12 research outputs found
A Macromolecular Approach to Eradicate Multidrug Resistant Bacterial Infections while Mitigating Drug Resistance Onset
Polymyxins remain the last line treatment for multidrug-resistant (MDR) infections. As polymyxins resistance emerges, there is an urgent need to develop effective antimicrobial agents capable of mitigating MDR. Here, we report biodegradable guanidinium-functionalized polycarbonates with a distinctive mechanism that does not induce drug resistance. Unlike conventional antibiotics, repeated use of the polymers does not lead to drug resistance. Transcriptomic analysis of bacteria further supports development of resistance to antibiotics but not to the macromolecules after 30 treatments. Importantly, high in vivo treatment efficacy of the macromolecules is achieved in MDR A. baumannii-, E. coli-, K. pneumoniae-, methicillin-resistant S. aureus-, cecal ligation and puncture-induced polymicrobial peritonitis, and P. aeruginosa lung infection mouse models while remaining non-toxic (e.g., therapeutic index—ED50/LD50: 1473 for A. baumannii infection). These biodegradable synthetic macromolecules have been demonstrated to have broad spectrum in vivo antimicrobial activity, and have excellent potential as systemic antimicrobials against MDR infections
Formation of Disk- and Stacked-Disk-like Self-Assembled Morphologies from Cholesterol-Functionalized Amphiphilic Polycarbonate Diblock Copolymers
A cholesterol-functionalized aliphatic
cyclic carbonate monomer,
2-(5-methyl-2-oxo-1,3-dioxane-5-carboxyloyloxy)ethyl carbamate (MTC-Chol),
was synthesized. The organocatalytic ring-opening polymerization of
MTC-Chol was accomplished by using <i>N</i>-(3,5-trifluoromethyl)phenyl-<i>N</i>′-cyclohexylthiourea (TU) in combinations with bases
such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and (−)-sparteine,
and kinetics of polymerization was monitored. By using mPEG-OH as
the macroinitiator, well-defined amphiphilic diblock copolymers mPEG<sub>113</sub>-<i>b</i>-P(MTC-Chol)<sub><i>n</i></sub> (<i>n</i> = 4 and 11) were synthesized. Under aqueous
conditions, these block copolymers self-assembled to form unique nanostructures.
Disk-like micelles and stacked-disk morphology were observed for mPEG<sub>113</sub>-<i>b</i>-P(MTC-Chol)<sub>4</sub> and mPEG<sub>113</sub>-<i>b</i>-P(MTC-Chol)<sub>11</sub>, respectively,
by transmission electron microscopy (TEM). Small-angle neutron scattering
supports the disk-like morphology and estimates the block copolymer
micelle aggregation number in the dispersed solution. The hydrophobic
nature of the cholesterol-containing block provides a versatile self-assembly
handle to form complex nanostructures using biodegradable and biocompatible
polymers for applications in drug delivery
Biodegradable Block Copolyelectrolyte Hydrogels for Tunable Release of Therapeutics and Topical Antimicrobial Skin Treatment
Biodegradable polycarbonate-based
ABA triblock copolyelectrolytes
were synthesized and formulated into physically cross-linked hydrogels.
These biocompatible, cationically, and anionically charged hydrogel
materials exhibited pronounced shear-thinning behavior, making them
useful for a variety of biomedical applications. For example, we investigated
the antimicrobial activity of positively charged thiouronium functionalized
hydrogels by microbial growth inhibition assays against several clinically
relevant Gram-negative and Gram-positive bacteria. It is noteworthy
that these hydrogels exhibited broad spectrum killing efficiencies
approaching 100%, thereby rendering these thixotropic materials attractive
for treatment of skin and other surface bound infections. Finally,
cationic trimethylammonium containing hydrogels and anionic carboxylic
acid functionalized hydrogels were utilized to sustain the release
of negatively charged (diclofenac) and positively charged (vancomycin)
therapeutics, respectively. Collectively, the present work introduces
a simple method for formulating charged hydrogel materials that are
capable of interacting with various analytes of interest through noncovalent
interactions
Biodegradable Strain-Promoted Click Hydrogels for Encapsulation of Drug-Loaded Nanoparticles and Sustained Release of Therapeutics
Biodegradable
polycarbonate-based ABA triblock copolymers were
synthesized via organocatalyzed ring-opening polymerization and successfully
formulated into chemically cross-linked hydrogels by strain-promoted
alkyne–azide cycloaddition (SPAAC). The synthesis and cross-linking
of these polymers are copper-free, thereby eliminating the concern
over metallic contaminants for biomedical applications. Gelation occurs
rapidly within a span of 60 s by simple mixing of the azide- and cyclooctyne-functionalized
polymer solutions. The resultant hydrogels exhibited pronounced shear-thinning
behavior and could be easily dispensed through a 22G hypodermic needle.
To demonstrate the usefulness of these gels as a drug delivery matrix,
doxorubicin (DOX)-loaded micelles prepared using catechol-functionalized
polycarbonate copolymers were incorporated into the polymer solutions
to eventually form micelle/hydrogel composites. Notably, the drug
release rate from the hydrogels was significantly more gradual compared
to the solution formulation. DOX release from the micelle/hydrogel
composites could be sustained for 1 week, while the release from the
micelle solution was completed rapidly within 6 h of incubation. Cellular
uptake of the released DOX from the micelle/hydrogel composites was
observed at 3 h of incubation of human breast cancer MDA-MB-231 cells.
A blank hydrogel containing PEG-(Cat)<sub>12</sub> micelles showed
almost negligible toxicity on MDA-MB-231cells where cell viability
remained high at >80% after treatment. When the cells were treated
with the DOX-loaded micelle/hydrogel composites, there was a drastic
reduction in cell viability with only 25% of cells surviving the treatment.
In all, this study introduces a simple method of formulating hydrogel
materials with incorporated micelles for drug delivery applications
A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics
10.1002/advs.202001374ADVANCED SCIENCE71
Injectable Coacervate Hydrogel for Delivery of Anticancer Drug-Loaded Nanoparticles in vivo
In this study, bortezomib
(BTZ, a cytotoxic water-insoluble anticancer
drug) was encapsulated in micellar nanoparticles having a catechol-functionalized
polycarbonate core through a pH-sensitive covalent bond between phenylboronic
acid (PBA) in BTZ and catechol, and these drug-loaded micelles were
incorporated into hydrogels to form micelle/hydrogel composites. A
series of injectable, biodegradable hydrogels with readily tunable
mechanical properties were formed and optimized for sustained delivery
of the BTZ-loaded micelles through ionic coacervation between PBA-functionalized
polycarbonate/poly(ethylene glycol) (PEG) “ABA” triblock
copolymer and a cationic one having guanidinium- or thiouronium-functionalized
polycarbonate as “A” block. An in vitro release study
showed the pH dependence in BTZ release. At pH 7.4, the BTZ release
from the micelle/hydrogel composite remained low at 7%, whereas in
an acidic environment, ∼85% of BTZ was released gradually over
9 days. In vivo studies performed in a multiple myeloma MM.1S xenograft
mouse model showed that the tumor progression of mice treated with
BTZ-loaded micelle solution was similar to that of the control group,
whereas those treated with the BTZ-loaded micelle/hydrogel composite
resulted in significant delay in the tumor progression. The results
demonstrate that this hydrogel has great potential for use in subcutaneous
and sustained delivery of drug-loaded micelles with superior therapeutic
efficacy
Self-Assembled, Biodegradable Magnetic Resonance Imaging Agents: Organic Radical-Functionalized Diblock Copolymers
We report the design,
synthesis, and evaluation of biodegradable
amphiphilic poly(ethylene glycol)-<i>b</i>-polycarbonate-based
diblock copolymers containing pendant persistent organic radicals
(e.g., PROXYL). These paramagnetic radical-functionalized polymers
self-assemble into micellar nanoparticles in aqueous media, which
preferentially accumulate in tumor tissue via the enhanced permeability
and retention (EPR) effect. Through <i>T</i><sub>1</sub> relaxation NMR studies, as well as magnetic resonance imaging (MRI)
studies on mice, we show that these nanomaterials are effective as
metal-free, biodegradable MRI contrast agents. We also demonstrate
anticancer drugs can be readily loaded into the nanoparticles, conferring
therapeutic delivery properties in addition to their imaging properties
making these materials potential theranostic agents in the treatment
of cancer