedical fields

Guest Guest moleculemolecule

dendrimedendrimerr

InteractioInteraction patternn pattern

GoalGoal AdministrAdministration ation routeroute

5-flurouracil5-flurouracil PEG PEG modified G4 modified G4 PAMAMPAMAM

encapsulatiencapsulationon

PharmacokiPharmacokinetic netic studiesstudies

IVIV

MethotrexatMethotrexatee

Folic acid Folic acid coated coated PAMAMPAMAM

ConjugationConjugation Cancer Cancer chemotherachemotherapypy

IVIV

DNADNA G9 PAMAMG9 PAMAM Electrostatic Electrostatic interactioninteraction

Lung gene Lung gene transfectiontransfection

IVIV

DNADNA PAMAM PAMAM dendrimers dendrimers

Electrostatic Electrostatic interactioninteraction

Tumour Tumour targetingtargeting

IntraperitoneIntraperitonealal

DNADNA PAMAMPAMAM Electrostatic Electrostatic interactioninteraction

Inhibition of Inhibition of tumour tumour growth & growth & angiogenesiangiogenesiss

intratumoralintratumoral

GlucosaminGlucosaminee

G1 PAMAMG1 PAMAM ConjugationConjugation Biological Biological modulatorsmodulators

IntraperitoneIntraperitonealal

Dendrimers in oral drug delivery:-5 flurouracil has high toxic effects for which attempts has been made to reduce it by using polymeric carriers. Surface group modification of PAMAM dendrimer & then coating with phospholipids was found to be more effective than free drug

Dendrimers in transdermal drug delivery:-transdermal delivery of ketoprofen & indomethacin using PAMAM dendrimers effectively facilitated skin penetration of these NSAIDS

Dendrimers in ocular drug delivery:-dendritic polymers dissolve hydrophobic drugs in their cavities & accomplish both retention & sustained/controlled release of drugs.

Eye diseases such as diabetic retinopathy, retinitis are located in posterior segment of eye where drugs from eye drops rarely reach the therapeutic levels in affected posterior tissues. Recently dendrimers have proved to be suitable in treating posterior segment eye diseases

Polymeric nanoparticles tend to be removed by lachrymal drainage whereas microparticles of larger sizes are less tolerable because they may cause eye irritation & tend to be eliminated by the flow of tears.

These dendritic polymers might dissolve hydrophobic drugs in their cavities & accomplish both retention & sustained/controlled release of drugs

Dendrimer conc. & surface functional groups for controlled delivery, dendrimer size, molecular weight, charge intensity, molecular geometry influenced occular delivery efficiency

Dendrimers in other drug delivery:- Dendrimers are used as carriers for other

routes such as rectal, vaginal, or nasal. It is well known that PAMAM dendrimers can easily penetrate through the epithelium of intestines. Dendrimer based microbicide Vivagel has been administered topically in the vagina

Iontophoresis is effective tech. where ionic drugs can penetrate into different tissues driven by weak electric current (transdermal & ocular). Dendrimers with large amount of charges on the outer surface can be applied as carriers