Reactive oxygen species (ROS)-responsive polymersomes with site-specific chemotherapeutic delivery into tumors via spacer design chemistry
2020
The lack of cellular
and tissue specificities in conventional chemotherapies
along with the generation of a complex tumor microenvironment (TME)
limits the dosage of active agents that reaches tumor sites, thereby
resulting in ineffective responses and side effects. Therefore, the
development of selective TME-responsive nanomedicines is of due relevance
toward successful chemotherapies, albeit challenging. In this framework,
we have synthesized novel, ready-to-use ROS-responsive amphiphilic
block copolymers (BCs) with two different spacer chemistry designs
to connect a hydrophobic boronic ester-based ROS sensor to the polymer
backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics
(MF) was used in the preparation of well-defined ROS-responsive PSs;
these were further characterized by a combination of techniques [1H NMR, dynamic light scattering (DLS), static light scattering
(SLS), transmission electron microscopy (TEM), and cryogenic TEM (cryo-TEM)].
The reaction with hydrogen peroxide releases an amphiphilic phenol
or a hydrophilic carboxylic acid, which affects polymersome (PS) stability
and cargo release. Therefore, the importance of the spacer chemistry
in BC deprotection and PS stability and cargo release is herein highlighted.
We have also evaluated the impact of spacer chemistry on the PS-specific
release of the chemotherapeutic drug doxorubicin (DOX) into tumors
in vitro and in vivo. We demonstrate that by spacer chemistry design
one can enhance the efficacy of DOX treatments (decrease in tumor
growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma.
Side effects (weight loss and cardiotoxicity) were also reduced compared
to free DOX administration, highlighting the potential of the well-defined
ROS-responsive PSs as TME-selective nanomedicines. The PSs could also
find applications in other environments with high ROS levels, such
as chronic inflammations, aging, diabetes, cardiovascular diseases,
and obesity.
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