Phosphorus-Containing Polymers: A Great Opportunity for the

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Phosphorus-Containing Polymers: A Great Opportunity for the Biomedical Field Sophie Monge,* Benjamin Canniccioni, Alain Graillot, and Jean-Jacques Robin Institut Charles Gerhardt Montpellier UMR5253 CNRS-UM2-ENSCM-UM1 - Equipe Ingenierie et Architectures Macromoleculaires, Universite Montpellier II cc1702, Place Eugene Bataillon 34095 Montpellier Cedex 5 ABSTRACT: This Review is focused on the growing interest brought to phosphorus-containing organic materials for applications in the biomedical field, mainly because of their properties such as biocompatibility, hemocompatibility, and protein adsorption resistance. It mainly describes relevant works achieved on these materials for various applications: dentistry, regenerative medicine, and drug delivery. Special attention was given to 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer as the latter appeared of great importance because of its biomimetic structure due to the presence of the phospholipid group on its structure. As a result, much research effort is currently concentrated on the development of phosphorylcholine-containing (co)polymers that represent a promising class of materials.

1. INTRODUCTION For the past years, phosphorus-containing monomers and polymers have been the subject of extensive research.1
6 Indeed, the different possible chemical environments of phosphorus atom (Scheme 1) lead to very peculiar and interesting properties,7 which make these materials highly attractive. As a consequence, various syntheses of monomers and polymers were carried out following different procedures: phosphorinated moieties were introduced onto polymers by (co)polymerization of monomers bearing the phosphorus atom or by the grafting of phosphorus-based group onto the polymer. Phosphorus-containing materials can be employed for a large range of technological applications.8 For instance, they were largely used in industry because of their aptitude to bind metals.9
12 Indeed, organophosphonates exhibited interesting complexing properties13,14 and were used as dispersants, corrosion inhibiting agent, or for preventing deposit formation.15 Recently, the development of free halogen materials due to latest legislation gave phosphorinated polymers new opportunities to be used in flame retardancy,16
18 where phosphorus is known to be efficient. Phosphorinated halogen-free retardant coatings can lead to a char or a protective coating avoiding any oxygen transport toward the burning area and giving fire extinguishing. Polymeric materials bearing phosphonic sites were also developed in alternative energy production because they have been involved in proton-conducting fuel-cell membranes.19
22 It was shown that phosphonic acid moieties had higher chemical and thermal stability than sulfonic acid materials, usually used for such purpose. Recently, the interest of phosphorus-based materials (polyphosphates, polyphosphonates, polyphosphoesters, phosphonated poly(meth)acrylates, etc.) used in the biomedical field is r 2011 American Chemical Society

accelerating because they proved to be biodegradable and bloodcompatible, showed reduced protein adsorption, and led to strong interactions with dentin, enamel, or bones. As a consequence, they appear as an interesting class of materials, which will lead to further developments in this field of applications. This Review presents relevant work achieved to date on phosphorus-containing polymers for potential biomedical applications. It is important to notice that polyphosphazene derivatives were not evaluated in this Review even if they were quite developed for such purpose because we considered that they represented a particular class of materials due to the phosphorus/nitrogen double bond. First studies described in the literature dealt with the use of phosphorus-containing derivatives for dental applications as the incorporation of a phosphonic function led to a better adhesion on the tooth surface23 because of complexes formation with calcium in hydroxyapatite (HAP).24 This property also led to the employment of these functionalized polymers in bone tissue engineering scaffolds design. Finally, phosphorus polymers proved to play a major role as carriers for bioactive molecules.25 In this last context, the importance of a monomer, namely, the 2-methacryloyloxyethyl phosphorylcholine (MPC), will be highlighted. Indeed, polymers derived from MPC proved to be particularly interesting because of their biomimetic nature and will probably lead to important innovations in the next future.

2. DENTAL APPLICATIONS Among all self-etching adhesive systems developed in dentistry for bonding of resin composite to enamel or dentin, Received: March 7, 2011 Revised: May 6, 2011 Published: May 10, 2011 1973

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Biomacromolecules primers containing phosphoric acid esters have been quite largely considered. Indeed, such derivatives were potentially interesting as the incorporation of a phosphonic function would result in an increase in the biocompatibility and in the adhesion due to the chelation with calcium ions in the tooth surface23 because of complexes formation with calcium in HAP.24 This mineral is partially dissociated by phosphonic acid26 to give brushite acting as macromolecules cross-linker,27 and the bond strength depends on the alkyl chain length of the monomer.28,29 In general, phosphorus-containing monomers are (meth)acrylic derivatives, Scheme 1. Some Chemical Environments of Phosphorus Atom Mainly Encountered in Phosphorus-Containing Monomers and Polymersa

a

Polyphosphazenes were not considered in the present Review.

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mainly (meth)acrylates monomers, but other functional groups such as (meth)acrylamides were also studied because of their high reactivity under UV radiations (Scheme 2). Diverse methacrylate monomers containing phosphonic acid or acidic phosphate groups were first prepared and evaluated.30
32 These monomers gave good photopolymerization rates and high conversion under UV polymerization, and resulting polymers were able to etch enamel and dentin. Unfortunately, they were unstable because of the hydrolysis of the phosphate ester bonds that could occur in water, often used as cosolvent in self-etching and enamel-dentin adhesives. To overcome this problem, other chemical structures were designed.33
35 For instance, phosphonated groups were preferred because they improved hydrolytic stability and proved to be efficient as calcium sequestrants, inhibiting the crystal growth of calcium phosphate (CaP).36 First works reported in the literature proved that phosphonated copolymers could improve the adhesion of filling composites and decrease the adsorption of proteins onto enamel.37,38 In this context, phosphonated methacrylates39
42 and acrylates30,39,43,44 were prepared and polymerized. In general, changing the spacer length allowed the control of the polymerization reactivity. The monomers with phosphorus atoms close to the double bond

Scheme 2. Monomers Used for Dental Applications Bringing One Polymerizable Group

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Scheme 3. Monomers Used for Dental Applications Bringing Two Polymerizable Groups

were not reactive in homopolymerizations. It was demonstrated that monomer reactivities increased with decreasing steric hindrance, increasing hydrogen-bonding capacity, or both.43 Phosphonated acrylic monomer derivatives with ester43,45 or ether linkage42,46 or even with only alkalene spacer43,45,47 were also reported in the literature. At last, new monomers based on heterocyclic structures including sulfur atom were shown to be efficient for the adhesion of polymeric resins onto precious metal based alloys.48 Special attention was given to phosphonated (meth)acrylamides30,44,49,50 because of the hydrolytic stability of the amide function. However, it was shown that N,N-disubstituted methacrylamides led to low reactivity in radical homopolymerization due to the steric effect of the substituents of the amido group.49 For instance, radical polymerization of the N,N-diethylacrylamide monomer led to poor yield (23 wt %).44 Nevertheless, this monomer was able to generate a bond between the dentin surface and the composite. 2-(N-Methylacrylamido)ethylphosphonic acid, 6-(N-methylacrylamido)hexylphosphonic acid, 10-(N-methylacrylamido)decylphosphonic acid, and 4-(Nmethylacrylamido)benzylphosphonic acid were also studied.50 Because all monomers were hydrolytically stable in aqueous solution, free radical polymerization was carried out in an ethanol/water mixture and gave homopolymers with excellent yields. The photopolymerization of these monomers with N,N0 diethyl-1,3-bis(acrylamido)propane was investigated by differential scanning calorimetry (DSC). Dentin shear bond strength measurements showed that primers based on (N-methacylamido)alkylphosphonic acids assured a strong bond between the tooth substrate and a dental composite. The monomer with the longest spacer group provided the highest shear bond strength. Monomers containing two (meth)acryloyl functions associated with phosphonate groups were also employed (Scheme 3). Because aliphatic monomers led to relatively poor mechanical

properties, aromatic monomers were preferred.23,40,41,51,52 Such monomers were expected to bring comparable properties to those observed with aromatic dimethacrylate monomers currently used extensively in dentistry53 such as bisphenol A glycidyl methacrylate (Bis-GMA). Phosphorus-containing monomer with a chemical structure close to the one of Bis-GMA was copolymerized in bulk and led to cross-linking upon UVirradiation in the presence of free radical initiator. Although no tests of biocompatibility and adhesion to the tooth were reported, such monomers led to interesting materials for potential use in dental composites. Similar diacrylate derivative was also prepared. For both mono and diacrylates, hydrolysis of the tert-butyl groups of the monomers increased the reactivity and the polymerization rate. Diacrylates derived from bisphenol A glycidyl methacrylate led to low photopolymerization maximum rate and conversion for the phosphonic ester form, whereas phosphonic acid derivative did not polymerize at all.42 Finally, some polyols such as glycerol, D-mannitol, D-sorbitol, pentaerythrit, and others54 were used as precursors of new monomers. For example, a multiacrylate molecule named dipentaerythrolpentaacryloyl dihydrogen phosphate30 was also described as being able to improve bonding with human dentin when added to phosphorus oxychloride.

3. TISSUE ENGINEERING Bone tissue malfunction, degeneration, and damage remain serious health problems despite advances in medical technology. In that context, polymers are often used as matrices to initiate a repair or a regenerative response, often referred to as tissue engineering. The latter typically involves the seeding of biodegradable polymeric scaffolds with differentiated or pluripotent cells in vitro, followed by implantation of the whole cell
scaffold system into the region of tissue loss or damage. Polymeric 1975

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Biomacromolecules Scheme 4. Ethylene Glycol (Meth)acrylate Used in Tissue Engineering

materials, especially phosphonated polymers, already proved to be of great interest in this field. Indeed, researchers tried to promote interactions of biomaterials with bone cells, and the protein interactions were favored when phosphorus-grafted polymeric surfaces were used. Very recently, polyphosphazenetype polymers, especially alanine polyphosphazene materials, proved to be promising materials for tissue and organ regeneration.55 Experimental evaluations were also achieved with vinyl phosphonic acid, which was grafted by photopolymerization onto surfaces with comonomers such as acrylamide and showed osteoblast-like cell adhesion as well as proliferation.56 So, poly(vinyl phosphonic acid) copolymers could be used in bonetissue-engineering scaffolds design.57 (Meth)acrylate-based polymers showed very interesting properties too. Ethylene glycol acrylate phosphate (MAEP) and ethylene glycol methacrylate phosphate (MOEP) (Scheme 4) were polymerized through reversible addition
fragmentation chain transfer (RAFT)mediated polymerization to achieve low-molecular-weight polymers.58 Both the PMAEP and PMOEP polymers showed a CaP layer, and a secondary CaP mineral growth with a typical HAP globular morphology was found on the PMOEP gel. Crosslinked copolymers of 2-hydroxyethyl methacrylate (HEMA) and MOEP were also studied.59 The incorporation of phosphate pendant groups into cross-linked PHEMA hydrogel significantly altered the mechanism of water transport into the polymer matrix, and 3
20 mol % MOEP polymers appeared to be the most promising material for biomedical applications. Copolymer series using increasing concentrations of MOEP with (diethylamino)ethyl methacrylate (DEAEMA) and 1-vinyl-2-pyrrolidone (VP) were also prepared60 to study the influence of phosphate content and distribution on the capacity to constitute calcium-rich layer. The amounts of calcium increased when higher concentrations of MOEP were used, and best results were obtained with MOEP-VP copolymers because the amine group might favor the attraction of phosphorus, creating another way for the nucleation of calcium/phosphate crystals. Finally, polymeric grafting with phosphate-containing monomers such as MAEP and MOEP was carried out onto poly(tetrafluoroethylene) (PTFE) membranes, which were already used in facial augmentation and as a craniofacial implant material.61 The surface modification led to an increase in hydrophilicity on the surface. Moreover, MAEP-modified membrane with an external surface coverage of 44% or above was demonstrated to be promising as an improved biomaterial because these modified materials were able to induce CaP nucleation.62 Poly(phosphoesters) (Scheme 5) were also evaluated as tissue engineering scaffolds materials. Poly(bis(hydroxyethyl)terephthalate-ethyl ortho-phosphorylate/terephthaloyl chloride) (P(BHET-EOT/ TC)) materials63 were found to possess good physicochemical

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Scheme 5. Poly(phosphoester) Structures Used in Tissue Engineering Scaffold Materials

and film-forming properties. These poly(phosphoesters) were ionically cross-linked with calcium ions, and ionomer derivatives proved to be useful as an intermediate for the conjugation of peptides or other amino-containing entities. Unsaturated polyphosphoester (UPPE) based on bis(1,2-propylene glycol) fumarate and ethyl dichlorophosphate was prepared by polycondensation reaction.64 This polyphosphoester can form crosslinking matrix with mechanical properties close to natural trabecular bone and is a potential injectable tissue engineering scaffold material with excellent operation properties. Recently, Pramanik et al.65 prepared nanocomposites from HAP nanoparticles and poly(vinyl alcohol) (PVA) bearing phosphates groups. These composites showed an excellent hemocompatibility, opening the way to implant applications. Similar materials were designed to lead to cross-linked hybrid compositions showing bioactivity controlled by structural factors such as cross-linking rate, silica proportion, and others.66 At last, Greish67 demonstrated the possibility to prepare organic
inorganic composites by solid-state reaction of poly(vinyl phosphonic acid) with tetracalcium phosphate.

4. DRUG DELIVERY Phosphorus-containing polymers can be used as carriers for biologically active substances. Among all possible chemical structures, polyphosphate derivatives (Scheme 6) were pointed out because of their interesting properties. Indeed, they exhibit many advantages such as biodegradability through hydrolysis and can possibly be degradable by enzymatic digestion of phosphate linkages under physiological conditions.68 They are biocompatible and present structural similarities to the naturally occurring nucleic and teichoic acids. Poly(oxyethylene H-phosphonates)69
71 were also used in biomedical field because of their biocompatibility, controlled biodegradability, and the presence of a highly reactive P
H bond in the building units of the polymer chain (Scheme 7). These water-soluble polymers showed low toxicity and could be easily functionalized.72
74 For example, immobilization of aminothiols on poly(oxyalkylene phosphates) was achieved: the incorporation of the cysteamine, a well-known clinically tested chemical radioprotector, into poly(oxyethylene phosphate) led to a significant reduction of its toxicity. The drug dose needed for efficient radio protection was also reduced.75 Poly(oxyethylene H-phosphonates) and poly(oxyethylene phosphates) polymeric protective agents were evaluated either with other radioprotectors such as amifostine or 1-(3-aminopropyl)aminoethanethiol76 or for the fixation of other pharmacologically active amines on polyphosphonates. For example, hydrosoluble poly(3,6,9-trioxaundecamethylene phosphonates) with attached bis(2-chloroethyl)amine (BCEA) in the side chain were synthesized by chemical modification of the corresponding polyphosphonate.77 The main difficulty encountered with alkylating agents such as BCEA, widely used in cancer 1976

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Scheme 6. Chemical Structure of Polyphosphoesters Used As Drug Carriers

Scheme 7. Chemical Structure of Poly(oxyethylene H-phosphonates) Used As Drug Carriers

chemotherapy, is that they are not specific. They are active against tumor cells but also against normal cells leading to severe side effects. To overcome this problem, we used macromolecular prodrug to improve the body distribution and increase the tumor cell specificity. Polyphosphates were chosen as starting materials and chemically modified to afford water-soluble polymers bearing the BCEA group, released after hydrolytic or enzymatic cleavage. In vitro cytotoxic studies were carried out on polymeric derivative using human hepatocellular carcinoma cell line HepG2 and murine leukemia cell line L1210 and led to encouraging results. Poly(oxyethylene H-phosphonates) also allowed the synthesis of polyphosphoesters bearing, on the one hand, P
H or P
OCH3 groups in the main chain and, on the other hand, 1,3-dioxolan-2-one rings or hydroxyurethane fragments attached to the polymer backbone through a P
C bond.78 Resulting polymers presented biodegradability and versatile reactivity that enabled attachment of bioactive compounds. Biodegradable copolymers containing both phosphonates and lactide ester linkages in the polymer backbone were also

investigated. Paclitaxel delivery from novel polyphosphoesters was evaluated79 and proved to be continuous in vitro and in vivo over at least 60 days. Paclitaxel released from microspheres had significant antitumor activity. Biodegradable polyphosphoester was used to produce microspheres, notably from poly(bis(hydroxyethyl)terephthalateethyl ortho-phosphorylate/terephthaloyl chloride (P(BHET-EOP/ TC). The resulting material was evaluated for controlled delivery of neurotrophic proteins to a target tissue to treat various diseases of the nervous system.80 It was demonstrated that sustained release of nerve growth factor for a prolonged period from microspheres loaded into synthetic nerve guide conduits might improve peripheral nerve regeneration.81 Poly(phosphoesters) were involved in the fabrication of nerve guide conduits because of their high biocompatibility, adjustable biodegradability, flexibility in coupling fragile biomolecules under physiological conditions, and a wide variety of physicochemical properties.82,83 Tunable thermosensitive polymer micelles based on polyphosphoester and poly(ε-caprolactone) block copolymers were also studied, especially for in vivo biomedical applications. The lower critical solution temperature was adjusted by controlling the molecular weights of the biodegradable polyphosphoester blocks.84

5. POLY(METHACRYLOYLOXYETHYL PHOSPHORYLCHOLINE)-BASED MATERIALS: A GREAT OPPORTUNITY FOR BIOMEDICAL APPLICATIONS According to different results reported in the literature and described in this Review, phosphorus-containing polymers have already been successfully involved in many examples dealing with the biomedical field. These last few years, a new phosphonated monomer, namely, MPC, was used for the synthesis of various (co)polymers evaluated for different biomedical purposes. These PMPC-based polymers appear today as a very useful new class of materials due to the biomimetic structure of MPC via its phospholipid group. In particular, PMPC proved to bring blood 1977

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Scheme 8. Chemical Structure of the 2-Methacryloyloxyethyl Phosphorylcholine (MPC) and Derivatives

Scheme 9. Phosphorylcholine Moieties Bound to the Main Polymer Chain via an Amide Function

compatibility and protein adsorption resistance, notably leading to their use for tissue engineering or for drug delivery systems. As a result, (co)polymers derived from MPC possess essential properties that allowed their use in vivo, and as a consequence, we consider that PMPC-based materials are bound to be further developed in the near future. Blood Compatibility and Protein Adsorption Resistance. Specific properties such as blood compatibility and protein adsorption of poly(2-methacryloyloxyethyl phosphorylcholine)based polymers were already widely studied. In contact with living organisms, materials cause biological side effects such as thrombus formation and immunoresponses, inducing many problems in the treatment of patients using such biomedical devices. As a consequence, blood compatibility appears to be a very important parameter that must be taken into consideration. In that context, polymers having a phospholipid polar group such as MPC or derivatives (Scheme 8) were evaluated because they led to a biomembrane-like surface. In general, these materials manifested protein adsorption resistance that is essential for potential applications in blood-contacting medical devices that require biocompatibility and low risk of postoperative infection. Poly(2-methacryloyloxyethyl phosphorylcholine) exhibited good biological properties.85
87 For instance, graft polymerization of MPC on PE proved to be effective for preventing platelet adhesion.88 Grafting of MPC onto polyvinylidene difluoride and cellulose acetate microfiltration membranes after plasma etching was also reported.89 Improvement in membrane performance was observed, concomitant with a reduction in protein fouling on the surface and within the matrix of the coated membranes. When PMPC was terminated with a specific group, differences were observed. The MPC polymer terminated with one pendant tocopheryl moiety (PMPC-Toco) was prepared by radical polymerization in the presence of 2-mercaptoethanol as chain transfer agent.90 Unfortunately, PMPC-Toco exhibited lower blood compatibility than PMPC homopolymers, even if it was expected to be improved by introducing a suitably long PMPC chain. On the reverse, when MPC and a cross-linker, 2-(methacryloyloxy)ethyl-[N-(2-methacryloyloxyethyl)], were combined to prepare biocompatible ocular materials,88 resulting hydrogels exhibited excellent protein adsorption resistance and ultrahydrophilicity. Statistical copolymers with both MPC and alkyl methacrylates (n-butyl, tert-butyl, n-hexyl, n-dodecyl, and n-stearyl groups) were synthesized.91,92 Adhesion of blood cells on the MPC copolymers after contact to the whole blood was strongly influenced by MPC composition and the chemical structure of the copolymer. Among all of these copolymers, poly(MPC-co-nbutyl methacrylate) exhibited excellent blood compatibility, as shown by the reduction of platelet and aggregation and by suppression of protein adsorption.93,94 The authors reported that such kind of copolymers was an effective treatment for both improving hemocompatibility and reducing protein fouling on the cellulose acetate flat membranes and hollow fiber membranes.95,96 It was also demonstrated that blood compatibility of

polysulfone or polyethersulfone97 was improved with the reduction of protein and platelet adhesion. Poly(2-methacryloyloxyethyl phosphorylcholine-co-2-vinylnaphtalene) was also prepared92 and proved to form a phosphorylcholine group-enriched surface from its solution during the polymer-coating process on poly(ethylene terephthalate) plates. Heterogeneous block copolymers composed of poly(2-methacryloyloxyethyl phosphorylcholine) and poly(dimethylsiloxane) (PDMS) exhibited good properties. These copolymers were prepared by solvent cast method and were evaluated in terms of protein adsorption and cell adhesion.98 Experimental results indicated that segregated hydrophobic domains on a biocompatible PMPC surface strongly affected serum protein adhesion, promoting considerable cell adhesion even if the surface was hydrophilic. To conclude, PMPC-based copolymers showed an artificial surface similar to a biomembrane surface; as a consequence, the resulting properties allowed the use of such materials for hightech biomedical applications such as, for instance, the working out of implants and of drug delivery systems. Medical Implants and Tissue Engineering. Triblock copolymers based on MPC were described in the literature99 for their use in medical implants involving titanium. The aim was to improve the biocompatibility of titanium to allow implants by immobilization of multilayered phospholipid polymer hydrogel as they reduce protein adsorption and cell adhesion. Titanium and its alloys are very useful for load-bearing applications such as orthopedic and cardiovascular implants as they own excellent tissue compatibility and corrosion resistance.100 However, in blood-contacting devices, the bare Ti surface promotes unnecessary protein adsorption.101,102 Copolymers were synthesized from MPC, n-butyl methacrylate, and 4-vinylphenylboronic acid. Then, the multilayered hydrogels were prepared from triblock copolymer (PMBV) and PVA. It was shown that PMBV/PVA successfully covered the titanium substrate surface and that the PMBV outermost layer inhibited cell attachment. MPC derivatives such as 6-methacryloyloxyethyl phosphorylcholine (MHPC) and 10-methacryloyloxydecyl phosphorylcholine (MDPC) (Scheme 8) were also grafted onto PE. Plasma protein adsorption and fibroblast cell adhesion were evaluated by taking into account the chemical structure, surface density, mobility, and orientation of the grafted poly(ω-methacryloyloxyalkyl phosphorylcholine).103 Other derivatives bringing an amide function and the phosphorylcholine group (Scheme 9) were also described104 and copolymerized with other monomers such as acrylic acid, styrene sulfonate, and maleic acid. The goal of this study was to investigate how nonfouling surfaces could be obtained. Resulting polymers were deposited onto poly(styrene sulfonate)/poly(allylamine) multilayer films. The authors investigated the influence of various parameters such as the nature of 1978

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Biomacromolecules the polyelectrolyte backbone, the nature of the antifouling moiety, and the grafting ratio on the reduction of protein adsorption. It was shown that antifouling properties were obtained and that protein adsorption usually decreased with decreasing absolute charge. Poly(2-methacryloyloxyethyl phosphorylcholine) grafted polyethylene (PE) was involved in artificial hip joints105,106 as well. PMPC-grafted PE led to a higher longevity of joints, which improved the care quality of patients having joint replacement. Surface treatments for metallic coronary stents were successfully achieved with phosphorylcholinebased polymer to improve their biocompatibility within the body and to provide a vehicle for the delivery of therapeutics.107
109 Another example concerns nanoneedle surface modification by MPC to reduce nonspecific protein adsorption in living cells.110 MPC polymers decreased nonspecific adsorption of cytosolic proteins onto the nanoneedle surface inside the cell. This indicated that protein interaction on the nanoneedle surface was controlled by surface modification. Finally, poly(2-methacryloyloxyethyl phosphorylcholine) was involved in the development of a temporary vascular scaffold facilitating tissue integration in situ while avoiding acute thrombosis.111 Blending the poly(2-methacryloyloxyethyl phosphorylcholine-co-methacryloyloxyethylbutylurethane) with the poly(ester urethane) urea resulted in reduced thrombogenicity and complete endothelialization, and good anastomotic integration was obtained. A carbohydrate-immobilized phosphorylcholine polymer for surface modification of medical devices such as reliable bioartificial liver112 was produced to control the interface with living cells. A random copolymer composed of MPC, nbutyl methacrylate, and 2-lactobionamidoethyl methacrylate was synthesized by radical polymerization and showed promising results in terms of cultivation of hepatocytes. Drug Delivery. Important research was focused on the use of the MPC to achieve materials for drug delivery. Many examples reported in the literature deal with the use of copolymers containing MPC moiety and describe the physical encapsulation of drugs using PMPC-based micelles with the sequestration of drugs in the hydrophobic core.113
117 For instance, morphology and in vitro release kinetics of drug-loaded micelles based on well-defined PMPC-b-poly(butyl methacrylate) copolymer were achieved.118 It was shown that such copolymer enabled high loading (above 13%, w/w) of Paclitaxel. The copolymers had low critical micellar concentration (CMC) values that suggested their potential use in intravenous injection. Hydrogels containing MPC moieties were formed from aqueous solutions with water-soluble MPC-based random or block polymers119 because of hydrogen-bonding formation. For example, poly(2-methacryloyloxyethyl phosphorylcholine-co-methacrylic acid) and poly(2methacryloyloxyethyl phosphorylcholine-co-butyl methacrylate) (Scheme 10) led to spontaneous gelation when mixed.120 These copolymers acted as hydrogel physical cross-linkers. The authors demonstrated that the release depended on the polymer structure and on the diffusion of the loaded drugs and that released properties would be different according to the molecular weight of the drugs.121 The combination of poly[MPC-co-4-(2methacryloyloxyethyl) trimellitic acid] and poly[MPC-co-benzyl methacrylate] was also studied122 and showed improved mechanical properties resulting from the structures of their functional monomer units. As a conclusion, it was proved that MPC polymer hydrogels could be used as material for a drug reservoir123 and that copolymer chemical structure had to be selected according to the nature of the drug.

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Scheme 10. Chemical Structures of Copolymers Leading to Phospholipid Polymer Hydrogels

Other block copolymers, namely, PMPC-b-poly(D,L-lactide), were considered for drug delivery as they led to polymer nanoparticles.124 Their low cytotoxicity was notably proved by growth inhibition assays with human fibroblast cells. Amphiphilic block copolymers composed of poly(butyl acrylate) and poly(2methacryloyloxy phosphorylcholine) were reached by reversible addition
fragmentation transfer polymerization (RAFT).125 Light scattering studies showed the self-assembly into micelles, which could be suitable nanocontainers for biomedical applications such as controlled drug delivery if RAFT agent is proved to be nontoxic. Atom transfer radical polymerization (ATRP) allowed the synthesis of biocompatible poly(2-methacryloyloxy phosphorylcholine)-b-poly(2-hydroxypropyl methacrylate), which was evaluated for the intracellular delivery of a fluorescent dye (rhodamine B octadecyl ester) and proved to be efficient when formed colloidal aggregates efficiently solubilized the amphiphilic dye.126 A linkage chemistry between the PMPC and pendant drugs was also achieved. Polymer
drug conjugates consisting of zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) as polymer and camptothecin as drug were synthesized.127 The linkage chemistry between the PMPC backbone and the pendant drugs was achieved using “click” chemistry. Resulting graft copolymers were tested in vitro with a variety of cancer cell lines. Drug release was achieved thanks to the ester bond cleavage, and very interesting results were obtained in terms of anticancer activity.

6. CONCLUSIONS AND FUTURE PERSPECTIVES Organophosphorus polymers are of great interest in the biomedical field. They can be employed for many applications because phosphoric acid, phosphonic acid, and phosphonic ester groups notably increased the biocompatibility and adhesion properties. Among all possible chemical structures, MPC proved to be extremely interesting because it resisted to protein adsorption and cell adhesion, and polymers derived from MPC were already successfully used in drug delivery and tissue engineering. Polyphosphoesters with phosphoester group in the main chain were mainly used for their low toxicity, biocompatibility, and biodegradability specificities. Other phosphorus-containing polymers such as methacrylic derivatives also exhibited good properties and found applications in dental adhesion. All examples developed in this Review have shown that organophosphorus polymers could be successfully employed in the biomedical field with possible industrial developments, which make them very attractive for academic research. We can assume that the chemistry of organophosphorus polymers will be further 1979

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Biomacromolecules developed in the coming years because of the very attractive properties of such derivatives. In particular, the biomimetic structure of some phosphorus-containing polymers bringing phospholipid group showed unquestionable enhancement in comparison with “classical” systems already developed for the biomedical field. Even if they were not described in this Review devoted to usual polymer architectures, phosphorus-containing dendrimers must also be mentioned because they represent a very important and promising class of phosphorus-containing polymers used for biomedical applications.128 Such materials were largely developed in the group of Majoral and Caminade129
131 and proved to be suitable for biomedical applications because of their specific biological properties.132 Phosphorus notably permitted the development of adaptable and biocompatible organic nanodots133,134 thanks to its versatility and also allowed specific targeting and activating of the human immune system. Cationic phosphorus-containing dendrimers were also employed for gene transfection.135,136 In vitro experiments showed that the generation had an influence on both efficiency of transfection and cytotoxic behavior.137 Mainly other biological applications of phosphorus dendrimers dealt with their use as antiprion138,139 and anti HIV agents,140,141 against Alzheimer disease,142 and so on. More recently, they were involved to elaborate biological sensor devices143 or for ocular drug delivery.144 To conclude, phosphorus-containing dendrimers appear today as an important sort of materials that can be used in the biomedical area. For information, a bibliographic research in the most famous databases combining “dendrimers” and “biological applications” showed an increasing number of publications these last 10 years. As a consequence, we do believe that the dendrimers represent a potential way of development of organophosphorus polymers. Finally, among the different kinds of polymers reported in this Review, MPC-based polymers appeared to be very promising because of their interesting properties, which led to their use in a wide range of biomedical purposes, as already discussed. As a consequence, much work is expected in developing such zwitterionic polymers. In this scope, a recent study using a new synthetic strategy dealt with the introduction of the phosphorylcholine group after polymerization of appropriate functionalized lactide or ε-caprolactone for the synthesis of polyester-graftphosphorylcholine145 using 1,3-Huisgen cycloaddition “click” reaction.146 These polymers proved to be water-soluble and biodegradable, which suggested their use for integration into medical devices, biomaterials, and drug delivery vehicles. Such example showed that “click” chemistry could be potentially interesting for the synthesis of organophosphorus polymers from appropriate prepolymers and could lead to the development of phosphorus-containing new chemical structures easy to achieve.

’ AUTHOR INFORMATION Corresponding Author

*Tel: 33-4-67-14-41-58. Fax: 33-4-67-14-40-28. E-mail: Sophie. [email protected].

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