dendrimers as drug carriers by pravin chinchole
TRANSCRIPT
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