PLA-PEG forming worm-like nanoparticles despite unfavorable packing parameter: Formation mechanism, thermal stability and potential for cell internalization

Most nanoparticles produced for drug delivery purposes are spherical. However, the literature suggests that elongated particles are advantageous, notably in terms of cellular uptake. Thus, we synthesized biocompatible polylactide-b-poly(ethylene glycol) (PLA-PEG) polymers bearing carboxylate moieties, and used them to formulate worm-like nanoparticles by a simple emulsion-evaporation process. Worm-like nanoparticles with variable aspect ratio were obtained by simply adjusting the molar mass of the PLA block: the shorter the molar mass of the PLA block, the more elongated the particles. As PLA molar mass decreased from 80,000 g/mol to 13,000 g/mol, the proportion of worm-like nanoparticles increased from 0 to 46%, in contradiction with the usual behavior of block polymers based on their packing parameter. To explain this unusual phenomenon, we hypothesized the shape arises from a combination of steric and electrostatic repulsions between PEG chains bearing a carboxylate moiety present at the dichloromethane-water interface during the evaporation process. Worm-like particles turned out to be unstable when incubated at 37 degrees C, above polymer glass transition temperature. Indeed, above Tg, a Plateau-Rayleigh instability occurs, leading to the division of the worm-like particles into spheres. However, this instability was slow enough to assess worm-like particles uptake by murine macrophages. A slight but significant increase of internalization was observed for worm-like particles, compared to their spherical counterparts, confirming the interest of developing biocompatible anisotropic nanoparticles for pharmaceutical applications such as drug delivery.

Automated summary

Most nanoparticles used for drug delivery are spherical, but elongated particles have advantages in cellular uptake. In this study, we synthesized biocompatible polylactide-b-poly(ethylene glycol) (PLA-PEG) polymers with carboxylate moieties and used them to form worm-like nanoparticles. By adjusting the molar mass of the PLA block, we obtained worm-like nanoparticles with varying aspect ratios. The proportion of worm-like particles increased as the molar mass of the PLA block decreased, contrary to the usual behavior of block polymers. These anisotropic nanoparticles showed increased cellular uptake compared to their spherical counterparts, highlighting their potential for drug delivery applications.