Drug Delivery Systems based on RAFT-Polymerization

Controlled/Living radical polymerization methods, including Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization, are highly efficient tools to prepare well-defined amphiphilic block copolymers which have the ability to form micelles in aqueous media.[1] Due to their versatile usage, especially in the medical field, this type of block copolymers has received an ever increasing interest in recent years.

Using RAFT polymerization allows preparing polymers with defined molecular weights and narrow molecular weight distributions. Furthermore, RAFT polymerization can be used for the polymerization of a broad variety of monomers under various conditions (e.g. solvent, temperature…).

 

RAFT Polymerization

The key compound in RAFT polymerization is the so called RAFT agent or chain transfer agent (CTA), which consists of a dithio-group connected to an R group and a Z group. By varying these two groups it is possible to modify the RAFT agent in regard to the used class of monomer (e.g. acrylates, vinyl esters…) and also reaction conditions (e.g. water solubility).

In Figure 1 the mechanism of the RAFT polymerization is shown, where it can be seen that the polymer always forms between the sulfur atom of the C-S bond and the R-group. The fact, that the dithio-group is still attached to the polymer as active end group after the polymerization, provides the possibility for elongation of the polymer either by the same monomer or a different one.

image.alternative

Controlled/Living radical polymerization methods, including Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization, are highly efficient tools to prepare well-defined amphiphilic block copolymers which have the ability to form micelles in aqueous media.[1] Due to their versatile usage, especially in the medical field, this type of block copolymers has received an ever increasing interest in recent years.

Using RAFT polymerization allows preparing polymers with defined molecular weights and narrow molecular weight distributions. Furthermore, RAFT polymerization can be used for the polymerization of a broad variety of monomers under various conditions (e.g. solvent, temperature…).

 

RAFT Polymerization

The key compound in RAFT polymerization is the so called RAFT agent or chain transfer agent (CTA), which consists of a dithio-group connected to an R group and a Z group. By varying these two groups it is possible to modify the RAFT agent in regard to the used class of monomer (e.g. acrylates, vinyl esters…) and also reaction conditions (e.g. water solubility).

In Figure 1 the mechanism of the RAFT polymerization is shown, where it can be seen that the polymer always forms between the sulfur atom of the C-S bond and the R-group. The fact, that the dithio-group is still attached to the polymer as active end group after the polymerization, provides the possibility for elongation of the polymer either by the same monomer or a different one.

image.alternative

In Figure 1 the mechanism of the RAFT polymerization is shown, where it can be seen that the polymer always forms between the sulfur atom of the C-S bond and the R-group. The fact, that the dithio-group is still attached to the polymer as active end group after the polymerization, provides the possibility for elongation of the polymer either by the same monomer or a different one.

 

image.alternative

In Figure 1 the mechanism of the RAFT polymerization is shown, where it can be seen that the polymer always forms between the sulfur atom of the C-S bond and the R-group. The fact, that the dithio-group is still attached to the polymer as active end group after the polymerization, provides the possibility for elongation of the polymer either by the same monomer or a different one.

 

image.alternative

                                                     Figure 1: RAFT mechanism

 

Synthesis of block copolymers

The preparation of block copolymers via RAFT polymerization is possible in two ways (see Figure 2). The first is a one pot reaction whereat monomer A, CTA and an initiator allowed to react until all the monomer is consumed. Then, monomer B is added directly to the reaction mixture and the reaction is stopped when the polymerization of the second block is completed (one pot). The second possibility is a synthesis via a two-step process. Again, monomer A is polymerized by using a CTA and an initiator, but the resulting polymer is isolated by precipitation. This so called macro CTA is then used for the synthesis of the second block by reacting it with monomer B and initiator (sequential).

image.alternative

                                                     Figure 1: RAFT mechanism

 

Synthesis of block copolymers

The preparation of block copolymers via RAFT polymerization is possible in two ways (see Figure 2). The first is a one pot reaction whereat monomer A, CTA and an initiator allowed to react until all the monomer is consumed. Then, monomer B is added directly to the reaction mixture and the reaction is stopped when the polymerization of the second block is completed (one pot). The second possibility is a synthesis via a two-step process. Again, monomer A is polymerized by using a CTA and an initiator, but the resulting polymer is isolated by precipitation. This so called macro CTA is then used for the synthesis of the second block by reacting it with monomer B and initiator (sequential).

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                                                       Figure 2: Block copolymer synthesis

 

Our research

The aim of our research in that field is to develop smart drug carriers from RAFT generated amphiphilic block copolymers. These should give the possibility for targeted drug delivery, so that only/mainly affected cells get into contact with the applied drug. Along with this, side effects like loss of hair should be reduced. So far, we developed a system based on a methacrylate and an acrylamide, which is able to form micelles in water.

Currently we are focusing on the RAFT polymerization of vinyl esters. The main goal thereby is the synthesis of biodegradable block copolymers based on this type of monomers and the subsequent preparation of micelles, which are soluble in aqueous media. Furthermore, these micelles should be stabilized by efficient crosslinking. Another task will be the decoration of the shell of such micelles with tissue specific molecules in order to allow targeted drug delivery. 

[1]        York, A.W., S.E. Kirkland, and C.L. McCormick, Advances in the synthesis of amphiphilic block copolymers via RAFT polymerization: Stimuli-responsive drug and gene delivery. Advanced Drug Delivery Reviews, 2008. 60(9): p. 1018-1036.

 

                                                       Figure 2: Block copolymer synthesis

 

Our research

The aim of our research in that field is to develop smart drug carriers from RAFT generated amphiphilic block copolymers. These should give the possibility for targeted drug delivery, so that only/mainly affected cells get into contact with the applied drug. Along with this, side effects like loss of hair should be reduced. So far, we developed a system based on a methacrylate and an acrylamide, which is able to form micelles in water.

Currently we are focusing on the RAFT polymerization of vinyl esters. The main goal thereby is the synthesis of biodegradable block copolymers based on this type of monomers and the subsequent preparation of micelles, which are soluble in aqueous media. Furthermore, these micelles should be stabilized by efficient crosslinking. Another task will be the decoration of the shell of such micelles with tissue specific molecules in order to allow targeted drug delivery. 

[1]        York, A.W., S.E. Kirkland, and C.L. McCormick, Advances in the synthesis of amphiphilic block copolymers via RAFT polymerization: Stimuli-responsive drug and gene delivery. Advanced Drug Delivery Reviews, 2008. 60(9): p. 1018-1036.