Hydrolysable crosslinkers containing hydrolysable segments different from polyesters

In general, this crosslinking agent is formed with a block of PLA of low molecular weight (MW < 2000). It contains more PEG than the corresponding reverse sequence. It is well-known that the balance in the content of PLA and PEG in the crosslinking agent influences the swelling and degradation properties of hydrogels in which it is incorporated.Consequently, an increasing amount of PEG implies a faster degradation profil.

In the model of PEG-PLA-PEG crosslinker described previously, the polyester segments can be replaced by poly(malic acid) (PMA) to obtain a triblock PMA-PEG-PMA diacrylate crosslinker (Poon et al. 2009). However, this method required several synthesis steps to form the cyclic compound necessary for the ROP. A less complex method was developed via the addition of polymerizable double bonds on PMA obtained by polycondensation (Leboucher-Durand et al. 1996). In this case, chemical modifications are performed on the carboxylic pendant groups of the PMA chain. For example, this approach was used to graft HEMA residues on PMA chains to make possible the formation of crosslinked PMA (He et al. 2006).

3.2.2. Hydrolysable crosslinkers containing hydrolysable segments

molecule which makes this crosslinker an interesting compounds to formulate implants with controlled released properties in fluorouracil.

N N O

O

F O Cl

O

N N O

O

F O

O

O O HO

OH

O

O

*

*

Figure 19. Synthesis and chemical structure of a polymerizable derivative of fluororacil dicarbonate containing crosslinker. (The stars point out carbonate functions).

In another synthesis, a dicarbonate containing crosslinker was obtained from the combination of HEMA with triethylene glycol through a 2 steps reaction (Fig. 20) (Bruining et al. 1999, Bruining et al. 2000).

Figure 20. Scheme of the synthesis of polycarbonate based crosslinker designed by Bruining et al. (Bruining et al. 1999)

Keeping the carbonate group as the hydrolysable function in the crosslinker, Sharifi et al.

(Sharifi et al. 2009) have introduced a new family of polycarbonate crosslinkers based on

poly(hexa methylene carbonate) (PHMC). Starting the synthesis of the crosslinker with this molecule has several advantages such as the possibility to modulate the nature of the compound providing with the double bonds. Indeed, this can come from acrylate residues or from fumarates. It is also possible to introduce PEG segments to obtain an amphiphilic macromer (Fig.21).

Figure 21. Scheme of the synthesis of polycarbonate containing hydrolysable crosslinkers

from poly(hexamethylene carbonate) (PHMC). (A) poly(hexamethylene carbonate-fumarate) (PHMCF), (B) poly(hexamethylene carbonate) diacrylate (PHMCA) and (C) poly(ethylene glycol fumarate-co-hexamethylene carbonatefumarate) (PEGF-co-PHMCF) (Sharifi et al.

2009).

When hydrolysable segments are poly(phosphazene), the grafting of compounds containing a polymerizable double bond can be achieved by nucleophilic substitutions on the phosphorous atoms of the phosphazene molecular unit (Allcock et al. 1991). Following this scheme, numerous polyphosphazenes based crosslinker were synthesized by adding small molecules containing carbon-carbon double bond including for instance 2-butenoxy and 4- (allyl-oxyphenyl)phenoxy (Allcock and Ambrosio 1996). In another work, Grosse-Sommer and Prud'homme (Grosse-Sommer and Prud'homme 1996) have achieved the synthesis of a poly(phosphazene) containing degradable crosslinker with allylamine and imidazole substituants as illustrated in Fig. 22. The degradation rate of this crosslinker can be modulated by varying the ratio between the content of the two substituants.

Figure 22. Chemical structure of trimeric phosphazene crosslinkers with allylamine and imidazole substituted (Grosse-Sommer and Prud'homme 1996).

In a more recent work, following the approach of Grosse-Sommer and Prud'homme, Allcock et al. have synthesized polyphosphazene containing crosslinkers with methoxyethoxyethoxy and cinnamyl groups as substituants (Allcock et al. 2006).

Considering polyanhydrides, these compounds may contain double bonds in their structure that are readily available for a radical polymerization. In general, polyanhydrides are

obtained from the copolymerization of unsaturated and saturated di-acids including fumaric acid and sebacic acid for instance (Domb et al. 1996). Their general structure is shown in Fig.

23. The double bond which remains intact after the polymerization of the diacids is available to achieve the crosslinking reaction between polymer chains. Several polyanhydride based crosslinkers were synthesized from fatty acids and amino acids (Kumar et al. 2002).

Figure 23. Chemical structure of the polyanhydride containing crosslinker model suggested by Domb et al. (Domb et al. 1996)

Similarly to polyanhydrides, double bonds are also readily available in poly(propylene fumarates) to achieved the crosslinking of polymers (Jo et al. 2001, Yan et al. 2011) (Fig. 7).

It was observed that networks formed with these crosslinkers kept their degradability and hydrophilic/hydrophobic properties. The physico-chemical properties of the crosslinkers can be modulated by incorporation of polymeric segments of a different nature. For instance, PEG segments can be added to improve the water absorbance capacity of hydrogels obtained with these crosslinkers (Jo et al. 2001). In addition to a PPF and a PEG segment, the crosslinker can also include a PCL fragment. All the modifications can be considered to tune the properties of the crosslinker in such a way that the final material will have the desired properties in term of degradation rate, mechanical strength, softness and swelling capacity.

One of the main challenges found with the previously described hydrolysable crosslinkers is that they are extremely sensitive to the presence of moisture. This implies that they should be kept in a very dry environment during storage. Ulbrich et collaborators has developed the crosslinker N,O-dimethacryloyl hydroxylamine (Subr and Ulbrich 1992; Ulbrich et al. 1993,

Ulbrich et al. 1995) (Fig. 24) based on N,O-dicarbonyl hydroxylamine groupments (COONCO) which can be stored in acid solutions (aqueous buffers with pH < 5) but is hydrolysable at physiological pH (7.4) (Ulbrich et al. 1995). This crosslinker can be easily obtained via a one-step reaction between methacryloyl chloride and hydroxylamine, as shown in Fig. 24.

Figure 24. Scheme of the synthesis of N,O-dimethacryloylhydroxylamine (Subr and Ulbrich 1992).

A couple of works have investigated the N,O-dimethacryloyl hydroxylamine containing crosslinker(Hor k and Chaykivskyy 2002, Hor k et al. 2004, Pr dny et al. 2006, Sykov et al. 2006, Chivukula et al. 2006, Smith et al. 2010, Scheler et al. 2011). A large panel was synthesized by Zhang et al. including a series of linear and star shape aliphatic and aromatic molecules (Zhang and Schwarz 2006). They all can be used to synthesize degradable hydrogels (Fig. 25).

Figure 25. General structures of the panel of hydroxylamine containing crosslinkers proposed by Zhang et al. (Zhang and Schwarz 2006).

4. Formulation and applications of