Improving aqueous solubility of paclitaxel with polysarcosine-b-poly(γ-benzyl glutamate) nanoparticles

New stealth amphiphilic copolymers based on polysarcosine (PSar) rather than poly(ethylene glycol) (PEG) have gained more attention for their use as excipients in nanomedicine. In this study, several polysarcosine-b-poly(γ-benzyl glutamate) (PSar-b-PGluOBn) block copolymers were synthesized by ring opening polymerization (ROP) of the respective N-carboxyanhydrides (NCAs) and were characterized by Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H NMR) and size-exclusion chromatography (SEC).

Copolymers had different PGluOBn block configuration (racemic L/D, pure L or pure D), degrees of polymerization of PSar between 28 and 76 and PGluOBn between 9 and 93, molar masses (M_n) between 5.0 and 24.6 kg.mol^-1 and dispersities (Đ) lower than 1.4. Nanoparticles of PSar-b-PGluOBn loaded with paclitaxel (PTX), a hydrophobic anti-cancer drug, were obtained by nanoprecipitation.

Their hydrodynamic diameter (D_h) ranged from 27 to 118 nm with polydispersity indexes (PDI) between 0.01 and 0.20, as determined by dynamic light scattering (DLS). Their morphology was more spherical for copolymers with a racemic L/D PGluOBn block configuration synthesized at 5 °C. PTX loading efficiency was between 63 and 92% and loading contents between 7 and 15%. Using PSar-b-PGluOBn copolymers as excipients, PTX apparent water-solubility was significantly improved by a factor up to 6600 to 660 µg.mL^-1.

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Materials

Neopentylamine was purchased from TCI Europe. Paclitaxel was purchased from Key Organics. LGluOBn NCA, DGluOBn NCA and Sar NCA were sampled from PMC Isochem batches. DMF NORMAPUR® grade with a maximum water content of 0.05%, was purchased from Avantor. Ethyl acetate and methyl tertiary-butyl ether (MTBE) were purchased respectively from Brenntag and Univar. Acetonitrile (HPLC grade) was purchased from VWR. α-Cyano-4-hydroxycinnamic acid (α-CHCA, used as the matrix for MALDI-TOF experiments, was of the highest grade available and used without further purification) was purchased from Sigma Aldrich. Water was ultrapure grade. Unless stated otherwise, materials and solvents were used as such and the temperature was room temperature (22 – 28 °C).

Coralie Lebleu, Laetitia Plet, Florène Moussy, Gaëtan Gitton, Rudy Da Costa Moreira, Ludmilla Guduff, Barbara Burlot, Rodolphe Godiveau, Aïnhoa Merry, Sébastien Lecommandoux, Gauthier Errasti, Christiane Philippe, Thomas Delacroix, Raj Chakrabarti, Improving aqueous solubility of paclitaxel with polysarcosine-b-poly(γ-benzyl glutamate) nanoparticles, International Journal of Pharmaceutics, 2022, 122501, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2022.122501.