DENDRIMERS POLYMER TECHNIQUE SPEED UP DRUG DISCOVERY PROCESS

Article written and published by www.worldofchemicals.com

ABSTRACT

Dendrimers are novel and exciting class of highly branched three-dimensional polymer in which growth emanates from a central core molecule such as ammonia, ethylenediamine, and polydiamine or benzene tricarboxylic acid chloride. Dendrimers are considered as the Polymers of 21st century.

The discovery and creation of new drugs is timely and costly process. It is estimated that every new drug takes 12 to 15 years to develop, at a cost of over $800 million. A controlled release system can improve the effectiveness of drug delivery by sustained release of the compound over time or by release at a specific target.

Currently the two common drug delivery systems are liposomes and polymeric systems. These both have limited applications, as liposome-based systems have poor stability and difficulty targeting specific tissues and linear polymers are polydisperse, there by dendrimers came into focus to solve these difficulties. Current article will give the basic concepts, advantages, applications of dendrimers and their role in drug delivery. 

INTRODUCTION

Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their molecular weight and chemical composition, thereby allowing predictable tuning of their biocompatibility and pharmacokinetics.

Advances in our understanding of the role of molecular weight and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors.

Dendrimers are repetitively branched molecules. The first dendrimers were made by divergent synthesis approaches by Fritz Vogtle in 1978, R.G. Denksewalter at Allied Corporation in 1981, Donald Tomalia at Dow Chemical in 1983, and in 1985, and by George Newkome in 1985. In 1990 a convergent synthetic approach was introduced by Jean Frechet.

Dendrimers are large and complex molecules with very well-defined chemical structures. Dendritic molecules are characterized by structural perfection. They consist of three major architectural components.

Core Branches End/Terminal Groups

 DENDRIMER STRUCTURE

DIFFERENT PROCESS METHODS

Dendritic architecture is one of the most universal topologies. This topology provides enhancement of particular properties. Dendrimers are generally prepared using either a divergent method or a convergent one. There is a fundamental difference between these two construction concepts.

Divergent Method Divergent method was introduced by Tomali. In the divergent

method, dendrimer grows outwards from a multifunctional core molecule. The core molecule reacts with monomer molecules containing one reactive and two dormant groups giving the first generation dendrimer. Then the new periphery of the molecule is activated for reactions with more monomers. The process is repeated for several generations and a dendrimer is built layer after layer.

PREPARATION OF DENDRIMERS THROUGH DIVERGENT METHOD

CONVERGENT METHOD

The convergent methods were developed as a response to the weaknesses of the divergent synthesis. The most attractive feature of the convergent synthesis is that requires a very small number of transformations per molecule in the coupling step.

In the convergent approach, the dendrimer is constructed stepwise, starting from the end groups and progressing inwards. When the growing wedges are large enough, several are attached to a suitable core to give a complete dendrimer.

Convergent growth method has several advantages like relatively easy to purify the desired product, occurrence of defects in the final structure is minimised, does not allow the formation of high generation dendrimer because stearic problems occur in the reactions of the dendrons and the core molecule.

PREPARATION OF DENDRIMERS THROUGH CONVERGENT METHOD

MECHANISMS OF DRUG DELIVERY Encapsulation of drugs Dendrimer - drug conjugates Encapsulation of drugs Kono and coworkers used G3 and G4 ethylenediamine based

polyamidoamine (PAMAM) dendrimers with poly (ethyleneglycol) monomethyl ether (M-PEG) grafts to encapsulate the anticancer drugs methotrexate (MTX), and doxorubicin (DOX).

Higher affinity for MTX was reported based on a greater number of encapsulated molecules by UV spectroscopy and thus suggested more favorable acid-base interactions between the drug and the basic, hydrophobic interior of the dendrimer.

DOX drug will release faster than MTX from the dendrimer when measured by diffusion through a dialysis bag. To achieve easier targeted drug delivery sustained release is preferable. Nature of drug and dendrimer structure will influence the encapsulation of drugs.

MECHANISMS OF DRUG DELIVERY CONT .. Dendrimer-Drug Conjugates

In 2002, Baker and coworkers conjugated both p-nitrobenzoic acid by either an amide or ester bond, and DOX by an amide bond to a G5 capped ammonia based PAMAM dendrimer and tested the cytotoxic response towards human carcinoma cells.

Conjugate uptake by cells was measured by a fluorescein tag on the dendrimers. MTX-FA-dendrimer conjugates entered the cells with similar uptake to folic acid-dendrimer conjugates while the dendrimer alone showed less than 10% uptake.

The amide conjugate was less toxic suggesting that the higher cytotoxicity for the ester conjugate resulted from intracellular drug delivery and release.

ADVANTAGES

Dendrimers offers various advantages over other polymers: (1) Dendrimers have nanoscopic particle size range from 1-100 nm, which

makes them less susceptible for reticulum endothelium uptake. (2) They have lower polydispersity index, due to stringent control during

synthesis. As the density of branches increases the outer most branches arrange themselves surrounding a lower density core in the form of spheres and outer surface density is more and most of the space remains hollow towards core. This region can be utilized for drug entrapment.

(3) Multiple functional groups are present on outer surface of dendrimers, which can be used to attach vector devices for targeting to particular site in the body.

(4) Dendrimers can be modified as stimuli responsive to release drug. (5) Dendrimers might show an enhanced permeability and retention effect which

allows them to target tumour cells more effectively than small molecules. (6) They can be synthesized and designed for specific applications. Due to their

feasible topology, functionality and dimensions, they are ideal drug delivery systems, and also, their size is very close to various important biological polymers and assemblies such as DNA and proteins which are physiologically idea

APPLICATIONS

The properties of dendrimers like unparalled molecular uniformity, multifunctional surface and presence of internal cavities makes it suitable for a variety of high technology uses.

Pharmaceutical applications Therapeutic applications Diagnostic applications Dendritic Catalysts / Enzymes Industrial Processes

CURRENT AND POTENTIAL APPLICATIONS OF DENDRIMERS

Single dendrimer molecule has hundreds of possible sites to couple to an active species. This property of dendrimers makes researchers to attach both targeting molecules and drug molecules to the same dendrimer, which could reduce negative side effects of medications on healthy cells.

Alert ticket for Anthrax Detection Priofect™, Priostar™ and Starburst for targeted

diagnostic, therapeutic delivery for cancer cells SuperFect for Gene Transfection Vivagel for preventing HIV

CONCLUSION

Diversified applications for dendrimers can be obtained by controlling the architecture, shape, branching length and density, and their surface functionality of dendrimer.

The high density of surface groups allows attachment of targeting groups as well as groups that modify the solution performance or toxicity of dendrimers.

As the research progresses the dendrimer applications will integrate into the different sectors and it will helpful to the universal drug delivery mechanisms.

The area of dendrimers for drug delivery is continuing to grow with the recent reports of cascade release dendrimers and additional ways to release drugs. 

REFERENCE

1] Barbara Klajnert, and Maria Bryszewska, Dendrimers: properties and application, Vol. 48 No. 1/2001, 199–208, Available from - http://www.actabp.pl/pdf/1_2001/199-208.pdf

[2] Catherine A. Brummond, APPLICATIONS OF DENDRIMERS TO DRUG DELIVERY, March 4, 2004; Available from- http://chemistry.illinois.edu/research/organic/seminar_extracts/2003_2004/Brummond.pdf 

[3] Tarun Garg, Onkar Singh, Saahil Arora, RSR Murthy, DENDRIMER- A NOVEL SCAFFOLD FOR DRUG DELIVERY, Volume 7, Issue 2, Article-039; April 2011- Available from - http://globalresearchonline.net/journalcontents/volume7issue2/Article-039.pdf