Polymorphic Transformation of Drugs Induced by Glycopolymeric Vesicles Designed for Anticancer Therapy Probed by Solid-State NMR Spectroscopy

Understanding
the nature of the drug–polymer interactions
in micellar drug delivery systems and what happens with the drug and
the polymer once the complex has formed is essential for the rational
design of the polymeric matrices suitable for a particular drug. In
this work, glycopolymeric vesiclesa block copolymer, poly­(1-O-methacryloyl-β-d-fructopyranose)-b-poly­(methyl methacrylate), (PFru36-PMMA160),designed to target tumor cells loaded with two
drugs, ellipticine and curcumin, were characterized. Advanced solid-state
NMR spectroscopy and single-crystal/powder X-ray diffraction (XRD)
combined with CASTEP calculations shed light on the nature of the
drug, the polymer, and their interactions. While the low drug loading
(ca. 5%) ensured that the structure, size, and shape of the polymeric
vesicles did not change significantly, the solid-state forms of the
drugs changed markedly. Upon loading into the vesicles, ellipticine
favored a highly ordered form distinctly different from the bulk drug
as indicated by 13C solid-state NMR spectroscopy. A detailed
analysis of the CASTEP-calculated 13C spectra derived from
crystallographic data based on the lowest mean absolute error showed
the best match with form I. Moreover, ellipticine before loading was
found as a new polymorph and was described by single-crystal XRD as
a new orthorhombic Form III. Likewise, curcumin, originally present
in monoclinic Form I was found to recrystallize as metastable orthorhombic
Form II inside the vesicles. Intermolecular interactions between the
polymeric vesicles and the drugs, ellipticine as well as curcumin,
were detected using 2D 1H magic angle spinning experiments,
indicating that the drugs are localized in the hydrophobic layer of
the vesicles.