bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 22, 2024
Abstract
Systemic
delivery
of
immunotherapy
is
dose-limited
and
often
causes
serious
immune-related
adverse
events.
Intratumoral
injections
can
reduce
systemic
immunotoxicities
increase
concentrations
within
a
tumor.
However,
high
pressures
associated
with
direct
tumor
injection
limits
injectate
retention,
as
low
viscosity,
saline-based
solutions
rapidly
leak
out
tumors.
Viscoelastic
solids,
such
hydrogels,
improve
local
retention
co-formulated
immunotherapies
provide
sustained
delivery.
Prior
work
demonstrated
that
chitosan-based
hydrogel,
XCSgel,
was
shear-thinning,
self-healing,
injectable,
biocompatible,
clinically
imageable.
Here,
we
investigated
XCSgel
localized
intratumoral
platform
in
the
context
murine
models
orthotopic
triple-negative
breast
cancer.
The
immunotherapeutics
characterized
both
ex
vivo
via
fluorescence
imaging.
Histopathological
responses
to
alone
were
scored
by
veterinary
pathologist.
Initial
antitumor
studies
evaluated
range
cytokines
XCSgel.
Subsequent
rechallenge
efficacy
single
interleukin-12
(IL-12)
(XCSgel-IL12)
control
growth
primary
abscopal
tumors
while
inducing
protective
immunity.
Pharmacokinetics
quantified
dissemination
IL-12
consequent
production
interferon-gamma
following
co-formulation.
Spectral
flow
cytometry
used
document
changes
tumor-immune
microenvironment
(TIME).
resisted
leakage
slowly
released
three
model
cytokines.
could
be
tuned
for
faster
or
slower
release
embedded
therapeutics.
XCSgel-IL12
outperformed
formulations
other
commonly
A
eliminated
86%
E0771
20%
mWnt
TNBC
Mice
rendered
tumor-free
live
challenge.
also
67%
untreated
induced
profound
TIME,
including
3-fold
reduction
frequency
exhausted
CD8
+
T
cells
3.2-fold
activated,
proliferating
cells.
promising
well-suited
enhance
activity
potent
immunotherapeutics.
eliminate
solid
tumors,
indicating
may
not
required
Synopsis
novel
injectable
localize
triple
negative
cancer
injection.
Drug Development Research,
Год журнала:
2024,
Номер
86(1)
Опубликована: Дек. 25, 2024
Poor
selectivity
to
tumor
cells
is
a
major
drawback
in
the
clinical
application
of
antitumor
drug
docetaxel
(DTX).
Peptide-drug
conjugates
(PDCs)
constructed
by
modifying
drugs
with
peptide
ligands
that
have
high
affinity
certain
overexpressed
receptors
are
increasingly
assessed
for
their
possibility
tumor-selective
delivery.
In
present
research,
DTX
condensed
3-(pyridin-2-yldisulfanyl)
propanoic
acid
via
ester
bond
obtain
intermediate
Py-SS-DTX.
Two
GSS-DTX
and
RGDC-SS-DTX
were
obtained
conjugation
Py-SS-DTX
glutathione
(GSH)
RGDC
through
thiol-disulfide
exchange
reaction.
Afterwards,
these
two
peptide-DTX
characterized
proton
nuclear
magnetic
resonance,
Fourier
transform
infrared
spectroscopy,
high-resolution
mass
spectrometry.
The
further
evaluated
terms
release,
cell
cycle
inhibition,
apoptosis,
cytotoxicity.
results
show
both
exhibit
reduction-responsive
release
higher
reduction-responsiveness.
vitro
activity
study
shows
exhibits
enhanced
G2/M
phase
arrest,
apoptosis
rate,
cytotoxicity
as
compared
free
DTX.
Besides,
reduced
on
normal
synthesized
this
represents
novel
conjugate
effectively
selectively
inhibit
cells.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 22, 2024
Abstract
Systemic
delivery
of
immunotherapy
is
dose-limited
and
often
causes
serious
immune-related
adverse
events.
Intratumoral
injections
can
reduce
systemic
immunotoxicities
increase
concentrations
within
a
tumor.
However,
high
pressures
associated
with
direct
tumor
injection
limits
injectate
retention,
as
low
viscosity,
saline-based
solutions
rapidly
leak
out
tumors.
Viscoelastic
solids,
such
hydrogels,
improve
local
retention
co-formulated
immunotherapies
provide
sustained
delivery.
Prior
work
demonstrated
that
chitosan-based
hydrogel,
XCSgel,
was
shear-thinning,
self-healing,
injectable,
biocompatible,
clinically
imageable.
Here,
we
investigated
XCSgel
localized
intratumoral
platform
in
the
context
murine
models
orthotopic
triple-negative
breast
cancer.
The
immunotherapeutics
characterized
both
ex
vivo
via
fluorescence
imaging.
Histopathological
responses
to
alone
were
scored
by
veterinary
pathologist.
Initial
antitumor
studies
evaluated
range
cytokines
XCSgel.
Subsequent
rechallenge
efficacy
single
interleukin-12
(IL-12)
(XCSgel-IL12)
control
growth
primary
abscopal
tumors
while
inducing
protective
immunity.
Pharmacokinetics
quantified
dissemination
IL-12
consequent
production
interferon-gamma
following
co-formulation.
Spectral
flow
cytometry
used
document
changes
tumor-immune
microenvironment
(TIME).
resisted
leakage
slowly
released
three
model
cytokines.
could
be
tuned
for
faster
or
slower
release
embedded
therapeutics.
XCSgel-IL12
outperformed
formulations
other
commonly
A
eliminated
86%
E0771
20%
mWnt
TNBC
Mice
rendered
tumor-free
live
challenge.
also
67%
untreated
induced
profound
TIME,
including
3-fold
reduction
frequency
exhausted
CD8
+
T
cells
3.2-fold
activated,
proliferating
cells.
promising
well-suited
enhance
activity
potent
immunotherapeutics.
eliminate
solid
tumors,
indicating
may
not
required
Synopsis
novel
injectable
localize
triple
negative
cancer
injection.
