8 research outputs found
Construction of a Reactive Diblock Copolymer, Polyphosphoester-<i>block</i>-Poly(l‑lactide), as a Versatile Framework for Functional Materials That Are Capable of Full Degradation and Nanoscopic Assembly Formation
The development of a diblock copolymer,
polyphosphoester-<i>block</i>-polyÂ(l-lactide),
which has potential for
being fully degradable and biocompatible, was achieved by one-pot
sequential ring-opening polymerizations (ROPs) of two cyclic monomers:
alkyne-functionalized phospholane and l-lactide (LLA). A
kinetic study of the polymerization in each step was investigated
in a detailed manner by nuclear magnetic resonance (NMR) spectroscopy
and gel permeation chromatography (GPC), revealing living/controlled
characteristics with narrow molecular weight distributions and a linear
increase of molecular weights vs monomer conversion and time. Subsequently,
photoinduced thiol-yne “click” reactions with small-molecule
thiols bearing either carboxylic acid or amino groups afforded amphiphilic
diblock copolymers with carboxylate or amino side-chain functionalities
along the polyphosphoester segment of the diblock copolymer backbone.
Finally, direct dissolution of the two different types of amphiphilic
diblock copolymers in aqueous solutions yielded well-defined spherical
micelles with corresponding negative or positive surface charges,
respectively, as confirmed by transmission electron microscopy (TEM),
dynamic light scattering (DLS), and zeta potential analyses
Detection of Living Anionic Species in Polymerization Reactions Using Hyperpolarized NMR
Intermediates during
the anionic polymerization of styrene were
observed using hyperpolarized NMR. Dissolution dynamic nuclear polarization
(DNP) of monomers provides a sufficient signal-to-noise ratio for
detection of <sup>13</sup>C NMR signals in real time as the reaction
progresses. Because of its large chemical shift dispersion, <sup>13</sup>C is well-suited to distinguish and characterize the chemical species
that arise during the reaction. At the same time, incorporation of
hyperpolarized small-molecule monomers is a unique way to generate
polymers that exhibit a transient signal enhancement at the active
site. This strategy is applicable despite the decay of the hyperpolarization
of the polymer due to rapid spin–lattice relaxation. Real-time
measurements on polymerization reactions provide both mechanistic
and kinetic information without the need for stable isotope labeling
of the molecules of interest. These capabilities are orthogonal to
currently established methods that separate synthesis and analysis
into two steps, making dissolution DNP an attractive method to study
polymerization reactions
Functionalizable Hydrophilic Polycarbonate, Poly(5-methyl-5-(2-hydroxypropyl)aminocarbonyl-1,3-dioxan-2-one), Designed as a Degradable Alternative for PHPMA and PEG
Drawbacks of polyÂ(ethylene glycol)
(PEG), the most widely used water-soluble polymer in nanomedicines,
have stimulated development of alternative hydrophilic polymers. Among
the substitutes, polyÂ(<i>N</i>-(2-hydroxypropyl)Âmethacrylamide)
(PHPMA) exhibits water solubility, minimal toxicity, and the possibility
to introduce functionalities through pendant hydroxyl groups; however,
nondegradability may cause long-term health and environmental issues.
Alternatively, polycarbonates based on bis-MPA derivatives, which
are well-known to be biocompatible, biodegradable, and of low toxicity <i>in vivo</i>, could be utilized as degradable equivalents to
polymethacrylates. Therefore, we developed a polycarbonate-based PHPMA
analogue, polyÂ(5-methyl-5-(2-hydroxypropyl)Âaminocarbonyl-1,3-dioxan-2-one)
(PMHPAC), by amidation of carboxylic acid-functional polycarbonates
with 1-amino-2-propanol. The resulting PMHPAC was highly water-soluble,
with low cyto-/immuno-toxicities, and readily functionalizable. These
characteristics make PMHPAC a promising candidate as a degradable
alternative to PEG and PHPMA. Furthermore, a fully degradable PMHPAC
block copolymer was synthesized to demonstrate synthetic versatility
and formation of nanostructures in aqueous solution for potential
biomedical applications
Poly(d‑glucose carbonate) Block Copolymers: A Platform for Natural Product-Based Nanomaterials with Solvothermatic Characteristics
A natural product-based polymer platform,
having the characteristics
of being derived from renewable materials and capable of breaking
down, ultimately, into natural byproducts, has been prepared through
the ring-opening polymerization (ROP) of a glucose-based bicyclic
carbonate monomer. ROP was carried out via chain extension of a polyphosphoester
(PPE) macroinitiator in the presence of 1,5,7-triazabicyclo[4.4.0]Âdec-5-ene
(TBD) organocatalyst to afford the PPE-<i>b</i>-polyÂ(d-glucose carbonate) (PDGC) block copolymer. This new copolymer
represents a functional architecture that can be rapidly transformed
through thiol-yne reactions along the PPE segment into a diverse variety
of amphiphilic polymers, which interestingly display stimuli-sensitive
phase behavior in the form of a lower critical solution temperature
(LCST). Below the LCST, they undergo self-assembly to form spherical
core–shell nanostructures that display a poorly defined core–shell
morphology. It is expected that hydrophobic patches are exposed within
the micellar corona, reminiscent of the surface complexity of proteins,
making these materials of interest for triggered and reversible assembly
disassembly processes
A Vinyl Ether-Functional Polycarbonate as a Template for Multiple Postpolymerization Modifications
A highly reactive
vinyl ether-functionalized aliphatic polycarbonate
and its block copolymer were developed as templates for multiple postpolymerization
conjugation chemistries. The vinyl ether-functional six-membered cyclic
carbonate monomer was synthesized by a well-established two-step procedure
starting from 2,2-bisÂ(hydroxymethyl)Âpropionic acid. An organobase-catalyzed
ring-opening polymerization of the synthesized monomer afforded polycarbonates
with pendant vinyl ether functionalities (PMVEC). The vinyl ether
moieties on the resulting polymers were readily conjugated with hydroxyl-
or thiol-containing compounds via three different postpolymerization
modification chemistries: acetalization, thio-acetalization, and
thiol–ene reaction. Acetal-functionalized polycarbonates were
studied in depth to exploit their acid-labile acetal functionalities.
Acetalization of the amphiphilic diblock copolymer of polyÂ(ethylene
glycol) methyl ether (mPEG) and PMVEC, mPEG<sub>113</sub>-<i>b</i>-PMVEC<sub>13</sub>, with the model hydroxyl compound 4-methylbenzyl
alcohol resulted in a maximum of 42% acetal and 58% hydroxyl side
chain groups. Nonetheless, the amphiphilicity of the block polymer
allowed for its self-assembly in water to afford nanostructures, as
characterized via dynamic light scattering and transmission electron
microscopy. The kinetics of acetal cleavage within the block polymer
micelles were examined in acidic buffered solutions (pH 4 and 5).
In addition, mPEG-<i>b</i>-PMVEC and its hydrolyzed polymer
mPEG-<i>b</i>-PMHEC (i.e., after full cleavage of acetals)
exhibited minimal cytotoxicity to RAW 264.7 mouse macrophages, indicating
that this polymer system represents a biologically nonhazardous material
with pH-responsive activity
Development of a Vinyl Ether-Functionalized Polyphosphoester as a Template for Multiple Postpolymerization Conjugation Chemistries and Study of Core Degradable Polymeric Nanoparticles
A novel
polyphosphoester (PPE) with vinyl ether side chain functionality
was developed as a versatile template for postpolymerization modifications,
and its degradability and biocompatibility were evaluated. An organocatalyzed
ring-opening polymerization of ethylene glycol vinyl ether-pendant
cyclic phosphotriester monomer allowed for construction of polyÂ(ethylene
glycol vinyl ether phosphotriester) (PEVEP). This vinyl ether-functionalized
PPE scaffold was coupled with hydroxyl- or thiol-containing model
small molecules via three different types of conjugation chemistriesthiol–ene
“click” reaction, acetalization, or thio-acetalization
reactionî—¸to afford modified polymers that accommodated either
stable thio–ether or hydrolytically labile acetal or thio–acetal
linkages. Amphiphilic diblock copolymers of polyÂ(ethylene glycol)
and PEVEP formed well-defined micelles with a narrow and monomodal
size distribution in water, as confirmed by dynamic light scattering
(DLS), transmission electron microscopy, and atomic force microscopy.
The stability of the micelles and the hydrolytic degradability of
the backbone and side chains of the PEVEP block segment were assessed
by DLS and nuclear magnetic resonance spectroscopy (<sup>1</sup>H
and <sup>31</sup>P), respectively, in aqueous buffer solutions at
pH values of 5.0 and 7.4 and at temperatures of 25 and 37 °C.
The hydrolytic degradation products of the PEVEP segments of the block
copolymers were then identified by electrospray ionization, gas chromatography,
and matrix-assisted laser desorption/ionization mass spectrometry.
The parent micelles and their degradation products were found to be
non-cytotoxic at concentrations up to 3 mg/mL, when evaluated with
RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma
cells
Holistic Assessment of Covalently Labeled Core–Shell Polymeric Nanoparticles with Fluorescent Contrast Agents for Theranostic Applications
The successful development of degradable
polymeric nanostructures
as optical probes for use in nanotheranostic applications requires
the intelligent design of materials such that their surface response,
degradation, drug delivery, and imaging properties are all optimized.
In the case of imaging, optimization must result in materials that
allow differentiation between unbound optical contrast agents and
labeled polymeric materials as they undergo degradation. In this study,
we have shown that use of traditional electrophoretic gel-plate assays
for the determination of the purity of dye-conjugated degradable nanoparticles
is limited by polymer degradation characteristics. To overcome these
limitations, we have outlined a holistic approach to evaluating dye
and peptide–polymer nanoparticle conjugation by utilizing steady-state
fluorescence, anisotropy, and emission and anisotropy lifetime decay
profiles, through which nanoparticle–dye binding can be assessed
independently of perturbations, such as those presented during the
execution of electrolyte gel-based assays. This approach has been
demonstrated to provide an overall understanding of the spectral signature–structure–function
relationship, ascertaining key information on interactions between
the fluorophore, polymer, and solvent components that have a direct
and measurable impact on the emissive properties of the optical probe.
The use of these powerful techniques provides feedback that can be
utilized to improve nanotheranostics by evaluating dye emissivity
in degradable nanotheranostic systems, which has become increasingly
important as modern platforms transition to architectures intentionally
reliant on degradation and built-in environmental responses
Preparation and <i>in Vitro</i> Antimicrobial Activity of Silver-Bearing Degradable Polymeric Nanoparticles of Polyphosphoester-<i>block</i>-Poly(l‑lactide)
The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach, and fundamental understanding of the developed NPs, <i>e.g.,</i> drug loading/release, particle stability, and other characteristics. Herein, we developed and evaluated the <i>in vitro</i> antimicrobial activity of silver-bearing, fully biodegradable and functional polymeric NPs. A series of degradable polymeric nanoparticles (dNPs), composed of phosphoester and l-lactide and designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core, were prepared as potential delivery carriers for three different types of silver-based antimicrobials–silver acetate or one of two silver carbene complexes (SCCs). Silver-loading capacities of the dNPs were not influenced by the hydrophilic block chain length, loading site (<i>i.e.</i>, core or shell), or type of silver compound, but optimization of the silver feed ratio was crucial to maximize the silver loading capacity of dNPs, up to <i>ca.</i> 12% (w/w). The release kinetics of silver-bearing dNPs revealed 50% release at <i>ca.</i> 2.5–5.5 h depending on the type of silver compound. In addition, we undertook a comprehensive evaluation of the rates of hydrolytic or enzymatic degradability and performed structural characterization of the degradation products. Interestingly, packaging of the SCCs in the dNP-based delivery system improved minimum inhibitory concentrations up to 70%, compared with the SCCs alone, as measured <i>in vitro</i> against 10 contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. We conclude that these dNP-based delivery systems may be beneficial for direct epithelial treatment and/or prevention of ubiquitous bacterial infections, including those of the skin and urinary tract