posted on 2021-06-02, 15:03authored byDaniel Braatz, Mathias Dimde, Guoxin Ma, Yinan Zhong, Michael Tully, Carsten Grötzinger, Yuanyuan Zhang, Alexandros Mavroskoufis, Michael Schirner, Zhiyuan Zhong, Matthias Ballauff, Rainer Haag
In
this paper, we present well-defined dPGS-SS-PCL/PLGA/PLA micellar
systems demonstrating excellent capabilities as a drug delivery platform
in light of high stability and precise in vitro and in vivo drug release combined with active targetability
to tumors. These six amphiphilic block copolymers were each targeted
in two different molecular weights (8 or 16 kDa) and characterized
using 1H NMR, gel permeation chromatography (GPC), and
elemental analysis. The block copolymer micelles showed monodispersed
size distributions of 81–187 nm, strong negative charges between
−52 and −41 mV, and low critical micelle concentrations
(CMCs) of up to 1.13–3.58 mg/L (134–527 nM). The serum
stability was determined as 94% after 24 h. The drug-loading efficiency
for Sunitinib ranges from 38 to 83% (8–17 wt %). The release
was selectively triggered by glutathione (GSH) and lipase, reaching
85% after 5 days, while only 20% leaching was observed under physiological
conditions. Both the in vitro and in vivo studies showed sustained release of Sunitinib over 1 week. CCK-8
assays on HeLa lines demonstrated the high cell compatibility (1 mg/mL,
94% cell viability, 48 h) and the high cancer cell toxicity of Sunitinib-loaded
micelles (IC50 2.5 μg/mL). By in vivo fluorescence imaging studies on HT-29 tumor-bearing mice, the targetability
of dPGS7.8-SS-PCL7.8 enabled substantial accumulation
in tumor tissue compared to nonsulfated dPG3.9-SS-PCL7.8. As a proof of concept, Sunitinib-loaded dPGS-SS-poly(ester)
micelles improved the antitumor efficacy of the chemotherapeutic.
A tenfold lower dosage of loaded Sunitinib led to an even higher tumor
growth inhibition compared to the free drug, as demonstrated in a
HeLa human cervical tumor-bearing mice model. No toxicity for the
organism was observed, confirming the good biocompatibility of the
system.