2 research outputs found
Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics
An effective chemotherapy for neoplastic
diseases requires the
use of drugs that can reach the site of action at a therapeutically
efficacious concentration and maintain it at a constant level over
a sufficient period of time with minimal side effects. Currently,
conjugates of high-molecular-weight hydrophilic polymers or biocompatible
nanoparticles with stimuli-releasable anticancer drugs are considered
to be some of the most promising systems capable of fulfilling these
criteria. In this work, conjugates of thermoresponsive diblock copolymers
with the covalently bound cancerostatic drug pirarubicin (PIR) were
synthesized as a reversible micelle-forming drug delivery system combining
the benefits of the above-mentioned carriers. The diblock copolymer
carriers were composed of hydrophilic poly[<i>N</i>-(2-hydroxypropyl)methacrylamide]-based
block containing a small amount (∼5 mol %) of comonomer units
with reactive hydrazide groups and a thermoresponsive poly[2-(2-methoxyethoxy)ethyl
methacrylate] block. PIR was attached to the hydrophilic block of
the copolymer through the pH-sensitive hydrazone bond designed to
be stable in the bloodstream at pH 7.4 but to be degraded in an intratumoral/intracellular
environment at pH 5–6. The temperature-induced conformation
change of the thermoresponsive block (coil–globule transition),
followed by self-assembly of the copolymer into a micellar structure,
was controlled by the thermoresponsive block length and PIR content.
The cytotoxicity and intracellular transport of the conjugates as
well as the release of PIR from the conjugates inside the cells, followed
by its accumulation in the cell nuclei, were evaluated in vitro using
human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated
that the studied conjugates have a great potential to become efficacious
in vivo pharmaceuticals
Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant
Structure-based
vaccine design has been used to develop immunogens
that display conserved neutralization sites on pathogens such as HIV-1,
respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity
of these designed immunogens with adjuvants will require formulations
that do not alter protein antigenicity. Here, we show that nanoparticle-forming
thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion
(F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a)
to enhance protective immunity. Although primary amine conjugation
of TLR-7/8a to F trimers severely disrupted the recognition of critical
neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles
retained appropriate antigenicity and elicited high titers of prefusion-specific,
T<sub>H</sub>1 isotype anti-RSV F antibodies following vaccination.
Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in
∼3-fold higher binding and neutralizing antibody titers than
soluble F trimers admixed with TLR-7/8a and conferred protection from
intranasal RSV challenge. Overall, these data show that TRP nanoparticles
may provide a broadly applicable platform for eliciting neutralizing
antibodies to structure-dependent epitopes on RSV, influenza, HIV-1,
or other pathogens