Doxorubicin loaded magnetic polymersomes: theranostic nanocarriers for MR imaging and magneto-chemotherapy.

Hydrophobically modified maghemite (γ-Fe(2)O(3)) nanoparticles were encapsulated within the membrane of poly(trimethylene carbonate)-b-poly(l-glutamic acid) (PTMC-b-PGA) block copolymer vesicles using a nanoprecipitation process. This formation method gives simple access to highly magnetic nanoparticles (MNPs) (loaded up to 70 wt %) together with good control over the vesicles size (100-400 nm). The simultaneous loading of maghemite nanoparticles and doxorubicin was also achieved by nanoprecipitation. The deformation of the vesicle membrane under an applied magnetic field has been evidenced by small angle neutron scattering. These superparamagnetic hybrid self-assemblies display enhanced contrast properties that open potential applications for magnetic resonance imaging. They can also be guided in a magnetic field gradient. The feasibility of controlled drug release by radio frequency magnetic hyperthermia was demonstrated in the case of encapsulated doxorubicin molecules, showing the viability of the concept of magneto-chemotherapy. These magnetic polymersomes can be used as efficient multifunctional nanocarriers for combined therapy and imaging.

A simple method to achieve high doxorubicin loading in biodegradable polymersomes.

Doxorubicin (Dox), an anthracycline anticancer drug, was successfully incorporated into block copolymer vesicles of poly(trimethylene carbonate)-b-poly(L-glutamic acid) (PTMC-b-PGA) by a solvent-displacement (nanoprecipitation) method. pH conditions were shown to have a strong influence on loading capacity and release profiles. Substantial drug loading (47% w/w) was achieved at pH 10.5. After pH neutralization, aqueous dispersions of drug-loaded vesicles were found stable for a prolonged period of time (at least 6months) without vesicle disruption or drug precipitation. Dox-loaded vesicles exhibited in vitro pH and temperature-dependent drug release profiles: release kinetics fastened in acid conditions or by increasing temperature. These features strongly support the interest of developing PTMC-b-PGA polymersomes as carriers for the controlled delivery of Dox.

Biocompatible and biodegradable poly(trimethylene carbonate)-b-poly(L-glutamic acid) polymersomes: size control and stability.

Poly(trimethylene carbonate)-b-poly(L-glutamic acid) (PTMC-b-PGA) diblock copolymers have been synthesized by ring-opening polymerization (ROP) of gamma-benzyl-L-glutamate N-carboxyanhydride (BLG) initiated by amino functionalized PTMC and subsequent hydrogenation. Self-assembly in water gave well-defined vesicles which have been studied combining light and neutron scattering techniques with electron microscopy imaging. The size and dispersity of vesicles have been tuned by varying preparation conditions, direct dissolution, or nanoprecipitation. In addition, PGA conformation could be reversibly manipulated as a function of environmental changes such as pH and ionic strength. Vesicles showed high tolerance and stability toward nonionic surfactant and pH due to a thick membrane and were revealed to be nonpermeable to water. Nevertheless, they can be rapidly degraded by enzymatic hydrolysis of the polycarbonate block. The ability to tune their size through the formation process, their stimuli responsiveness, their high stability, and their biodegradability make them suitable for biomedical applications.

Biodegradable polycarbonate-b-polypeptide and polyester-b-polypeptide block copolymers: synthesis and nanoparticle formation towards biomaterials.

The amino poly(trimethylene carbonate)-NHt-Boc (PTMC-NHt-Boc) and poly(epsilon-caprolactone)-NH -Boc (PCL-NHt-Boc) were synthesized by ring-opening polymerization (ROP) of TMC or CL and subsequently deprotected into the corresponding PTMC-NH2 and PCL-NH2. These functional homopolymers were used as macroinitiators for the ROP of gamma-benzyl-L-glutamate N-carboxyanhydride (BLG), consequently, giving the respective diblock copolymers PTMC-b-PBLG and PCL-b-PBLG in almost quantitative yields. The (co)polymers have been characterized by NMR and SEC analyses. DSC and IR studies confirmed the block structure of the copolymers and highlighted a phase separation between the rigid peptide (alpha-helix conformation) and the more flexible polyester segments. The self-assembly and the degradation behaviors of the copolymers depended on the nature of the polyester block and on the copolymer composition. Nanoparticles obtained from PBLG block copolymers were twice smaller ( RH < 100 nm) than those formed from PTMC and PCL homopolymers. Finally, their enzymatic degradation revealed that PTMC nanoparticles degraded faster than those made of PCL.

Unprecedented polymerization of trimethylene carbonate initiated by a samarium borohydride complex: mechanistic insights and copolymerization with epsilon-caprolactone.

Poly(trimethylene carbonate) (PTMC) was synthesized through ring-opening polymerization by using a rare-earth borohydride initiator, [Sm(BH(4))(3)(thf)(3)]. This initiator shows a high activity to give high-molar-mass PTMCs with molar-mass distributions ranging from 1.2 to 1.4, and with a regular structure void of ether linkages. The polymers were characterized by (1)H and (13)C NMR spectroscopy, (1)H-(1)H COSY, (1)H-(13)C HMQC NMR spectroscopy, size-exclusion chromatography (SEC), viscosimetry, and MALDI-TOF MS analyses. A coordination-insertion mechanism was established based on detailed NMR characterizations, especially of the polymer chain end-functions. The monomer initially coordinates the samarium to give [Sm(BH(4))(3)(tmc)(3)], 1. The monomer then opens up through cleavage of the cyclic ester oxygen--acyl bond and inserts into the Sm--HBH(3) bond resulting in an alkoxide complex, [Sm{O(CH(2))(3)OC(O)HBH(3)}(3)], 2, or [Sm{O(CH(2))(3)OC(O)H}(3)], 2', which then propagates the polymerization of TMC to give the active polymer [Sm({O(CH(2))(3)OC(O)}(n)O(CH(2))(3)OC(O)HBH(3))(3)], 3 or [Sm(O(CH(2))(3)OC(O){O(CH(2))(3)OC(O)}(n)O(CH(2))(3)OC(O)H)(3)], 3'. Finally, acidic hydrolysis of 3 or 3' gives HO(CH(2))(3)OC(O)[O(CH(2))(3)OC(O)](n)O(CH(2))(3)OC(O)H, 4. This novel alpha-hydroxy,omega-formatetelechelic PTMC represents the first example of a formate-terminated polycarbonate. TMC and epsilon-caprolactone (CL) were copolymerized to afford both random PTMC-co-PCL and block PTMC-b-PCL copolymers that were characterized by (1)H NMR spectroscopy, SEC, and differential scanning calorimetry (DSC). The structure of the block copolymers depends on the order of addition of monomers: if CL is introduced first, dihydroxytelechelic HO-PTMC-b-PCL-OH polymers are formed, whereas introduction of TMC first or simultaneous addition of comonomers leads to hydroxyformatetelechelic HC(O)O-PTMC-b-PCL-OH analogues.

Unprecedented polymerization of epsilon-Caprolactone initiated by a single-site lanthanide borohydride complex, [Sm(eta-C5Me5)2(BH4)(thf)]: mechanistic insights.

The monoborohydride lanthanide complex [Sm(Cp*)2(BH4)(thf)] (1a) (Cp* = eta-C5Me5), has been successfully used for the controlled ring-opening polymerization of epsilon-caprolactone (epsilon-CL). The organometallic samarium(III) initiator 1 a produces, in quantitative yields, alpha,omega-dihydroxytelechelic poly(epsilon-caprolactone) displaying relatively narrow polydispersity indices (<1.3) within a short period of time (30 min). The polymers have been characterized by 1H and 13C NMR, SEC, and MALDI-TOF MS analyses. Use of the single-site initiator 1 a allows a better understanding of the polymerization mechanism, in particular with the identification of the intermediate compound [Sm(Cp*)2(BH4)(epsilon-CL)] (1b). Indeed, one molecule of epsilon-CL initially displaces the coordinated THF in 1 a to give 1 b. Then, epsilon-CL opening (through cleavage of the cyclic ester oxygen-acyl bond) and insertion into the Sm--HBH3 bond followed by reduction of the carbonyl function by the BH3 end-group ligand, leads to the samarium alkoxyborane derivative [Sm(Cp*)2[O(CH2)6O(BH2)]] (2). This compound subsequently initiates the polymerization of epsilon-CL through a coordination-insertion mechanism. Finally, upon hydrolysis, alpha,omega-dihydroxypoly(epsilon-caprolactone), HO(CH2)5C(O)[O(CH2)5C(O)]nO(CH2)6OH (4) is recovered. The stereoelectronic contribution of the two Cp* ligands appears to slow down the polymerization and to limit transesterification reactions.