Self-assembly of i-PEGose-b-PLA into polymeric microcubes Jean-Baptiste Masclef, J. Prunet*, B.V.K.J. Schmidt* School of Chemistry, University of Glasgow, Joseph Black Building, G12 8QQ, Glasgow, UK Polymeric nanoparticles have been widely used for the encapsulation and the release of various drugs. Among the different parameters that influence a nanoparticle efficiency, the nanoparticle size has been extensively studied and has been found to affect its pharmacokinetics 1 . Another parameter that has been investigated is the nanoparticle shape. Usually, for a given amphiphilic block copolymer structure, three morphologies can be obtained: micelles, worm-like micelles, and vesicles 2 . Micelles have been shown to have an increased stability, worm-like micelles have a high cell penetration and vesicles can encapsulate both hydrophobic and hydrophilic drugs 3 . Recently, nanoparticles with anisotropic morphologies have been reported 4 . Among them, cubic nanoparticles exhibited a far better cell uptake than their spherical counterparts 5 . However, very few block copolymers have been shown to self-assemble into cubic morphologies and those who do often require intricate methods or special equipment 6 . In this regard, PEGose, a polysaccharide mimic developed in the Prunet group has been used as a hydrophilic block to synthesize the amphiphilic block copolymer i-PEGose- b -PDLLA, which can self-assemble into microcubes. Scheme 1. Synthesis of i-PEGose- b -PDLLA: ring-opening polymerization of enantiopure butadiene monoxide, followed by ring-closing metathesis, ring-opening polymerization of D,L-lactide and dihydroxylation. The tacticity of the polymer was carefully controlled by performing the ring-opening polymerization of an enantiopure butadiene monoxide and a D,L-lactide. The stereochemistry of the polymer has been found to be essential for the formation of these polymeric microcubes, since the atactic polymer would not yield any cubic shaped nanoparticles. Another key parameter to obtain microcubes was the type of buffer used during the self- assembly. Indeed, i-PEGose- b -PDLLA formed nanospheres in deionized water but microcubes after a few days in a NaCl solution. A range of block copolymers have been synthesized with various block lengths. The block copolymers and their self-assemblies have been characterized by 1 H NMR, diffusion ordered spectroscopy, size-exclusion chromatography, multi-angle dynamic light scattering, scanning electron microscopy, transmission electron microscopy, X-ray diffraction, circular dichroism, and differential scanning calorimetry. To conclude, a novel diblock copolymer with a stereocontrolled structure has been synthesized. i-PEGose- b -PDLLA can self-assemble into microcubes and could be used as a drug delivery system with a potentially enhanced cellular uptake compared to more conventional polymeric nanoparticles 5 .
Figure 1. TEM image of i-PEGose- b -PDLLA in a) deionized water, b) 1 hour in a 50 mg/mL NaCl solution, c) 3 days in a 50 mg/mL NaCl solution. References 1. S. Biswas, P. Kumari, P. M. Lakhani and B. Ghosh, Eur. J. Pharm. Sci. , 2016, 83 , 184–202. 2. J. Nicolas et al., Chem. Soc. Rev. , 2013, 42 , 1147–1235. 3. A. Blanazs, S. P. Armes and A. J. Ryan, Macromol. Rapid Commun. , 2009, 30 , 267–277.
4. Y. Hu, Y. Chen and J. Du, Polym. Chem. , 2019, 10 , 3020–3029. 5. J. F. Alexander et al., Adv. Healthc. Mater. , 2015, 4 , 2657–2666. 6. S. E. A. Gratton et al., Proc. Natl. Acad. Sci. , 2008, 105 , 11613–11618.
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