15 research outputs found
Nanoassemblies of Tissue-Reactive, Polyoxazoline Graft-Copolymers Restore the Lubrication Properties of Degraded Cartilage
Osteoarthritis
leads to an alteration in the composition of the
synovial fluid, which is associated with an increase in friction and
the progressive and irreversible destruction of the articular cartilage.
In order to tackle this degenerative disease, there has been a growing
interest in the medical field to establish effective, long-term treatments
to restore cartilage lubrication after damage. Here we develop a series
of graft-copolymers capable of assembling selectively on the degraded
cartilage, resurfacing it, and restoring the lubricating properties
of the native tissue. These comprise a polyglutamic acid backbone
(PGA) coupled to brush-forming, poly-2-methyl-2-oxazoline (PMOXA)
side chains, which provide biopassivity and lubricity to the surface,
and to aldehyde-bearing tissue-reactive groups, for the anchoring
on the degenerated cartilage <i>via</i> Schiff bases. Optimization
of the graft-copolymer architecture (<i>i.e</i>., density
and length of side chains and amount of tissue-reactive functions)
allowed a uniform passivation of the degraded cartilage surface. Graft-copolymer-treated
cartilage showed very low coefficients of friction within synovial
fluid, reestablishing and in some cases improving the lubricating
properties of the natural cartilage. Due to these distinctive properties
and their high biocompatibility and stability under physiological
conditions, cartilage-reactive graft-copolymers emerge as promising
injectable formulations to slow down the progression of cartilage
degradation, which characterizes the early stages of osteoarthritis
Hairy and Slippery Polyoxazoline-Based Copolymers on Model and Cartilage Surfaces
Comb-like polymers
presenting a hydroxybenzaldehyde (HBA)-functionalized
poly(glutamic acid) (PGA) backbone and poly(2-methyl-2-oxazoline)
(PMOXA) side chains chemisorb on aminolized substrates, including
cartilage surfaces, forming layers that reduce protein contamination
and provide lubrication. The structure, physicochemical, biopassive,
and tribological properties of PGA-PMOXA-HBA films are finely determined
by the copolymer architecture, its reactivity toward the surface,
i.e. PMOXA side-chain crowding and HBA density, and by the copolymer
solution concentration during assembly. Highly reactive species with
low PMOXA content form inhomogeneous layers due to the limited possibility
of surface rearrangements by strongly anchored copolymers, just partially
protecting the functionalized surface from protein contamination and
providing a relatively weak lubrication on cartilage. Biopassivity
and lubrication can be improved by increasing copolymer concentration
during assembly, leading to a progressive saturation of surface defects
across the films. In a different way, less reactive copolymers presenting
high PMOXA side-chain densities form uniform, biopassive, and lubricious
films, both on model aminolized silicon oxide surfaces, as well as
on cartilage substrates. When assembled at low concentrations these
copolymers adopt a “lying down” conformation, i.e. adhering
via their backbones onto the substrates, while at high concentrations
they undergo a conformational transition, assuming a more densely
packed, “standing up” structure, where they stretch
perpendicularly from the substrate. This specific arrangement reduces
protein contamination and improves lubrication both on model as well
as on cartilage surfaces
Poly(2-oxazoline)–Pterostilbene Block Copolymer Nanoparticles for Dual-Anticancer Drug Delivery
Functional block
copolymers based on poly(2-oxazoline)s are versatile
building blocks for the fabrication of dual-drug delivery nanoparticles
(NPs) for anticancer chemotherapy. Core–shell NPs are
fabricated from diblock copolymers featuring a long and hydrophilic
poly(2-methyl-2-oxazoline) (PMOXA) block coupled to a relatively short
and functionalizable poly(2-methylsuccinate-2-oxazoline) (PMestOXA)
segment. The PMOXA block stabilizes the NP dispersions, whereas the
PMestOXA segment is used to conjugate pterostilbene, a natural bioactive
phenolic compound that is used as lipophilic model-drug and constitutes
the hydrophobic core of the designed NPs. Subsequent loading of the
NPs with clofazimine (CFZ), an inhibitor of the multidrug resistance
pumps typically expressed in a large variety of cancer cells, provides
an additional function to their formulation. Optimization of the copolymer
composition allows the design of polymer scaffolds showing low toxicity
and capable of assembling into highly stable NPs dispersions at physiologically
relevant pH. In addition, the incorporation of CFZ increases the stability
of the NPs and stimulates their internalization by RAW 264.7 cells
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps
C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes
Poly(2-methyl-2-oxazoline) (PMOXA)
is an alternative promising polymer to poly(ethylene glycol) (PEG)
for design and engineering of macrophage-evading nanoparticles (NPs).
Although PMOXA-engineered NPs have shown comparable pharmacokinetics
and <i>in vivo</i> performance to PEGylated stealth NPs
in the murine model, its interaction with elements of the human innate
immune system has not been studied. From a translational angle, we
studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived
organically modified silica NPs (PMOXA-coated NPs) of approximately
100 nm in diameter with human complement system, blood leukocytes,
and macrophages and compared their performance with PEGylated and
uncoated NP counterparts. Through detailed immunological and proteomic
profiling, we show that PMOXA-coated NPs extensively trigger complement
activation in human sera exclusively through the classical pathway.
Complement activation is initiated by the sensing molecule C1q, where
C1q binds with high affinity (<i>K</i><sub>d</sub> = 11
± 1 nM) to NP surfaces independent of immunoglobulin binding.
C1q-mediated complement activation accelerates PMOXA opsonization
with the third complement protein (C3) through the amplification loop
of the alternative pathway. This promoted NP recognition by human
blood leukocytes and monocyte-derived macrophages. The macrophage
capture of PMOXA-coated NPs correlates with sera donor variability
in complement activation and opsonization but not with other major
corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps