109 research outputs found
P19-33. Trafficking of a synthetic vaccine vehicle made of poly(lactic acid) fluorescent nanoparticles, in intestinal mucosa
P11-15. Induction of a mucosal immune response to HIV after systemic immunization with poly(lactic acid) nanoparticles formulated with gag antigen and polyI:C
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Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients.
This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, â„12 to <18 years; cohort 2, â„6 to <12 years; cohort 3, â„2 to <6 years; cohort 4, â„3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [â„40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-â) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)
Development and characterization of an injectable dextrin-based hydrogel for bone regeneration
Bone is a dynamic, highly vascularized tissue that remodels itself continuously over an individual Ìs
lifetime. It
plays several important roles in
maintaining homeostasis of the body systems
[
1
,
2
]
.
However, this regenerative capac
ity is limited and,
as
in
the
case of large bone defects, where the
template for an orchestrated regeneration is absent, surgical proce
dures are needed
[
2
]
. In this respect
,
bone tissue engineering is a very challe
nging and promising field given
the need to mimic bone
mechanical and biological functions and also due to the failure of current orthoped
ic implants. The
general concept consists in the development of three
-
dimensional scaffolds, from biocompatible
materials (natu
ral or synthetic), which confer
temporary support for the regeneration of bone tissue,
while the scaffold itself will be resorbed
and replaced by new
ly formed tissue
[
2
,
3
]
.
Hydrogels are cross
-
linked networks made of natural or synthetic polymers,
which are able to
support high water contents
[
4
]
. These materials are usua
lly biocompatible, have the ability to mimic
physiological conditions, promote an environment that can protect cells or unstable drugs, their physical
characteristics can be controlled to some extent and some can be injected
in vivo
. These features make
th
em attractive materials in the biomedical field for cell encapsulation, drug or gene delivery or to act as
an interfa
ce between tissue and materials
[
4
-
7
]
. Natural polymers are advantageous for this kind of
applications since they are cheap raw materials, bear a great biocompatibility and are usually
biodegradable
[
8
]
. Dextrin is low molecular weight carbohydrate, generally regarded as safe (GRAS),
obtained from partial hydrolysis of starch or glycogen
[
9
]
. It is a glucose polymer linked by
α
-
1,4
glycosidic linkages with some degree of branching due to the presence of
α
-
1,6 bonds
[
10
]
.
I
t is
biocompatible and non
-
immunogenic, degradable by
α
-
amylases and can undergo renal clearance
avoiding tissue
accumulation
[
11
,
12
]
.
This work describes the preparation and characterization of
an injectable
dextrin
-
bas
ed
hydrogel
(oDex)
able to incorporate
nanoparticles
, cells, biomolecules or Bonelike
Âź
granules
[
13
]
.
Bonelike
Âź
is a
Biosckin
-
molecular and cell therapies S.A. proprietary synthetic bone graft, and the outcome of the
project will result in a novel injectable
presentation of
this product.
The hydrogel was produced by
dextrin oxidation with sodium periodate followed by cross
-
linking with a dihydrazide
[
14
]
. In vitro
characterization of oDex hydrogel has shown acceptable m
echanical properties, overall good
biocompatibility and the ability to be combined with other materials such as a nanogel and urinary
bladder matrix, without affecting its structure.
The cytotoxicity of the free
dihydrazide
was evaluated and
only a mild in
hibitory effect on cell proliferation was observed for the concentration used in the hydrogel
crosslinking.
The biocompatibilit
y of oDex hydrogels was confirmed
through the encapsulation of cells,
which were able to endure the gelation process.
Subcutaneou
s implants were performed in
Sasco
Sprague Dawley
rats in order to evaluate the inflammatory response and systemic effects of oDex
hydrogels and their
combination with Bonelike
Âź
and human mesenchymal
stem cells isolated from
umbilical cordâs Wharton jelly. After 3 and 15 days post
-
implantation, a quantitative evaluation of both
responses was performed according to ISO 10993 by a scoring system leading to a classification of the
implanted material as s
light irritant even when associated to Bonelike
Âź
or to the cellular system.
The
performance of oDex hydrogel combined with Bonelike granules and/or UBM in bone defects was
investigated in New Zealand rabbits. Bone defects in several anatomical locations (t
ibiae and cranium)
of non
-
critical and critical size were filled with those materials. Histological analysis showed that oDex
does not constitute a barrier for cellular colonization and proliferation since the defects that were filled
with these materials
presented a higher degree of regeneration and a higher amount of collagen fibers
with higher organization degrees, when compared with the empty defects.
Even though oDex hydrogels
purpose is to act as an injectable carrier for osteoconductive materials,
li
ke Bonelike
Âź
granules,
the
hydrogel itself seems to assists the regenerative pro
cess when compared with the empty defects. This
is
due to the 3D supp
ort conferred by hydrogels that
facilitates cell migration to the defect site.
Moreover, the presence of UB
M strongly stimulates the bone regeneration, for levels comparable with
the Bonelike
Âź
conditions, since an increase in cellular colonization and organization in the defect site
can be denoted. A sterilization protocol for oDex hydrogels by gamma and beta r
adiation was
investigated through irradiation of oxidized dextrin solutions. Despite b
oth kinds of radiation induced
slight differences in the storage modulus of the hydrogels, indicating the occurrence of chain
scission/cross
-
linking effects on the dextri
n cha
in, all
materials were gelable after the irradiation
treatments
. These effects seem to
not
be
dose or temperature dependent and
the irradiation process in
liquid or solid state also does not induce major differences in the rheology of the final hydrog
els. Due to
its known advantages, gamma radiation seems to be a suitable sterilization method for oxidized dextrin
solutions. The stability of gamma irradiated dextrin solutions was evaluated up to 8 months. Despite the
increase of storage modulus of the h
ydrogels over the time, this effect does not constitute a
disadvantage since it improves elastic behavior of the hydrogels.
oDex hydrogels provides a system
that can carry and stabilize cells, nanogels, Bonelike
Âź
granules and other biomolecules. It is a pr
omising
biomaterial due to its biocompatibility, and potential to promote an adequate environment for bone
regeneration. Its injectability allows
a minimal invasive surgical procedure with decreased patient
morbidity, lower risk of infection and reduced sc
ar formation.
This work has been developed in the scope of an European project that allowed collaborations with
research groups, which have complementary expertise. The tight collaboration between University of
Minho and Bioskin S.A. company, envisioning t
echnology transfer and product valorization, has resulted
in a published international patent of the product (
WO2011070529A2
)
[
15
]
. Currently, a new set of pre
-
clinical trials in sheep model
s are being planned as well as the submission of a request for the
authorization for the clinical trialsGrant SFRH/BD/64571/2009 from Fundação para a CiĂȘncia e Tecnologia
(FCT), Portugal. We thank FCT funding through EuroNanoMed ENMED/0002/2
Induction of HIV mucosal immunity at distal sites after encapsulation of NOD1 and NOD2 ligands in biodegradable nanocarriers
Synthetic lethal therapies for cancer: what's next after PARP inhibitors?
The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field
Synthesis and characterization of surface-cyanofunctionalized poly ( N -isopropylacrylamide) latexes
International audienc
Covalent immobilization of bovine serum albumin onto (maleic anhydride-alt-methyl vinyl ether) copolymers
International audienc
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